ALBERT

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Jade D. Bailey, Marina Diotallevi, Thomas Nicol, Eileen McNeill, Andrew Shaw, Surawee Chuaiphichai, Ashley Hale, Anna Starr, Manasi Nandi, Elena Stylianou, Helen McShane, Simon Davis, Roman Fischer, Benedikt M. Kessler, James McCullagh, Keith M. Channon, Mark J. Crabtree〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH〈sub〉4〈/sub〉) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719307843-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Marie-Kristin Raulf, Timo Johannssen, Svea Matthiesen, Konstantin Neumann, Severin Hachenberg, Sabine Mayer-Lambertz, Fridolin Steinbeis, Jan Hegermann, Peter H. Seeberger, Wolfgang Baumgärtner, Christina Strube, Jürgen Ruland, Bernd Lepenies〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Malaria represents a major cause of death from infectious disease. Hemozoin is a 〈em〉Plasmodium〈/em〉-derived product that contributes to progression of cerebral malaria. However, there is a gap of knowledge regarding how hemozoin is recognized by innate immunity. Myeloid C-type lectin receptors (CLRs) encompass a family of carbohydrate-binding receptors that act as pattern recognition receptors in innate immunity. In the present study, we identify the CLR CLEC12A as a receptor for hemozoin. Dendritic cell-T cell co-culture assays indicate that the CLEC12A/hemozoin interaction enhances CD8〈sup〉+〈/sup〉 T cell cross-priming. Using the 〈em〉Plasmodium berghei〈/em〉 Antwerpen-Kasapa (ANKA) mouse model of experimental cerebral malaria (ECM), we find that CLEC12A deficiency protects mice from ECM, illustrated by reduced ECM incidence and ameliorated clinical symptoms. In conclusion, we identify CLEC12A as an innate sensor of plasmodial hemozoin.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719307818-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 July 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 1〈/p〉 〈p〉Author(s): Xuezhou Hou, Guobao Chen, William Bracamonte-Baran, Hee Sun Choi, Nicola L. Diny, Jungeun Sung, David Hughes, Taejoon Won, Megan Kay Wood, Monica V. Talor, David Joel Hackam, Karin Klingel, Giovanni Davogustto, Heinrich Taegtmeyer, Isabelle Coppens, Jobert G. Barin, Daniela Čiháková〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Two types of monocytes, Ly6C〈sup〉hi〈/sup〉 and Ly6C〈sup〉lo〈/sup〉, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6C〈sup〉hi〈/sup〉 and Ly6C〈sup〉lo〈/sup〉 cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6C〈sup〉hi〈/sup〉 monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6C〈sup〉lo〈/sup〉 monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6C〈sup〉hi〈/sup〉 MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6C〈sup〉lo〈/sup〉 monocytes resume their differentiation into MHCII〈sup〉+〈/sup〉 macrophages. We propose that MHCII〈sup〉+〈/sup〉Ly6C〈sup〉lo〈/sup〉 MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930765X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Diletta Di Mitri, Michela Mirenda, Jelena Vasilevska, Arianna Calcinotto, Nicolas Delaleu, Ajinkya Revandkar, Veronica Gil, Gunther Boysen, Marco Losa, Simone Mosole, Emiliano Pasquini, Rocco D’Antuono, Michela Masetti, Elena Zagato, Giovanna Chiorino, Paola Ostano, Andrea Rinaldi, Letizia Gnetti, Mariona Graupera, Ana Raquel Martins Figueiredo Fonseca〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment supporting tumorigenesis. TAMs re-education has been proposed as a strategy to promote tumor inhibition. However, whether this approach may work in prostate cancer is unknown. Here we find that 〈em〉Pten〈/em〉-null prostate tumors are strongly infiltrated by TAMs expressing C-X-C chemokine receptor type 2 (CXCR2), and activation of this receptor through CXCL2 polarizes macrophages toward an anti-inflammatory phenotype. Notably, pharmacological blockade of CXCR2 receptor by a selective antagonist promoted the re-education of TAMs toward a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in 〈em〉Pten〈/em〉〈sup〉pc−/−〈/sup〉; 〈em〉Trp53〈/em〉〈sup〉pc−/−〈/sup〉 mice differentiated in tumor necrosis factor alpha (TNF-α)-releasing pro-inflammatory macrophages, leading to senescence and tumor inhibition. Mechanistically, 〈em〉PTEN〈/em〉-deficient tumor cells are vulnerable to TNF-α-induced senescence, because of an increase of 〈em〉TNFR1〈/em〉. Our results identify TAMs as targets in prostate cancer and describe a therapeutic strategy based on CXCR2 blockade to harness anti-tumorigenic potential of macrophages against this disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309726-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): John D. Gagnon, Robin Kageyama, Hesham M. Shehata, Marlys S. Fassett, Darryl J. Mar, Eric J. Wigton, Kristina Johansson, Adam J. Litterman, Pamela Odorizzi, Dimitre Simeonov, Brian J. Laidlaw, Marisella Panduro, Sana Patel, Lukas T. Jeker, Margaret E. Feeney, Michael T. McManus, Alexander Marson, Mehrdad Matloubian, Shomyseh Sanjabi, K. Mark Ansel〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Coordinate control of T cell proliferation, survival, and differentiation are essential for host protection from pathogens and cancer. Long-lived memory cells, whose precursors are formed during the initial immunological insult, provide protection from future encounters, and their generation is the goal of many vaccination strategies. microRNAs (miRNAs) are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle, survival, and memory T cell differentiation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle, survival, and memory.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309684-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Joshua J. Gruber, Justin Chen, Benjamin Geller, Natalie Jäger, Andrew M. Lipchik, Guangwen Wang, Allison W. Kurian, James M. Ford, Michael P. Snyder〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Individuals with a single functional copy of the 〈em〉BRCA2〈/em〉 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to 〈em〉BRCA2〈/em〉 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here, we establish an 〈em〉in vitro〈/em〉 model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from 〈em〉BRCA2〈/em〉 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis 〈em〉in vitro〈/em〉, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309611-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Adam J. Vogrin, Neil I. Bower, Menachem J. Gunzburg, Sally Roufail, Kazuhide S. Okuda, Scott Paterson, Stephen J. Headey, Steven A. Stacker, Benjamin M. Hogan, Marc G. Achen〈/p〉 〈div〉 〈h6〉Summary〈/h6〉 〈p〉Lymphatic vascular development establishes embryonic and adult tissue fluid balance and is integral in disease. In diverse vertebrate organs, lymphatic vessels display organotypic function and develop in an organ-specific manner. In all settings, developmental lymphangiogenesis is considered driven by vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3), whereas a role for VEGFR2 remains to be fully explored. Here, we define the zebrafish Vegf/Vegfr code in receptor binding studies. We find that while Vegfd directs craniofacial lymphangiogenesis, it binds Kdr (a VEGFR2 homolog) but surprisingly, unlike in mammals, does not bind Flt4 (VEGFR3). Epistatic analyses and characterization of a 〈em〉kdr〈/em〉 mutant confirm receptor-binding analyses, demonstrating that Kdr is indispensible for rostral craniofacial lymphangiogenesis, but not caudal trunk lymphangiogenesis, in which Flt4 is central. We further demonstrate an unexpected yet essential role for Kdr in inducing lymphatic endothelial cell fate. This work reveals evolutionary divergence in the Vegf/Vegfr code that uncovers spatially restricted mechanisms of developmental lymphangiogenesis.〈/p〉 〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309593-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Susan Lindtner, Rinaldo Catta-Preta, Hua Tian, Linda Su-Feher, James D. Price, Diane E. Dickel, Vanille Greiner, Shanni N. Silberberg, Gabriel L. McKinsey, Michael T. McManus, Len A. Pennacchio, Axel Visel, Alex S. Nord, John L.R. Rubenstein〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉DLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of 〈em〉Dlx1&2〈/em〉 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with 〈em〉in situ〈/em〉 hybridization (ISH), and 〈em〉in vivo〈/em〉 and 〈em〉in vitro〈/em〉 studies of regulatory element (RE) function. This revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to 〈em〉Dlx1&2〈/em〉 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930912X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Patrícia M. Silva, Charles Puerner, Agnese Seminara, Martine Bassilana, Robert A. Arkowitz〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉During symmetry breaking, the highly conserved Rho GTPase Cdc42 becomes stabilized at a defined site via an amplification process. However, little is known about how a new polarity site is established in an already asymmetric cell—a critical process in a changing environment. The human fungal pathogen 〈em〉Candida albicans〈/em〉 switches from budding to filamentous growth in response to external cues, a transition controlled by Cdc42. Here, we have used optogenetic manipulation of cell polarity to reset growth in asymmetric filamentous 〈em〉C. albicans〈/em〉 cells. We show that increasing the level of active Cdc42 on the plasma membrane results in disruption of the exocyst subunit Sec3 localization and a striking 〈em〉de novo〈/em〉 clustering of secretory vesicles. This new cluster of secretory vesicles is highly dynamic, moving by hops and jumps, until a new growth site is established. Our results reveal that secretory vesicle clustering can occur in the absence of directional growth.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309660-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Xiao Yu, Bo Li, Geng-Jen Jang, Shan Jiang, Daohong Jiang, Jyan-Chyun Jang, Shu-Hsing Wu, Libo Shan, Ping He〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Proper transcriptome reprogramming is critical for hosts to launch an effective defense response upon pathogen attack. How immune-related genes are regulated at the posttranscriptional level remains elusive. We demonstrate here that P-bodies, the non-membranous cytoplasmic ribonucleoprotein foci related to 5′-to-3′ mRNA decay, are dynamically modulated in plant immunity triggered by microbe-associated molecular patterns (MAMPs). The DCP1-DCP2 mRNA decapping complex, a hallmark of P-bodies, positively regulates plant MAMP-triggered responses and immunity against pathogenic bacteria. MAMP-activated MAP kinases directly phosphorylate DCP1 at the serine〈sup〉237〈/sup〉 residue, which further stimulates its interaction with XRN4, an exonuclease executing 5′-to-3′ degradation of decapped mRNA. Consequently, MAMP treatment potentiates DCP1-dependent mRNA decay on a specific group of MAMP-downregulated genes. Thus, the conserved 5′-to-3′ mRNA decay elicited by the MAMP-activated MAP kinase cascade is an integral part of plant immunity. This mechanism ensures a rapid posttranscriptional downregulation of certain immune-related genes that may otherwise negatively impact immunity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309581-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Guanming Wang, Takahisa Kouwaki, Masaaki Okamoto, Hiroyuki Oshiumi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Excessive innate immune response is harmful to the host, and aberrant activation of the cytoplasmic viral RNA sensors RIG-I and MDA5 leads to autoimmune disorders. ZNF598 is an E3 ubiquitin ligase involved in the ribosome quality control pathway. It is also involved in the suppression of interferon (IFN)-stimulated gene (ISG) expression; however, its underlying mechanism is unclear. In this study, we show that ZNF598 is a negative regulator of the RIG-I-mediated signaling pathway, and endogenous ZNF598 protein binds to RIG-I. ZNF598 ubiquitin ligase activity is dispensable for the suppression of RIG-I signaling. Instead, ZNF598 delivers a ubiquitin-like protein FAT10 to the RIG-I protein, resulting in the inhibition of RIG-I polyubiquitination, which is required for triggering downstream signaling to produce type I IFN. Moreover, ZNF598-mediated suppression is abrogated by FAT10 knockout. Our data elucidate the mechanism by which ZNF598 inhibits RIG-I-mediated innate immune response.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309854-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Amber Tariq, JiaBei Lin, Meredith E. Jackrel, Christina D. Hesketh, Peter J. Carman, Korrie L. Mack, Rachel Weitzman, Craig Gambogi, Oscar A. Hernandez Murillo, Elizabeth A. Sweeny, Esin Gurpinar, Adam L. Yokom, Stephanie N. Gates, Keolamau Yee, Saurabh Sudesh, Jacob Stillman, Alexandra N. Rizo, Daniel R. Southworth, James Shorter〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders. Problematically, potentiated MD variants can exhibit off-target toxicity. Here, we mine disaggregase sequence space to safely enhance Hsp104 activity via single mutations in nucleotide-binding domain 1 (NBD1) or NBD2. Like MD variants, NBD variants counter TDP-43, FUS, and α-synuclein toxicity and exhibit elevated ATPase and disaggregase activity. Unlike MD variants, non-toxic NBD1 and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity. Potentiating substitutions alter NBD1 residues that contact ATP, ATP-binding residues, or the MD. Mutating the NBD2 protomer interface can also safely ameliorate Hsp104. Thus, we disambiguate allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309738-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Roberto Costa, Roberta Peruzzo, Magdalena Bachmann, Giulia Dalla Montà, Mattia Vicario, Giulia Santinon, Andrea Mattarei, Enrico Moro, Rubén Quintana-Cabrera, Luca Scorrano, Massimo Zeviani, Francesca Vallese, Mario Zoratti, Cristina Paradisi, Francesco Argenton, Marisa Brini, Tito Calì, Sirio Dupont, Ildikò Szabò, Luigi Leanza〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Wnt signaling affects fundamental development pathways and, if aberrantly activated, promotes the development of cancers. Wnt signaling is modulated by different factors, but whether the mitochondrial energetic state affects Wnt signaling is unknown. Here, we show that sublethal concentrations of different compounds that decrease mitochondrial ATP production specifically downregulate Wnt/β-catenin signaling 〈em〉in vitro〈/em〉 in colon cancer cells and 〈em〉in vivo〈/em〉 in zebrafish reporter lines. Accordingly, fibroblasts from a GRACILE syndrome patient and a generated zebrafish model lead to reduced Wnt signaling. We identify a mitochondria-Wnt signaling axis whereby a decrease in mitochondrial ATP reduces calcium uptake into the endoplasmic reticulum (ER), leading to endoplasmic reticulum stress and to impaired Wnt signaling. In turn, the recovery of the ATP level or the inhibition of endoplasmic reticulum stress restores Wnt activity. These findings reveal a mechanism that links mitochondrial energetic metabolism to the control of the Wnt pathway that may be beneficial against several pathologies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309544-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Roja Babazadeh, Doryaneh Ahmadpour, Song Jia, Xinxin Hao, Per Widlund, Kara Schneider, Frederik Eisele, Laura Dolz Edo, Gertien J. Smits, Beidong Liu, Thomas Nystrom〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Spatial sorting to discrete quality control sites in the cell is a process harnessing the toxicity of aberrant proteins. We show that the yeast t-snare phosphoprotein syntaxin5 (Sed5) acts as a key factor in mitigating proteotoxicity and the spatial deposition and clearance of IPOD (insoluble protein deposit) inclusions associates with the disaggregase Hsp104. Sed5 phosphorylation promotes dynamic movement of COPII-associated Hsp104 and boosts disaggregation by favoring anterograde ER-to-Golgi trafficking. Hsp104-associated aggregates co-localize with Sed5 as well as components of the ER, 〈em〉trans〈/em〉 Golgi network, and endocytic vesicles, transiently during proteostatic stress, explaining mechanistically how misfolded and aggregated proteins formed at the vicinity of the ER can hitchhike toward vacuolar IPOD sites. Many inclusions become associated with mitochondria in a HOPS/vCLAMP-dependent manner and co-localize with Vps39 (HOPS/vCLAMP) and Vps13, which are proteins providing contacts between vacuole and mitochondria. Both Vps39 and Vps13 are required also for efficient Sed5-dependent clearance of aggregates.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930957X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Tiffany Wu, Borislav Dejanovic, Vineela D. Gandham, Alvin Gogineni, Rose Edmonds, Stephen Schauer, Karpagam Srinivasan, Melanie A. Huntley, Yuanyuan Wang, Tzu-Ming Wang, Maj Hedehus, Kai H. Barck, Maya Stark, Hai Ngu, Oded Foreman, William J. Meilandt, Justin Elstrott, Michael C. Chang, David V. Hansen, Richard A.D. Carano〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer’s disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309647-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Adam L. Burrack, Ellen J. Spartz, Jackson F. Raynor, Iris Wang, Margaret Olson, Ingunn M. Stromnes〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer resistant to immunotherapy. We create a PDA mouse model and show that neoantigen expression is required for intratumoral T cell accumulation and response to immune checkpoint blockade. By generating a peptide:MHC tetramer, we identify that PDA induces rapid intratumoral, and progressive systemic, tumor-specific T cell exhaustion. Monotherapy PD-1 or PD-L1 blockade enhances systemic T cell expansion and induces objective responses that require systemic T cells. However, tumor escape variants defective in IFNγ-inducible 〈em〉Tap1〈/em〉 and MHC class I cell surface expression ultimately emerge. Combination PD-1 + PD-L1 blockade synergizes therapeutically by increasing intratumoral KLRG1+Lag3−TNFα+ tumor-specific T cells and generating memory T cells capable of expanding to spontaneous tumor recurrence, thereby prolonging animal survival. Our studies support that PD-1 and PD-L1 are relevant immune checkpoints in PDA and identify a combination for clinical testing in those patients with neoantigen-specific T cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309635-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Raquel Buj, Chi-Wei Chen, Erika S. Dahl, Kelly E. Leon, Rostislav Kuskovsky, Natella Maglakelidze, Maithili Navaratnarajah, Gao Zhang, Mary T. Doan, Helen Jiang, Michael Zaleski, Lydia Kutzler, Holly Lacko, Yiling Lu, Gordon B. Mills, Raghavendra Gowda, Gavin P. Robertson, Joshua I. Warrick, Meenhard Herlyn, Yuka Imamura〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurs by activation of mTORC1 signaling, which directly mediates increased translation of the mRNA encoding ribose-5-phosphate isomerase A (〈em〉RPIA〈/em〉), a pentose phosphate pathway enzyme. p16 loss correlates with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibits proliferation only in p16-low cells by inducing senescence both 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719310009-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Mirunalini Ravichandran, Run Lei, Qin Tang, Yilin Zhao, Joun Lee, Liyang Ma, Stephanie Chrysanthou, Benjamin M. Lorton, Ales Cvekl, David Shechter, Deyou Zheng, Meelad M. Dawlaty〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The Retinoid inducible nuclear factor (Rinf), also known as CXXC5, is a nuclear protein, but its functions in the context of the chromatin are poorly defined. We find that in mouse embryonic stem cells (mESCs), Rinf binds to the chromatin and is enriched at promoters and enhancers of 〈em〉Tet1〈/em〉, 〈em〉Tet2〈/em〉, and pluripotency genes. The Rinf-bound regions show significant overlapping occupancy of pluripotency factors Nanog, Oct4, and Sox2, as well as Tet1 and Tet2. We found that Rinf forms a complex with Nanog, Oct4, Tet1, and Tet2 and facilitates their proper recruitment to regulatory regions of pluripotency and 〈em〉Tet〈/em〉 genes in ESCs to positively regulate their transcription. Rinf deficiency in ESCs reduces expression of Rinf target genes, including several pluripotency factors and Tet enzymes, and causes aberrant differentiation. Together, our findings establish Rinf as a regulator of the pluripotency network genes and Tet enzymes in ESCs.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309842-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Richard J. Smith, Marilia H. Cordeiro, Norman E. Davey, Giulia Vallardi, Andrea Ciliberto, Fridolin Gross, Adrian T. Saurin〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309714-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Qiuli Liang, Quan Zheng, Yong Zuo, Yalan Chen, Jiao Ma, Peihua Ni, Jinke Cheng〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Brown adipose tissue (BAT) is a thermogenic organ that maintains body temperature and energy homeostasis. Transcriptional regulation plays an important role in the program of brown adipogenesis. However, it remains unclear how the transcriptional events are controlled in this program. In this study, we analyze an SENP2 BAT conditional knockout mouse model and find that SENP2-mediated de-SUMOylation is essential for BAT development. SENP2 catalyzes de-SUMOylation of cAMP response element-binding protein (CREB) to suppress Necdin expression, which induces brown adipocyte differentiation and brown adipogenesis. Mechanistically, we find that SUMOylation enhances CREB interaction with serine/threonine protein phosphatase 2A (PP2A) to de-phosphorylate CREB, which activates Necdin transcription. SENP2 deficiency enhances the expression of Necdin to inhibit brown adipocyte differentiation. Therefore, we reveal a crucial role of SENP2-mediated de-SUMOylation of CREB in suppression of Necdin expression during brown adipose development and brown adipogenesis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309878-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Nergis Kara, Matthew R. Kent, Dominic Didiano, Kamya Rajaram, Anna Zhao, Emily R. Summerbell, James G. Patton〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Unlike the adult mammalian retina, Müller glia (MG) in the adult zebrafish retina are able to dedifferentiate into a “stem cell”-like state and give rise to multipotent progenitor cells upon retinal damage. We show that 〈em〉miR-216a〈/em〉 is downregulated in MG after constant intense light lesioning and that 〈em〉miR-216a〈/em〉 suppression is necessary and sufficient for MG dedifferentiation and proliferation during retina regeneration. 〈em〉miR-216a〈/em〉 targets the H3K79 methyltransferase Dot1l, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1l is necessary for MG reprogramming and mediates MG proliferation downstream of 〈em〉miR-216a〈/em〉. We further demonstrate that 〈em〉miR-216a〈/em〉 and Dot1l regulate MG-mediated retina regeneration through canonical Wnt signaling. This article reports a regulatory mechanism upstream of Wnt signaling during retina regeneration and provides potential targets for enhancing regeneration in the adult mammalian retina.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309659-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Hanna Sabelström, Rebecca Petri, Ksenya Shchors, Rahul Jandial, Christin Schmidt, Rohit Sacheva, Selma Masic, Edith Yuan, Trenten Fenster, Michael Martinez, Supna Saxena, Theodore P. Nicolaides, Shirin Ilkhanizadeh, Mitchel S. Berger, Evan Y. Snyder, William A. Weiss, Johan Jakobsson, Anders I. Persson〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 〈em〉in vivo〈/em〉 and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309751-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Carles Solà-Riera, Shawon Gupta, Kimia T. Maleki, Patricia González-Rodriguez, Dalel Saidi, Christine L. Zimmer, Sindhu Vangeti, Laura Rivino, Yee-Sin Leo, David Chien Lye, Paul A. MacAry, Clas Ahlm, Anna Smed-Sörensen, Bertrand Joseph, Niklas K. Björkström, Hans-Gustaf Ljunggren, Jonas Klingström〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order 〈em〉Bunyavirales〈/em〉, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309702-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Shaun Egolf, Yann Aubert, Miriam Doepner, Amy Anderson, Alexandra Maldonado-Lopez, Gina Pacella, Jessica Lee, Eun Kyung Ko, Jonathan Zou, Yemin Lan, Cory L. Simpson, Todd Ridky, Brian C. Capell〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis. As a result, drugs targeting the epigenome hold significant therapeutic potential. The histone demethylase, LSD1 (KDM1A), is overexpressed in numerous cancers, including epithelial cancers; however, its role in the skin is virtually unknown. Here we show that LSD1 directly represses master epithelial transcription factors that promote differentiation. LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors. This leads to both premature epidermal differentiation and the repression of squamous cell carcinoma. Together these data highlight both LSD1’s role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309623-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Khadar Abdi, Gabriel Neves, Joon Pyun, Emre Kiziltug, Angelica Ahrens, Chay T. Kuo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Specialized microenvironments, called niches, control adult stem cell proliferation and differentiation. The brain lateral ventricular (LV) neurogenic niche is generated from distinct postnatal radial glial progenitors (pRGPs), giving rise to adult neural stem cells (NSCs) and niche ependymal cells (ECs). Cellular-intrinsic programs govern stem versus supporting cell maturation during adult niche assembly, but how they are differentially initiated within a similar microenvironment remains unknown. Using chemical approaches, we discovered that EGFR signaling powerfully inhibits EC differentiation by suppressing multiciliogenesis. We found that EC pRGPs actively terminated EGF activation through receptor redistribution away from CSF-contacting apical domains and that randomized EGFR membrane targeting blocked EC differentiation. Mechanistically, we uncovered spatiotemporal interactions between EGFR and endocytic adaptor protein Numb. Ca〈sup〉2+〈/sup〉-dependent basolateral targeting of Numb is necessary and sufficient for proper EGFR redistribution. These results reveal a previously unknown cellular mechanism for neighboring progenitors to differentially engage environmental signals, initiating adult stem cell niche assembly.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930960X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 8〈/p〉 〈p〉Author(s): Thomas Z. Young, Ping Liu, Guste Urbonaite, Murat Acar〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Although double-strand break (DSB) repair is essential for a cell’s survival, little is known about how DSB repair mechanisms are affected by age. Here we characterize the impact of cellular aging on the efficiency of single-strand annealing (SSA), a DSB repair mechanism. We measure SSA repair efficiency in young and old yeast cells and report a 23.4% decline in repair efficiency. This decline is not due to increased use of non-homologous end joining. Instead, we identify increased G1 phase duration in old cells as a factor responsible for the decreased SSA repair efficiency. Expression of 3x〈em〉CLN2〈/em〉 leads to higher SSA repair efficiency in old cells compared with expression of 1x〈em〉CLN2〈/em〉, confirming the involvement of cell-cycle regulation in age-associated repair inefficiency. Examining how SSA repair efficiency is affected by sequence heterology, we find that heteroduplex rejection remains high in old cells. Our work provides insights into the links between single-cell aging and DSB repair efficiency.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309866-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Sarbajeet Nagdas, Jennifer A. Kashatus, Aldo Nascimento, Syed S. Hussain, Riley E. Trainor, Sarah R. Pollock, Sara J. Adair, Alex D. Michaels, Hiromi Sesaki, Edward B. Stelow, Todd W. Bauer, David F. Kashatus〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mitochondria undergo fission and fusion to maintain homeostasis, and tumors exhibit the dysregulation of mitochondrial dynamics. We recently demonstrated that ectopic HRas〈sup〉G12V〈/sup〉 promotes mitochondrial fragmentation and tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1). However, the role of Drp1 in the setting of endogenous oncogenic KRas remains unknown. Here, we show that Drp1 is required for KRas-driven anchorage-independent growth in fibroblasts and patient-derived pancreatic cancer cell lines, and it promotes glycolytic flux, in part through the regulation of hexokinase 2 (HK2). Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion. Rare tumors that arise in the absence of Drp1 have restored glycolysis but exhibit defective mitochondrial metabolism. This work demonstrates that Drp1 plays dual roles in KRas-driven tumor growth: supporting both glycolysis and mitochondrial function through independent mechanisms.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309283-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Shamsideen A. Ojelade, Tom V. Lee, Nikolaos Giagtzoglou, Lei Yu, Berrak Ugur, Yarong Li, Lita Duraine, Zhongyuan Zuo, Vlad Petyuk, Philip L. De Jager, David A. Bennett, Benjamin R. Arenkiel, Hugo J. Bellen, Joshua M. Shulman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The Alzheimer’s disease (AD) susceptibility gene, CD2-associated protein (〈em〉CD2AP〈/em〉), encodes an actin binding adaptor protein, but its function in the nervous system is largely unknown. Loss of the 〈em〉Drosophila〈/em〉 ortholog 〈em〉cindr〈/em〉 enhances neurotoxicity of human Tau, which forms neurofibrillary tangle pathology in AD. We show that Cindr is expressed in neurons and present at synaptic terminals. 〈em〉cindr〈/em〉 mutants show impairments in synapse maturation and both synaptic vesicle recycling and release. Cindr associates and genetically interacts with 14-3-3ζ, regulates the ubiquitin-proteasome system, and affects turnover of Synapsin and the plasma membrane calcium ATPase (PMCA). Loss of 〈em〉cindr〈/em〉 elevates PMCA levels and reduces cytosolic calcium. Studies of 〈em〉Cd2ap〈/em〉 null mice support a conserved role in synaptic proteostasis, and CD2AP protein levels are inversely related to Synapsin abundance in human postmortem brains. Our results reveal CD2AP neuronal requirements with relevance to AD susceptibility, including for proteostasis, calcium handling, and synaptic structure and function.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309386-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Cornelia N. Stacher Hörndli, Eleanor Wong, Elliott Ferris, Kathleen Bennett, Susan Steinwand, Alexis Nikole Rhodes, P. Thomas Fletcher, Christopher Gregg〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Complex ethological behaviors could be constructed from finite modules that are reproducible functional units of behavior. Here, we test this idea for foraging and develop methods to dissect rich behavior patterns in mice. We uncover discrete modules of foraging behavior reproducible across different strains and ages, as well as nonmodular behavioral sequences. Modules differ in terms of form, expression frequency, and expression timing and are expressed in a probabilistically determined order. Modules shape economic patterns of feeding, exposure, activity, and perseveration responses. The modular architecture of foraging changes developmentally, and different developmental, genetic, and parental effects are found to shape the expression of specific modules. Dissecting modules from complex patterns is powerful for phenotype analysis. We discover that both parental alleles of the imprinted Prader-Willi syndrome gene 〈em〉Magel2〈/em〉 are functional in mice but regulate different modules. Our study found that complex economic patterns are built from finite, genetically controlled modules.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309350-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Matthew A. Huggins, Frances V. Sjaastad, Mark Pierson, Tamara A. Kucaba, Whitney Swanson, Christopher Staley, Alexa R. Weingarden, Isaac J. Jensen, Derek B. Danahy, Vladimir P. Badovinac, Stephen C. Jameson, Vaiva Vezys, David Masopust, Alexander Khoruts, Thomas S. Griffith, Sara E. Hamilton〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Microbial exposures can define an individual’s basal immune state. Cohousing specific pathogen-free (SPF) mice with pet store mice, which harbor numerous infectious microbes, results in global changes to the immune system, including increased circulating phagocytes and elevated inflammatory cytokines. How these differences in the basal immune state influence the acute response to systemic infection is unclear. Cohoused mice exhibit enhanced protection from virulent 〈em〉Listeria monocytogenes〈/em〉 (LM) infection, but increased morbidity and mortality to polymicrobial sepsis. Cohoused mice have more TLR2〈sup〉+〈/sup〉 and TLR4〈sup〉+〈/sup〉 phagocytes, enhancing recognition of microbes through pattern-recognition receptors. However, the response to a TLR2 ligand is muted in cohoused mice, whereas the response to a TLR4 ligand is greatly amplified, suggesting a basis for the distinct response to 〈em〉Listeria monocytogenes〈/em〉 and sepsis. Our data illustrate how microbial exposure can enhance the immune response to unrelated challenges but also increase the risk of immunopathology from a severe cytokine storm.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309258-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Yasir S. Elhassan, Katarina Kluckova, Rachel S. Fletcher, Mark S. Schmidt, Antje Garten, Craig L. Doig, David M. Cartwright, Lucy Oakey, Claire V. Burley, Ned Jenkinson, Martin Wilson, Samuel J.E. Lucas, Ildem Akerman, Alex Seabright, Yu-Chiang Lai, Daniel A. Tennant, Peter Nightingale, Gareth A. Wallis, Konstantinos N. Manolopoulos, Charles Brenner〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Nicotinamide adenine dinucleotide (NAD〈sup〉+〈/sup〉) is modulated by conditions of metabolic stress and has been reported to decline with aging in preclinical models, but human data are sparse. Nicotinamide riboside (NR) supplementation ameliorates metabolic dysfunction in rodents. We aimed to establish whether oral NR supplementation in aged participants can increase the skeletal muscle NAD〈sup〉+〈/sup〉 metabolome and if it can alter muscle mitochondrial bioenergetics. We supplemented 12 aged men with 1 g NR per day for 21 days in a placebo-controlled, randomized, double-blind, crossover trial. Targeted metabolomics showed that NR elevated the muscle NAD〈sup〉+〈/sup〉 metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways, without altering mitochondrial bioenergetics. NR also depressed levels of circulating inflammatory cytokines. Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309404-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Alexander J. Baker-Williams, Fiza Hashmi, Marek A. Budzyński, Mark R. Woodford, Stephanie Gleicher, Samu V. Himanen, Alan M. Makedon, Derek Friedman, Stephanie Cortes, Sara Namek, William G. Stetler-Stevenson, Gennady Bratslavsky, Alaji Bah, Mehdi Mollapour, Lea Sistonen, Dimitra Bourboulia〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue inhibitor of metalloproteinases-2 (TIMP2) is a stress-inducible extracellular co-chaperone that binds to eHSP90, increases eHSP90 binding to ATP, and inhibits its ATPase activity. In addition to disrupting the eHSP90:MMP2 complex and terminally inactivating MMP2, TIMP2 loads the client to eHSP90, keeping the protease in a transient inhibitory state. Secreted activating co-chaperone AHA1 displaces TIMP2 from the complex, providing a “reactivating” mechanism for MMP2. Gene knockout or blocking antibodies targeting TIMP2 and AHA1 released by HT1080 cancer cells modify their gelatinolytic activity. Our data suggest that TIMP2 and AHA1 co-chaperones function as a molecular switch that determines the inhibition and reactivation of the eHSP90 client protein MMP2.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309490-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Jakob Neuser, Caroline C. Metzen, Bernd H. Dreyer, Claudio Feulner, Joost T. van Dongen, Romy R. Schmidt, Jos H.M. Schippers〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Plants continuously need to adapt to their environment and prioritize either growth or defense responses to secure survival and reproduction. Trade-offs between growth and defense are often attributed to the allocation of energy for growth to adaptation responses. Still, the exact mechanisms underlying growth and defense trade-offs are poorly understood. Here, we demonstrate that the growth-related transcription factor HOMOLOG OF BEE2 INTERACTING WITH IBH 1 (HBI1) regulates apoplastic reactive oxygen species (ROS) homeostasis by differentially controlling the expression of NADPH oxidases (NOXs) and peroxidases (POXs). The HBI1 target genes 〈em〉RESPIRATORY BURST OXIDASE HOMOLOG A〈/em〉 (〈em〉RbohA〈/em〉) and 〈em〉RbohC〈/em〉 have contrasting effects on the regulation of cell size. In addition, the HBI1-controlled 〈em〉NOX〈/em〉s and 〈em〉POX〈/em〉s oppositely regulate susceptibility toward 〈em〉Pseudomonas syringae〈/em〉. Our findings reveal that the incompatibility between growth and defense programs can be attributed to the way apoplastic ROS homeostasis is modulated during both processes.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930926X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Melanie Korbelius, Nemanja Vujic, Vinay Sachdev, Sascha Obrowsky, Silvia Rainer, Benjamin Gottschalk, Wolfgang F. Graier, Dagmar Kratky〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉As circulating lipid levels are balanced by the rate of lipoprotein release and clearance from the plasma, lipid absorption in the small intestine critically contributes to the maintenance of whole-body lipid homeostasis. Within enterocytes, excessive triglycerides are transiently stored as cytosolic lipid droplets (cLDs), and their mobilization sustains lipid supply during interprandial periods. Using mice lacking adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) exclusively in the intestine (intestine-specific double KO [iDKO]), we show that ATGL/CGI-58 are not involved in providing substrates for chylomicron synthesis. Massive intestinal cLD accumulation in iDKO mice independent of dietary lipids together with inefficient lipid incorporation into cLDs in the early absorption phase demonstrate the existence of a secretion/re-uptake cycle, corroborating the availability of two diverse cLD pools. This study identified ATGL/CGI-58 as critical players in the catabolism of basolaterally (blood) derived lipids and highlights the necessity to modify the current model of intestinal lipid metabolism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309271-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Penelope Kroustallaki, Lisa Lirussi, Sergio Carracedo, Panpan You, Q. Ying Esbensen, Alexandra Götz, Laure Jobert, Lene Alsøe, Pål Sætrom, Sarantis Gagos, Hilde Nilsen〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Telomerase biogenesis is a complex process where several steps remain poorly understood. Single-strand-selective uracil-DNA glycosylase (SMUG1) associates with the DKC1-containing H/ACA ribonucleoprotein complex, which is essential for telomerase biogenesis. Herein, we show that SMUG1 interacts with the telomeric RNA component (〈em〉hTERC〈/em〉) and is required for co-transcriptional processing of the nascent transcript into mature 〈em〉hTERC〈/em〉. We demonstrate that SMUG1 regulates the presence of base modifications in 〈em〉hTERC〈/em〉, in a region between the CR4/CR5 domain and the H box. Increased levels of 〈em〉hTERC〈/em〉 base modifications are accompanied by reduced DKC1 binding. Loss of SMUG1 leads to an imbalance between mature 〈em〉hTERC〈/em〉 and its processing intermediates, leading to the accumulation of 3′-polyadenylated and 3′-extended intermediates that are degraded in an EXOSC10-independent RNA degradation pathway. Consequently, SMUG1-deprived cells exhibit telomerase deficiency, leading to impaired bone marrow proliferation in 〈em〉Smug1〈/em〉-knockout mice.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309374-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Yuanming Cheng, Hanzhi Luo, Franco Izzo, Brian F. Pickering, Diu Nguyen, Robert Myers, Alexandra Schurer, Saroj Gourkanti, Jens C. Brüning, Ly P. Vu, Samie R. Jaffrey, Dan A. Landau, Michael G. Kharas〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Stem cells balance cellular fates through asymmetric and symmetric divisions in order to self-renew or to generate downstream progenitors. Symmetric commitment divisions in stem cells are required for rapid regeneration during tissue damage and stress. The control of symmetric commitment remains poorly defined. Using single-cell RNA sequencing (scRNA-seq) in combination with transcriptomic profiling of HSPCs (hematopoietic stem and progenitor cells) from control and m〈sup〉6〈/sup〉A methyltransferase 〈em〉Mettl3〈/em〉 conditional knockout mice, we found that m〈sup〉6〈/sup〉A-deficient hematopoietic stem cells (HSCs) fail to symmetrically differentiate. Dividing HSCs are expanded and are blocked in an intermediate state that molecularly and functionally resembles multipotent progenitors. Mechanistically, RNA methylation controls 〈em〉Myc〈/em〉 mRNA abundance in differentiating HSCs. We identified MYC as a marker for HSC asymmetric and symmetric commitment. Overall, our results indicate that RNA methylation controls symmetric commitment and cell identity of HSCs and may provide a general mechanism for how stem cells regulate differentiation fate choice.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309295-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Ishmail Abdus-Saboor, Nathan T. Fried, Mark Lay, Justin Burdge, Kathryn Swanson, Roman Fischer, Jessica Jones, Peter Dong, Weihua Cai, Xinying Guo, Yuan-Xiang Tao, John Bethea, Minghong Ma, Xinzhong Dong, Long Ding, Wenqin Luo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Rodents are the main model systems for pain research, but determining their pain state is challenging. To develop an objective method to assess pain sensation in mice, we adopt high-speed videography to capture sub-second behavioral features following hind paw stimulation with both noxious and innocuous stimuli and identify several differentiating parameters indicating the affective and reflexive aspects of nociception. Using statistical modeling and machine learning, we integrate these parameters into a single index and create a “mouse pain scale,” which allows us to assess pain sensation in a graded manner for each withdrawal. We demonstrate the utility of this method by determining sensations triggered by three different von Frey hairs and optogenetic activation of two different nociceptor populations. Our behavior-based “pain scale” approach will help improve the rigor and reproducibility of using withdrawal reflex assays to assess pain sensation in mice.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309076-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Miyuki Suzawa, Nigel M. Muhammad, Bradley S. Joseph, Michelle L. Bland〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Chronic enteropathogen infection in early childhood reduces circulating insulin-like growth factor 1 (IGF1) levels and restricts growth. Pathogen-derived molecules activate host Toll-like receptors to initiate the immune response, but whether this pathway contributes to growth inhibition is unclear. In 〈em〉Drosophila〈/em〉, activation of Toll receptors in larval fat body suppresses whole-animal growth. Here, using a transcriptomic approach, we identify 〈em〉Drosophila insulin-like peptide 6〈/em〉 (〈em〉Dilp6〈/em〉), a fat-body-derived IGF1 ortholog, as a selective target of Toll signaling induced by infection or genetic activation of the pathway. Using a tagged allele that we generated to measure endogenous Dilp6, we find a marked reduction in circulating hormone levels. Restoring Dilp6 expression in fat body rescues growth in animals with active Toll signaling. Our results establish that Toll signaling reduces growth by inducing hormone insufficiency, implying a mechanistic link between innate immune signaling and endocrine regulation of growth.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309052-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Chi-Jung Liang, Zih-Wun Wang, Yi-Wen Chang, Ko-Chuan Lee, Wei-Hsin Lin, Jia-Lin Lee〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Secreted frizzled-related proteins (SFRPs) are mainly known for their role as extracellular modulators and tumor suppressors that downregulate Wnt signaling. Using the established (CRISPR/Cas9 targeting promoters of SFRPs and targeting SFRPs transcript) system, we find that nuclear SFRPs interact with β-catenin and either promote or suppress TCF4 recruitment. SFRPs bind with β-catenin on both their N and C termini, which the repressive effects caused by SFRP-β-catenin-N-terminus binding overpower the promoting effects of their binding at the C terminus. By high Wnt activity, β-catenin and SFRPs only bind with their C termini, which results in the upregulation of β-catenin transcriptional activity and cancer stem cell (CSC)-related genes. Furthermore, we identify disulfide bonds of the cysteine-rich domain (CRD) and two threonine phosphorylation events of the netrin-related motif (NTR) domain of SFRPs that are essential for their role as biphasic modulators, suggesting that SFRPs are biphasic modulators of Wnt signaling-elicited CSC properties beyond extracellular control.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309131-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Aditya Mojumdar, Kyle Sorenson, Marcel Hohl, Mathias Toulouze, Susan P. Lees-Miller, Karine Dubrana, John H.J. Petrini, Jennifer A. Cobb〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Non-homologous end joining (NHEJ) and homologous recombination (HR) are the two major pathways of DNA double-strand break (DSB) repair and both are highly conserved from yeast to mammals. Nej1 has a role in DNA end-tethering at a DSB, and the Mre11/Rad50/Xrs2 (MRX) complex is important for its recruitment to the break. Nej1 and Dna2-Sgs1 interact with the C-terminal end of Mre11, which also includes the region where Rad50 binds. By characterizing the functionality of Nej1 in two 〈em〉rad50〈/em〉 mutants, which alter the structural features of MRX, we demonstrate that Nej1 inhibits the binding of Dna2 to Mre11 and Sgs1. Nej1 interactions with Mre11 promote tethering and inhibit hyper-resection, and when these events are compromised, large deletions develop at a DSB. The work indicates that Nej1 provides a layer of regulation to repair pathway choice and is consistent with its role in NHEJ.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309088-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Grit Bornschein, Jens Eilers, Hartmut Schmidt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Coupling distances between Ca〈sup〉2+〈/sup〉 channels and release sensors regulate vesicular release probability (〈em〉p〈/em〉〈sub〉v〈/sub〉). Tight coupling is thought to provide a framework for high 〈em〉p〈/em〉〈sub〉v〈/sub〉 and loose coupling for high plasticity at low 〈em〉p〈/em〉〈sub〉v〈/sub〉. At synapses investigated during development, coupling distances decrease, thereby increasing 〈em〉p〈/em〉〈sub〉v〈/sub〉 and transmission fidelity. We find that neocortical high-fidelity synapses deviate from these rules. Paired recordings from pyramidal neurons with “slow” and “fast” Ca〈sup〉2+〈/sup〉 chelators combined with experimentally constrained simulations suggest that coupling tightens significantly during development. However, fluctuation analysis revealed that neither 〈em〉p〈/em〉〈sub〉v〈/sub〉 (∼0.63) nor the number of release sites (∼8) changes concomitantly. Moreover, the amplitude and time course of presynaptic Ca〈sup〉2+〈/sup〉 transients are not different between age groups. These results are explained by high-〈em〉p〈/em〉〈sub〉v〈/sub〉 release sites with Ca〈sup〉2+〈/sup〉 microdomains in young synapses and nanodomains in mature synapses. Thus, at neocortical synapses, a developmental reorganization of the active zone leaves 〈em〉p〈/em〉〈sub〉v〈/sub〉 unaffected, emphasizing developmental and functional synaptic diversity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719308988-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Erin E. Talbert, Maria C. Cuitiño, Katherine J. Ladner, Priyani V. Rajasekerea, Melissa Siebert, Reena Shakya, Gustavo W. Leone, Michael C. Ostrowski, Brian Paleo, Noah Weisleder, Peter J. Reiser, Amy Webb, Cynthia D. Timmers, Daniel S. Eiferman, David C. Evans, Mary E. Dillhoff, Carl R. Schmidt, Denis C. Guttridge〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia is associated with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models, which fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology as cachectic patients. We envision that the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309064-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Runrui Zhang, Marcelo Boareto, Anna Engler, Angeliki Louvi, Claudio Giachino, Dagmar Iber, Verdon Taylor〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Neural stem cells (NSCs) in the adult mouse hippocampal dentate gyrus (DG) are mostly quiescent, and only a few are in cell cycle at any point in time. DG NSCs become increasingly dormant with age and enter mitosis less frequently, which impinges on neurogenesis. How NSC inactivity is maintained is largely unknown. Here, we found that 〈em〉Id4〈/em〉 is a downstream target of Notch2 signaling and maintains DG NSC quiescence by blocking cell-cycle entry. Id4 expression is sufficient to promote DG NSC quiescence and Id4 knockdown rescues Notch2-induced inhibition of NSC proliferation. 〈em〉Id4〈/em〉 deletion activates NSC proliferation in the DG without evoking neuron generation, and overexpression increases NSC maintenance while promoting astrogliogenesis at the expense of neurogenesis. Together, our findings indicate that Id4 is a major effector of Notch2 signaling in NSCs and a Notch2-Id4 axis promotes NSC quiescence in the adult DG, uncoupling NSC activation from neuronal differentiation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309040-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Katie M. Campbell, Kathleen A. O’Leary, Debra E. Rugowski, William A. Mulligan, Erica K. Barnell, Zachary L. Skidmore, Kilannin Krysiak, Malachi Griffith, Linda A. Schuler, Obi L. Griffith〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand 〈em〉rPrl〈/em〉 expression, establishes spontaneous ER+ mammary tumors in nulliparous females, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole-genome and exome sequencing in a discovery cohort (n = 5) of end-stage tumors revealed canonical activating mutations and copy number amplifications of 〈em〉Kras〈/em〉. The frequent mutations in this pathway were validated in an extension cohort, identifying activating 〈em〉Ras〈/em〉 alterations in 79% of tumors (23 of 29). Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors compared with preneoplastic tissues; in cell-intrinsic processes associated with mitosis, cell adhesion, and invasion; as well as in the surrounding tumor environment. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors that may model a subset of aggressive clinical ER+ breast cancers.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719308848-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Hui-Ying Lim, Hong Bao, Ying Liu, Weidong Wang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Septate junction (SJ) complex proteins act in unison to provide a paracellular barrier and maintain structural integrity. Here, we identify a non-barrier role of two individual SJ proteins, Coracle (Cora) and Kune-kune (Kune). Reactive oxygen species (ROS)-p38 MAPK signaling in non-myocytic pericardial cells (PCs) is important for maintaining normal cardiac physiology in 〈em〉Drosophila〈/em〉. However, the underlying mechanisms remain unknown. We find that in PCs, Cora and Kune are altered in abundance in response to manipulations of ROS-p38 signaling. Genetic analyses establish Cora and Kune as key effectors of ROS-p38 signaling in PCs on proper heart function. We further determine that Cora regulates normal Kune levels in PCs, which in turn modulates normal Kune levels in the cardiomyocytes essential for proper heart function. Our results thereby reveal select SJ proteins Cora and Kune as signaling mediators of the PC-derived ROS regulation of cardiac physiology.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719308885-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Irene Salas-Armenteros, Sonia I. Barroso, Ana G. Rondón, Mónica Pérez, Eloisa Andújar, Rosa Luna, Andrés Aguilera〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉THO/TREX is a conserved complex with a role in messenger ribonucleoprotein biogenesis that links gene expression and genome instability. Here, we show that human THO interacts with MFAP1 (microfibrillar-associated protein 1), a spliceosome-associated factor. Interestingly, MFAP1 depletion impairs cell proliferation and genome integrity, increasing γH2AX foci and DNA breaks. This phenotype is not dependent on either transcription or RNA-DNA hybrids. Mutations in the yeast orthologous gene 〈em〉SPP381〈/em〉 cause similar transcription-independent genome instability, supporting a conserved role. MFAP1 depletion has a wide effect on splicing and gene expression in human cells, determined by transcriptome analyses. MFAP1 depletion affects a number of DNA damage response (DDR) genes, which supports an indirect role of MFAP1 on genome integrity. Our work defines a functional interaction between THO and RNA processing and argues that splicing factors may contribute to genome integrity indirectly by regulating the expression of DDR genes rather than by a direct role.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309003-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Preston D. Crowell, Jonathan J. Fox, Takao Hashimoto, Johnny A. Diaz, Héctor I. Navarro, Gervaise H. Henry, Blake A. Feldmar, Matthew G. Lowe, Alejandro J. Garcia, Ye E. Wu, Dipti P. Sajed, Douglas W. Strand, Andrew S. Goldstein〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Aging is associated with loss of tissue mass and a decline in adult stem cell function in many tissues. In contrast, aging in the prostate is associated with growth-related diseases including benign prostatic hyperplasia (BPH). Surprisingly, the effects of aging on prostate epithelial cells have not been established. Here we find that organoid-forming progenitor activity of mouse prostate basal and luminal cells is maintained with age. This is caused by an age-related expansion of progenitor-like luminal cells that share features with human prostate luminal progenitor cells. The increase in luminal progenitor cells may contribute to greater risk for growth-related disease in the aging prostate. Importantly, we demonstrate expansion of human luminal progenitor cells in BPH. In summary, we define a Trop2〈sup〉+〈/sup〉 luminal progenitor subset and identify an age-related shift in the luminal compartment of the mouse and human prostate epithelium.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719308976-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 27 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 9〈/p〉 〈p〉Author(s): Pei-Tzu Huang, Brady James Summers, Chaoyi Xu, Juan R. Perilla, Viacheslav Malikov, Mojgan H. Naghavi, Yong Xiong〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309830-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Amania A. Sheikh, Lucy Cooper, Meiqi Feng, Fernando Souza-Fonseca-Guimaraes, Fanny Lafouresse, Brigette C. Duckworth, Nicholas D. Huntington, James J. Moon, Marc Pellegrini, Stephen L. Nutt, Gabrielle T. Belz, Kim L. Good-Jacobson, Joanna R. Groom〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309313-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Lucio M. Schiapparelli, Sahil H. Shah, Yuanhui Ma, Daniel B. McClatchy, Pranav Sharma, Jianli Li, John R. Yates, Jeffrey L. Goldberg, Hollis T. Cline〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The brain processes information and generates cognitive and motor outputs through functions of spatially organized proteins in different types of neurons. More complete knowledge of proteins and their distributions within neuronal compartments in intact circuits would help in the understanding of brain function. We used unbiased 〈em〉in vivo〈/em〉 protein labeling with intravitreal NHS-biotin for discovery and analysis of endogenous axonally transported proteins in the visual system using tandem mass spectrometric proteomics, biochemistry, and both light and electron microscopy. Purification and proteomic analysis of biotinylated peptides identified ∼1,000 proteins transported from retinal ganglion cells into the optic nerve and ∼575 biotinylated proteins recovered from presynaptic compartments of lateral geniculate nucleus and superior colliculus. Approximately 360 biotinylated proteins were differentially detected in the two retinal targets. This study characterizes axonally transported proteins in the healthy adult visual system by analyzing proteomes from multiple compartments of retinal ganglion cell projections in the intact brain.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309349-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Paramita Chakraborty, Silvia G. Vaena, Krishnamurthy Thyagarajan, Shilpak Chatterjee, Amir Al-Khami, Shanmugam Panneer Selvam, Hung Nguyen, Inhong Kang, Megan W. Wyatt, Uday Baliga, Zachariah Hedley, Rose N. Ngang, Beichu Guo, Gyda C. Beeson, Shahid Husain, Chrystal M. Paulos, Craig C. Beeson, Michael J. Zilliox, Elizabeth G. Hill, Meenal Mehrotra〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309416-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Stéphane G. Rolland, Sandra Schneid, Melanie Schwarz, Elisabeth Rackles, Christian Fischer, Simon Haeussler, Saroj G. Regmi, Assa Yeroslaviz, Bianca Habermann, Dejana Mokranjac, Eric Lambie, Barbara Conradt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The induction of the mitochondrial unfolded protein response (UPR〈sup〉mt〈/sup〉) results in increased transcription of the gene encoding the mitochondrial chaperone HSP70. We systematically screened the 〈em〉C. elegans〈/em〉 genome and identified 171 genes that, when knocked down, induce the expression of an 〈em〉hsp-6〈/em〉 HSP70 reporter and encode mitochondrial proteins. These genes represent many, but not all, mitochondrial processes (e.g., mitochondrial calcium homeostasis and mitophagy are not represented). Knockdown of these genes leads to reduced mitochondrial membrane potential and, hence, decreased protein import into mitochondria. In addition, it induces UPR〈sup〉mt〈/sup〉 in a manner that is dependent on ATFS-1 but that is not antagonized by the kinase GCN-2. We propose that compromised mitochondrial protein import signals the induction of UPR〈sup〉mt〈/sup〉 and that the mitochondrial targeting sequence of ATFS-1 functions as a sensor for this signal.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309532-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Maria Vono, Christiane Sigrid Eberhardt, Floriane Auderset, Beatris Mastelic-Gavillet, Sylvain Lemeille, Dennis Christensen, Peter Andersen, Paul-Henri Lambert, Claire-Anne Siegrist〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Maternal antibodies (MatAbs) protect offspring from infections but limit their responses to vaccination. The mechanisms of this inhibition are still debated. Using murine early-life immunization models mimicking the condition prevailing in humans, we observed the induction of CD4-T, T follicular helper, and germinal center (GC) B cell responses even when early-life antibody responses were abrogated by MatAbs. GC B cells induced in the presence of MatAbs form GC structures and exhibit canonical GC changes in gene expression but fail to differentiate into plasma cells and/or memory B cells in a MatAb titer-dependent manner. Furthermore, GC B cells elicited in the presence or absence of MatAbs use different V〈sub〉H〈/sub〉 and V〈sub〉k〈/sub〉 genes and show differences in genes associated with B cell differentiation and isotype switching. Thus, MatAbs do not prevent B cell activation but control the output of the GC reaction both quantitatively and qualitatively, shaping the antigen-specific B cell repertoire.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309519-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Stephanie A. Campbell, Cassandra L. McDonald, Nicole A.J. Krentz, Francis C. Lynn, Brad G. Hoffman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Appropriate regulation of genes that coordinate pancreas progenitor proliferation and differentiation is required for pancreas development. Here, we explore the role of H3K4 methylation and the Trithorax group (TrxG) complexes in mediating gene expression during pancreas development. Disruption of TrxG complex assembly, but not catalytic activity, prevented endocrine cell differentiation in pancreas progenitor spheroids. 〈em〉In vivo〈/em〉 loss of TrxG catalytic activity in PDX1〈sup〉+〈/sup〉 cells increased apoptosis and the fraction of progenitors in the G1 phase of the cell cycle. Pancreas progenitors were reallocated to the acinar lineage, primarily at the expense of NEUROG3〈sup〉+〈/sup〉 endocrine progenitors. Later in development, acinar and endocrine cell numbers were decreased, and increased gene expression variance and reduced terminal marker activation in acinar cells led to their incomplete differentiation. These findings demonstrate that TrxG co-activator activity is required for gene induction, whereas TrxG catalytic activity and H3K4 methylation help maintain transcriptional stability.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309325-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 13 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 7〈/p〉 〈p〉Author(s): Kari-Anne M. Frikstad, Elisa Molinari, Marianne Thoresen, Simon A. Ramsbottom, Frances Hughes, Stef J.F. Letteboer, Sania Gilani, Kay O. Schink, Trond Stokke, Stefan Geimer, Lotte B. Pedersen, Rachel H. Giles, Anna Akhmanova, Ronald Roepman, John A. Sayer, Sebastian Patzke〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉CEP104 is an evolutionarily conserved centrosomal and ciliary tip protein. 〈em〉CEP104〈/em〉 loss-of-function mutations are reported in patients with Joubert syndrome, but their function in the etiology of ciliopathies is poorly understood. Here, we show that 〈em〉cep104〈/em〉 silencing in zebrafish causes cilia-related manifestations: shortened cilia in Kupffer’s vesicle, heart laterality, and cranial nerve development defects. We show that another Joubert syndrome-associated cilia tip protein, CSPP1, interacts with CEP104 at microtubules for the regulation of axoneme length. We demonstrate in human telomerase reverse transcriptase-immortalized retinal pigmented epithelium (hTERT-RPE1) cells that ciliary translocation of Smoothened in response to Hedgehog pathway stimulation is both CEP104 and CSPP1 dependent. However, CEP104 is not required for the ciliary recruitment of CSPP1, indicating that an intra-ciliary CEP104-CSPP1 complex controls axoneme length and Hedgehog signaling competence. Our 〈em〉in vivo〈/em〉 and 〈em〉in vitro〈/em〉 analyses of CEP104 define its interaction with CSPP1 as a requirement for the formation of Hedgehog signaling-competent cilia, defects that underlie Joubert syndrome.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309222-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Hugues Petitjean, Farin B. Bourojeni, Deborah Tsao, Albena Davidova, Susana G. Sotocinal, Jeffrey S. Mogil, Artur Kania, Reza Sharif-Naeini〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The dorsal horn of the spinal cord is the first integration site of somatosensory inputs from the periphery. In the superficial layers of the dorsal horn, nociceptive inputs are processed by a complex network of excitatory and inhibitory interneurons whose function and connectivity remain poorly understood. We examined the role of calretinin-expressing interneurons (CR neurons) in such processing and show that they receive direct inputs from nociceptive fibers and polysynaptic inputs from touch-sensitive Aβ fibers. Their activation by chemogenetic or optogenetic stimulation produces mechanical allodynia and nocifensive responses. Furthermore, they monosynaptically engage spinoparabrachial (SPb) neurons in lamina I, suggesting CR neurons modulate one of the major ascending pain pathways of the dorsal horn. In conclusion, we propose a neuronal pathway in which CR neurons are positioned at the junction between nociceptive and innocuous circuits and directly control SPb neurons in lamina I.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309520-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Yoshimasa Oyama, Colleen M. Bartman, Stephanie Bonney, J. Scott Lee, Lori A. Walker, Jun Han, Christoph H. Borchers, Peter M. Buttrick, Carol M. Aherne, Nathan Clendenen, Sean P. Colgan, Tobias Eckle〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. Here, we investigate the intersection between light-sensing (Period 2 [PER2]) and oxygen-sensing (hypoxia-inducible factor [HIF1A]) pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia-elicited adenosine- and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array from intense light-exposed wild-type or 〈em〉Per2〈/em〉〈sup〉−/−〈/sup〉 mice and myocardial ischemia in endothelial-specific PER2-deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, tricarboxylic acid (TCA) cycle enzyme activity regulation, and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects identifies similar PER2 mechanisms, implicating the use of intense light for the treatment of cardiovascular disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309106-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Chiara Saponaro, Valéry Gmyr, Julien Thévenet, Ericka Moerman, Nathalie Delalleau, Gianni Pasquetti, Anais Coddeville, Audrey Quenon, Mehdi Daoudi, Thomas Hubert, Marie-Christine Vantyghem, Corinne Bousquet, Yvan Martineau, Julie Kerr-Conte, Bart Staels, François Pattou, Caroline Bonner〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The newest classes of anti-diabetic agents include sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor (GLP1R) agonists. The SGLT2 inhibitor dapagliflozin reduces glucotoxicity by glycosuria but elevates glucagon secretion. The GLP1R agonist liraglutide inhibits glucagon; therefore, we hypothesize that the cotreatment of dapagliflozin with liraglutide could reduce hyperglucagonemia and hyperglycemia. Here we use five complementary models: human islet cultures, healthy mice, 〈em〉db/db〈/em〉 mice, diet-induced obese (DIO) mice, and somatostatin receptor-2 (SSTR2) KO mice. A single administration of liraglutide and dapagliflozin in combination improves glycemia and reduces dapagliflozin-induced glucagon secretion in diabetic mice. Chronic treatment with liraglutide and dapagliflozin produces a sustainable reduction of glycemia compared with each drug alone. Moreover, liraglutide reduces dapagliflozin-induced glucagon secretion by enhancing somatostatin release, as demonstrated by SSTR2 inhibition in human islets and in mice. Collectively, these data provide mechanistic insights into how intra-islet GLP1R activation is critical for the regulation of glucose homeostasis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930899X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Jie Su, Dandan Zhu, Zijun Huo, Julian A. Gingold, Yen-Sin Ang, Jian Tu, Ruoji Zhou, Yu Lin, Haidan Luo, Huiling Yang, Ruiying Zhao, Christoph Schaniel, Kateri A. Moore, Ihor R. Lemischka, Dung-Fang Lee〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉A multitude of signals are coordinated to maintain self-renewal in embryonic stem cells (ESCs). To unravel the essential internal and external signals required for sustaining the ESC state, we expand upon a set of ESC pluripotency-associated phosphoregulators (PRs) identified previously by short hairpin RNA (shRNA) screening. In addition to the previously described Aurka, we identify 4 additional PRs (Bub1b, Chek1, Ppm1g, and Ppp2r1b) whose depletion compromises self-renewal and leads to consequent differentiation. Global gene expression profiling and computational analyses reveal that knockdown of the 5 PRs leads to DNA damage/genome instability, activating p53 and culminating in ESC differentiation. Similarly, depletion of genome integrity-associated genes involved in DNA replication and checkpoint, mRNA processing, and Charcot-Marie-Tooth disease lead to compromise of ESC self-renewal via an increase in p53 activity. Our studies demonstrate an essential link between genomic integrity and developmental cell fate regulation in ESCs.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309015-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Ana Uzquiano, Carmen Cifuentes-Diaz, Ammar Jabali, Delfina M. Romero, Anne Houllier, Florent Dingli, Camille Maillard, Anne Boland, Jean-François Deleuze, Damarys Loew, Grazia M.S. Mancini, Nadia Bahi-Buisson, Julia Ladewig, Fiona Francis〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Apical radial glia (aRGs) are predominant progenitors during corticogenesis. Perturbing their function leads to cortical malformations, including subcortical heterotopia (SH), characterized by the presence of neurons below the cortex. 〈em〉EML1〈/em〉/〈em〉Eml1〈/em〉 mutations lead to SH in patients, as well as to heterotopic cortex (〈em〉HeCo〈/em〉) mutant mice. In 〈em〉HeCo〈/em〉 mice, some aRGs are abnormally positioned away from the ventricular zone (VZ). Thus, unraveling EML1/Eml1 function will clarify mechanisms maintaining aRGs in the VZ. We pinpoint an unknown EML1/Eml1 function in primary cilium formation. In 〈em〉HeCo〈/em〉 aRGs, cilia are shorter, less numerous, and often found aberrantly oriented within vesicles. Patient fibroblasts and human cortical progenitors show similar defects. EML1 interacts with RPGRIP1L, a ciliary protein, and 〈em〉RPGRIP1L〈/em〉 mutations were revealed in a heterotopia patient. We also identify Golgi apparatus abnormalities in 〈em〉EML1〈/em〉/〈em〉Eml1〈/em〉 mutant cells, potentially upstream of the cilia phenotype. We thus reveal primary cilia mechanisms impacting aRG dynamics in physiological and pathological conditions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719308824-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Keith Conrad Fernandez, Jayanta Chaudhuri〈/p〉 〈div〉〈p〉Sundaravinayagam et al. (2019) uncovered a critical role of 53BP1 in class switch recombination in B cells beyond its role in limiting end resection.〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Jaichandar Subramanian, Katrin Michel, Marc Benoit, Elly Nedivi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉A key feature of brain plasticity is the experience-dependent selection of optimal connections, implemented by a set of activity-regulated genes that dynamically adjust synapse strength and number. The activity-regulated gene 〈em〉cpg15/neuritin〈/em〉 has been previously implicated in stabilization and maturation of excitatory synapses. Here, we combine two-photon microscopy with genetic and sensory manipulations to dissect excitatory synapse formation 〈em〉in vivo〈/em〉 and examine the role of activity and CPG15 in dendritic spine formation, PSD95 recruitment, and synapse stabilization. We find that neither visual experience nor CPG15 is required for spine formation. However, PSD95 recruitment to nascent spines and their subsequent stabilization requires both. Further, cell-autonomous CPG15 expression is sufficient to replace experience in facilitating PSD95 recruitment and spine stabilization. CPG15 directly interacts with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on immature dendritic spines, suggesting a signaling mode for this small extracellular molecule acting as an experience-dependent “selector” for spine stabilization and synapse maturation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309027-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 6 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 6〈/p〉 〈p〉Author(s): Charles Hillier, Mercedes Pardo, Lu Yu, Ellen Bushell, Theo Sanderson, Tom Metcalf, Colin Herd, Burcu Anar, Julian C. Rayner, Oliver Billker, Jyoti S. Choudhary〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Malaria represents a major global health issue, and the identification of new intervention targets remains an urgent priority. This search is hampered by more than one-third of the genes of malaria-causing 〈em〉Plasmodium〈/em〉 parasites being uncharacterized. We report a large-scale protein interaction network in 〈em〉Plasmodium〈/em〉 schizonts, generated by combining blue native-polyacrylamide electrophoresis with quantitative mass spectrometry and machine learning. This integrative approach, spanning 3 species, identifies 〉20,000 putative protein interactions, organized into 600 protein clusters. We validate selected interactions, assigning functions in chromatin regulation to previously unannotated proteins and suggesting a role for an EELM2 domain-containing protein and a putative microrchidia protein as mechanistic links between AP2-domain transcription factors and epigenetic regulation. Our interactome represents a high-confidence map of the native organization of core cellular processes in 〈em〉Plasmodium〈/em〉 parasites. The network reveals putative functions for uncharacterized proteins, provides mechanistic and structural insight, and uncovers potential alternative therapeutic targets.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471930909X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 28 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports〈/p〉 〈p〉Author(s): Saurabh Bhattacharya, Amit K. Baidya, Ritesh Ranjan Pal, Gideon Mamou, Yair E. Gatt, Hanah Margalit, Ilan Rosenshine, Sigal Ben-Yehuda〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We have previously described the existence of membranous nanotubes, bridging adjacent bacteria, facilitating intercellular trafficking of nutrients, cytoplasmic proteins, and even plasmids, yet components enabling their biogenesis remain elusive. Here we reveal the identity of a molecular apparatus providing a platform for nanotube biogenesis. Using 〈em〉Bacillus subtilis〈/em〉 (〈em〉Bs〈/em〉), we demonstrate that conserved components of the flagellar export apparatus (FliO, FliP, FliQ, FliR, FlhB, and FlhA), designated CORE, dually serve for flagellum and nanotube assembly. Mutants lacking 〈em〉CORE〈/em〉 genes, but not other flagellar components, are deficient in both nanotube production and the associated intercellular molecular trafficking. In accord, CORE components are located at sites of nanotube emergence. Deleting 〈em〉CORE〈/em〉s of distinct species established that CORE-mediated nanotube formation is widespread. Furthermore, exogenous 〈em〉CORE〈/em〉s from diverse species could restore nanotube generation and functionality in 〈em〉Bs〈/em〉 lacking endogenous 〈em〉CORE〈/em〉. Our results demonstrate that the CORE-derived nanotube is a ubiquitous organelle that facilitates intercellular molecular trade across the bacterial kingdom.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302347-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Luca Bartesaghi, Yiqiao Wang, Paula Fontanet, Simone Wanderoy, Finja Berger, Haohao Wu, Natalia Akkuratova, Filipa Bouçanova, Jean-Jacques Médard, Charles Petitpré, Mark A. Landy, Ming-Dong Zhang, Philip Harrer, Claudia Stendel, Rolf Stucka, Marina Dusl, Maria Eleni Kastriti, Laura Croci, Helen C. Lai, Gian Giacomo Consalez〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The sensation of pain is essential for the preservation of the functional integrity of the body. However, the key molecular regulators necessary for the initiation of the development of pain-sensing neurons have remained largely unknown. Here, we report that, in mice, inactivation of the transcriptional regulator PRDM12, which is essential for pain perception in humans, results in a complete absence of the nociceptive lineage, while proprioceptive and touch-sensitive neurons remain. Mechanistically, our data reveal that PRDM12 is required for initiation of neurogenesis and activation of a cascade of downstream pro-neuronal transcription factors, including NEUROD1, BRN3A, and ISL1, in the nociceptive lineage while it represses alternative fates other than nociceptors in progenitor cells. Our results thus demonstrate that PRDM12 is necessary for the generation of the entire lineage of pain-initiating neurons.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302840-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Jonas M.D. Enander, Henrik Jörntell〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉For neurons of the primary somatosensory cortex, the anatomy of the thalamocortical connections supports a digit-wise specialization, whereas the intracortical connections suggest cross-digit integration. To evaluate the digit-wise specialization in individual somatosensory neurons, we explored the decoding of eight spatiotemporally complex tactile input patterns delivered to two non-adjacent digits in the anaesthetized rat. A striking finding was a good decoding performance for the eight input patterns to the non-dominant digit of the neuron, which in some cases was even better than for the same inputs to the dominant digit. Moreover, individual neurons decoded not only the pattern received but also to which digit it was delivered. These neuronal decoding properties were uniform throughout the cortical layers. Our results indicate that non-trivial tactile inputs to a single digit engage a wide processing circuitry throughout the digit region and suggest a low impact for somatotopy on the organization of the information processing.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302852-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Olga N. Karpus, B. Florien Westendorp, Jacqueline L.M. Vermeulen, Sander Meisner, Jan Koster, Vanesa Muncan, Manon E. Wildenberg, Gijs R. van den Brink〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Intestinal epithelial cells have a defined hierarchy with stem cells located at the bottom of the crypt and differentiated cells more at the top. Epithelial cell renewal and differentiation are strictly controlled by various regulatory signals provided by epithelial as well as surrounding cells. Although there is evidence that stromal cells contribute to the intestinal stem cell niche, their markers and the soluble signals they produce have been incompletely defined. Using a number of established stromal cell markers, we phenotypically and functionally examined fibroblast populations in the colon. CD90+ fibroblasts located in close proximity to stem cells 〈em〉in vivo〈/em〉 support organoid growth 〈em〉in vitro〈/em〉 and express crucial stem cell growth factors, such as Grem1, Wnt2b, and R-spondin3. Moreover, we found that CD90+ fibroblasts express a family of proteins—class 3 semaphorins (Sema3)—that are required for the supportive effect of CD90+ fibroblasts on organoid growth.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302876-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Simon Desiderio, Simon Vermeiren, Claude Van Campenhout, Sadia Kricha, Elisa Malki, Sven Richts, Emily V. Fletcher, Thomas Vanwelden, Bela Z. Schmidt, Kristine A. Henningfeld, Tomas Pieler, C. Geoffrey Woods, Vanja Nagy, Catherine Verfaillie, Eric J. Bellefroid〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of nociceptors and plays a major role in pain processing. Mutations in 〈em〉PRDM12〈/em〉 have been identified in CIP patients that indicate a putative role for this transcriptional regulator in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we find that Prdm12 is required for the initiation and maintenance of the expression of TrkA by acting as a modulator of Neurogenin1/2 transcription factor activity, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302839-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Matteo Gentili, Xavier Lahaye, Francesca Nadalin, Guilherme P.F. Nader, Emilia Puig Lombardi, Solène Herve, Nilushi S. De Silva, Derek C. Rookhuizen, Elina Zueva, Christel Goudot, Mathieu Maurin, Aurore Bochnakian, Sebastian Amigorena, Matthieu Piel, Daniele Fachinetti, Arturo Londoño-Vallejo, Nicolas Manel〈/p〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Dennis J. Montoya, Priscila Andrade, Bruno J.A. Silva, Rosane M.B. Teles, Feiyang Ma, Bryan Bryson, Saheli Sadanand, Teia Noel, Jing Lu, Euzenir Sarno, Kristine B. Arnvig, Douglas Young, Ramanuj Lahiri, Diana L. Williams, Sarah Fortune, Barry R. Bloom, Matteo Pellegrini, Robert L. Modlin〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium 〈em〉Mycobacterium leprae〈/em〉 is characterized by the production of type I IFNs and antibody production. Dual RNA-seq on patient lesions identifies two independent molecular measures of 〈em〉M. leprae〈/em〉, each of which correlates with distinct aspects of the host immune response. The fraction of bacterial transcripts, reflecting bacterial burden, correlates with a host type I IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial mRNA:rRNA ratio, reflecting bacterial viability, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for the interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302955-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Lauren Figard, Liuliu Zheng, Natalie Biel, Zenghui Xue, Hasan Seede, Seth Coleman, Ido Golding, Anna Marie Sokac〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Environmental stress threatens the fidelity of embryonic morphogenesis. Heat, for example, is a teratogen. Yet how heat affects morphogenesis is poorly understood. Here, we identify a heat-inducible actin stress response (ASR) in 〈em〉Drosophila〈/em〉 embryos that is mediated by the activation of the actin regulator Cofilin. Similar to ASR in adult mammalian cells, heat stress in fly embryos triggers the assembly of intra-nuclear actin rods. Rods measure up to a few microns in length, and their assembly depends on elevated free nuclear actin concentration and Cofilin. Outside the nucleus, heat stress causes Cofilin-dependent destabilization of filamentous actin (F-actin) in actomyosin networks required for morphogenesis. F-actin destabilization increases the chance of morphogenesis mistakes. Blocking the ASR by reducing Cofilin dosage improves the viability of heat-stressed embryos. However, improved viability correlates with restoring F-actin stability, not rescuing morphogenesis. Thus, ASR endangers embryos, perhaps by shifting actin from cytoplasmic filaments to an elevated nuclear pool.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302785-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Francesco Chemello, Francesca Grespi, Alessandra Zulian, Pasqua Cancellara, Etienne Hebert-Chatelain, Paolo Martini, Camilla Bean, Enrico Alessio, Lisa Buson, Martina Bazzega, Andrea Armani, Marco Sandri, Ruggero Ferrazza, Paolo Laveder, Graziano Guella, Carlo Reggiani, Chiara Romualdi, Paolo Bernardi, Luca Scorrano, Stefano Cagnin〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Skeletal muscle is composed of different myofiber types that preferentially use glucose or lipids for ATP production. How fuel preference is regulated in these post-mitotic cells is largely unknown, making this issue a key question in the fields of muscle and whole-body metabolism. Here, we show that microRNAs (miRNAs) play a role in defining myofiber metabolic profiles. mRNA and miRNA signatures of all myofiber types obtained at the single-cell level unveiled fiber-specific regulatory networks and identified two master miRNAs that coordinately control myofiber fuel preference and mitochondrial morphology. Our work provides a complete and integrated mouse myofiber type-specific catalog of gene and miRNA expression and establishes miR-27a-3p and miR-142-3p as regulators of lipid use in skeletal muscle.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302918-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Dhanendra Tomar, Fabián Jaña, Zhiwei Dong, William J. Quinn, Pooja Jadiya, Sarah L. Breves, Cassidy C. Daw, Subramanya Srikantan, Santhanam Shanmughapriya, Neeharika Nemani, Edmund Carvalho, Aparna Tripathi, Alison M. Worth, Xueqian Zhang, Roshanak Razmpour, Ajay Seelam, Stephen Rhode, Anuj V. Mehta, Michael Murray, Daniel Slade〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mitochondrial Ca〈sup〉2+〈/sup〉 uniporter (MCU)-mediated Ca〈sup〉2+〈/sup〉 uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis 〈em〉in vivo〈/em〉 remains elusive. Here we demonstrate that deletion of the 〈em〉Mcu〈/em〉 gene in mouse liver (MCU〈sup〉Δhep〈/sup〉) and in 〈em〉Danio rerio〈/em〉 by CRISPR/Cas9 inhibits mitochondrial Ca〈sup〉2+〈/sup〉 (〈sub〉m〈/sub〉Ca〈sup〉2+〈/sup〉) uptake, delays cytosolic Ca〈sup〉2+〈/sup〉 (〈sub〉c〈/sub〉Ca〈sup〉2+〈/sup〉) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCU〈sup〉Δhep〈/sup〉 were a direct result of extramitochondrial Ca〈sup〉2+〈/sup〉-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca〈sup〉2+〈/sup〉 uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCU〈sup〉Δhep〈/sup〉 hepatocytes. Conversely, gain-of-function MCU promotes rapid 〈sub〉m〈/sub〉Ca〈sup〉2+〈/sup〉 uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca〈sup〉2+〈/sup〉 dynamics to hepatic lipid metabolism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302931-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Xiaoqing Ren, Boqiang Hu, Moshi Song, Zhichao Ding, Yujiao Dang, Zunpeng Liu, Weiqi Zhang, Qianzhao Ji, Ruotong Ren, Jianjian Ding, Piu Chan, Changtao Jiang, Keqiong Ye, Jing Qu, Fuchou Tang, Guang-Hui Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. Here, we demonstrate that CBX4 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. CBX4 protein is downregulated in aged hMSCs, whereas CBX4 knockout in hMSCs results in destabilized nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein translation, and accelerated cellular senescence. CBX4 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin (FBL) and heterochromatin protein KRAB-associated protein 1 (KAP1) at nucleolar rDNA, limiting the excessive expression of rRNAs. Overexpression of CBX4 alleviates physiological hMSC aging and attenuates the development of osteoarthritis in mice. Altogether, our findings reveal a critical role of CBX4 in counteracting cellular senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302748-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Leeanna El-Houjeiri, Elite Possik, Tarika Vijayaraghavan, Mathieu Paquette, José A. Martina, Jalal M. Kazan, Eric H. Ma, Russell Jones, Paola Blanchette, Rosa Puertollano, Arnim Pause〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉TFEB and TFE3 are transcriptional regulators of the innate immune response, but the mechanisms regulating their activation upon pathogen infection are poorly elucidated. Using 〈em〉C. elegans〈/em〉 and mammalian models, we report that the master metabolic modulator 5′-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN) act upstream of TFEB/TFE3 in the innate immune response, independently of the mTORC1 signaling pathway. In nematodes, loss of FLCN or overexpression of AMPK confers pathogen resistance via activation of TFEB/TFE3-dependent antimicrobial genes, whereas ablation of total AMPK activity abolishes this phenotype. Similarly, in mammalian cells, loss of FLCN or pharmacological activation of AMPK induces TFEB/TFE3-dependent pro-inflammatory cytokine expression. Importantly, a rapid reduction in cellular ATP levels in murine macrophages is observed upon lipopolysaccharide (LPS) treatment accompanied by an acute AMPK activation and TFEB nuclear localization. These results uncover an ancient, highly conserved, and pharmacologically actionable mechanism coupling energy status with innate immunity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302888-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Antoine Baudrimont, Vincent Jaquet, Sandrine Wallerich, Sylvia Voegeli, Attila Becskei〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Genetically identical cells contain variable numbers of molecules, even if the cells share the same environment. This stochastic variability is prominent when molecules have low abundance, which is the case for mRNA noise. Most studies focused on how transcription affects mRNA noise, and little is known about the role of RNA degradation. To discriminate the fluctuations in these processes during the decay of a pair of reporter mRNAs, we quantified the uncorrelated intrinsic and the correlated extrinsic noise using single-molecule RNA FISH. Intrinsic noise converges to the Poisson level during the decay. mRNAs that have a short half-life are more susceptible to extrinsic noise than stable mRNAs. However, the Xrn1 exonuclease and the NMD pathways, which degrade mRNAs rapidly, were found to have lower fluctuation, which mitigates the noise of the short-lived mRNAs. This permits low variability across the entire range of mRNA half-lives.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719303080-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 26 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 13〈/p〉 〈p〉Author(s): Anne Vehlow, Erik Klapproth, Sha Jin, Ricarda Hannen, Maria Hauswald, Jörg-Walter Bartsch, Christopher Nimsky, Achim Temme, Birgit Leitinger, Nils Cordes〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Glioblastoma (GBM) is highly refractory to therapy and associated with poor clinical outcome. Here, we reveal a critical function of the promitotic and adhesion-mediating discoidin domain receptor 1 (DDR1) in modulating GBM therapy resistance. In GBM cultures and clinical samples, we show a DDR1 and GBM stem cell marker co-expression that correlates with patient outcome. We demonstrate that inhibition of DDR1 in combination with radiochemotherapy with temozolomide in GBM models enhances sensitivity and prolongs survival superior to conventional therapy. We identify a 14-3-3-Beclin-1-Akt1 protein complex assembling with DDR1 to be required for prosurvival Akt and mTOR signaling and regulation of autophagy-associated therapy sensitivity. Our results uncover a mechanism driven by DDR1 that controls GBM therapy resistance and provide a rationale target for the development of therapy-sensitizing agents.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719302827-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Erik C. Gunther, Levi M. Smith, Mikhail A. Kostylev, Timothy O. Cox, Adam C. Kaufman, Suho Lee, Ewa Folta-Stogniew, George D. Maynard, Ji Won Um, Massimiliano Stagi, Jacqueline K. Heiss, Austin Stoner, Geoff P. Noble, Hideyuki Takahashi, Laura T. Haas, John S. Schneekloth, Janie Merkel, Christopher Teran, Zaha K. Naderi, Surachai Supattapone〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cellular prion protein (PrP〈sup〉C〈/sup〉) binds the scrapie conformation of PrP (PrP〈sup〉Sc〈/sup〉) and oligomeric β-amyloid peptide (Aβo) to mediate transmissible spongiform encephalopathy (TSE) and Alzheimer’s disease (AD), respectively. We conducted cellular and biochemical screens for compounds blocking PrP〈sup〉C〈/sup〉 interaction with Aβo. A polymeric degradant of an antibiotic targets Aβo binding sites on PrP〈sup〉C〈/sup〉 with low nanomolar affinity and prevents Aβo-induced pathophysiology. We then identified a range of negatively charged polymers with specific PrP〈sup〉C〈/sup〉 affinity in the low to sub-nanomolar range, from both biological (melanin) and synthetic (poly [4-styrenesulfonic acid-co-maleic acid], PSCMA) origin. Association of PSCMA with PrP〈sup〉C〈/sup〉 prevents Aβo/PrP〈sup〉C〈/sup〉-hydrogel formation, blocks Aβo binding to neurons, and abrogates PrP〈sup〉Sc〈/sup〉 production by ScN2a cells. We show that oral PSCMA yields effective brain concentrations and rescues APPswe/PS1ΔE9 transgenic mice from AD-related synapse loss and memory deficits. Thus, an orally active PrP〈sup〉C〈/sup〉-directed polymeric agent provides a potential therapeutic approach to address neurodegeneration in AD and TSE.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319326-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Arvind Kumar Shukla, Joshua Spurrier, Irina Kuzina, Edward Giniger〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Innate immunity is central to the pathophysiology of neurodegenerative disorders, but it remains unclear why immunity is altered in the disease state and whether changes in immunity are a cause or a consequence of neuronal dysfunction. Here, we identify a molecular pathway that links innate immunity to age-dependent loss of dopaminergic neurons in 〈em〉Drosophila〈/em〉. We find, first, that altering the expression of the activating subunit of the Cdk5 protein kinase (Cdk5α) causes severe disruption of autophagy. Second, this disruption of autophagy is both necessary and sufficient to cause the hyperactivation of innate immunity, particularly expression of anti-microbial peptides. Finally, it is the upregulation of immunity that induces the age-dependent death of dopaminergic neurons. Given the dysregulation of Cdk5 and innate immunity in human neurodegeneration and the conserved role of the kinase in the regulation of autophagy, this sequence is likely to have direct application to the chain of events in human neurodegenerative disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319557-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Surabhi Chowdhary, Amoldeep S. Kainth, David Pincus, David S. Gross〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transcriptional induction of heat shock protein (〈em〉HSP〈/em〉) genes is accompanied by dynamic changes in their 3D structure and spatial organization, yet the molecular basis for these phenomena remains unknown. Using chromosome conformation capture and single-cell imaging, we show that genes transcriptionally activated by Hsf1 specifically interact across chromosomes and coalesce into diffraction-limited intranuclear foci. Genes activated by the alternative stress regulators Msn2/Msn4, in contrast, do not interact among themselves nor with Hsf1 targets. Likewise, constitutively expressed genes, even those interposed between 〈em〉HSP〈/em〉 genes, show no detectable interaction. Hsf1 forms discrete subnuclear puncta when stress activated, and these puncta dissolve in concert with transcriptional attenuation, paralleling the kinetics of 〈em〉HSP〈/em〉 gene coalescence and dissolution. Nuclear Hsf1 and RNA Pol II are both necessary for intergenic 〈em〉HSP〈/em〉 gene interactions, while DNA-bound Hsf1 is necessary and sufficient to drive heterologous gene coalescence. Our findings demonstrate that Hsf1 can dynamically restructure the yeast genome.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319648-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Sarah M. Turpin-Nolan, Philipp Hammerschmidt, Weiyi Chen, Alexander Jais, Katharina Timper, Motoharu Awazawa, Susanne Brodesser, Jens C. Brüning〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Skeletal muscle accumulates ceramides in obesity, which contribute to the development of obesity-associated insulin resistance. However, it remained unclear which distinct ceramide species in this organ contributes to instatement of systemic insulin resistance. Here, ceramide profiling of high-fat diet (HFD)-fed animals revealed increased skeletal muscle C〈sub〉18:0〈/sub〉 ceramide content, concomitant with increased expression of ceramide synthase (CerS)1. Mice lacking 〈em〉CerS1〈/em〉, either globally or specifically in skeletal muscle (〈em〉CerS1〈/em〉〈sup〉ΔSkM〈/sup〉), exhibit reduced muscle C〈sub〉18:0〈/sub〉 ceramide content and significant improvements in systemic glucose homeostasis. 〈em〉CerS1〈/em〉〈sup〉ΔSkM〈/sup〉 mice exhibit improved insulin-stimulated suppression of hepatic glucose production, and lack of 〈em〉CerS1〈/em〉 in skeletal muscle improves systemic glucose homeostasis via increased release of Fgf21 from skeletal muscle. In contrast, muscle-specific deficiency of C〈sub〉16:0〈/sub〉 ceramide-producing 〈em〉CerS5〈/em〉 and 〈em〉CerS6〈/em〉 failed to protect mice from obesity-induced insulin resistance. Collectively, these results reveal the tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319612-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Don-Marc Franchini, Olivia Lanvin, Marie Tosolini, Emilie Patras de Campaigno, Anne Cammas, Sarah Péricart, Clara-Maria Scarlata, Morgane Lebras, Cédric Rossi, Laetitia Ligat, Fréderic Pont, Paola B. Arimondo, Camille Laurent, Maha Ayyoub, Fabien Despas, Maryse Lapeyre-Mestre, Stefania Millevoi, Jean-Jacques Fournié〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Despite the clinical success of blocking inhibitory immune checkpoint receptors such as programmed cell death-1 (PD-1) in cancer, the mechanisms controlling the expression of these receptors have not been fully elucidated. Here, we identify a post-transcriptional mechanism regulating PD-1 expression in T cells. Upon activation, the 〈em〉PDCD1〈/em〉 mRNA and ribonucleoprotein complexes coalesce into stress granules that require microtubules and the kinesin 1 molecular motor to proceed to translation. Hence, PD-1 expression is highly sensitive to microtubule or stress granule inhibitors targeting this pathway. Evidence from healthy donors and cancer patients reveals a common regulation for the translation of 〈em〉CTLA4〈/em〉, 〈em〉LAG3〈/em〉, 〈em〉TIM3〈/em〉, 〈em〉TIGIT〈/em〉, and 〈em〉BTLA〈/em〉 but not of the stimulatory co-receptors 〈em〉OX40〈/em〉, 〈em〉GITR〈/em〉, and 〈em〉4-1BB〈/em〉 mRNAs. In patients, disproportionality analysis of immune-related adverse events for currently used microtubule drugs unveils a significantly higher risk of autoimmunity. Our findings reveal a fundamental mechanism of immunoregulation with great importance in cancer immunotherapy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319259-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Avital Klein-Brill, Daphna Joseph-Strauss, Alon Appleboim, Nir Friedman〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Nucleosome organization has a key role in transcriptional regulation, yet the precise mechanisms establishing nucleosome locations and their effect on transcription are unclear. Here, we use an induced degradation system to screen all yeast ATP-dependent chromatin remodelers. We characterize how rapid clearance of the remodeler affects nucleosome locations. Specifically, depletion of Sth1, the catalytic subunit of the RSC (remodel the structure of chromatin) complex, leads to rapid fill-in of nucleosome-free regions at gene promoters. These changes are reversible upon reintroduction of Sth1 and do not depend on DNA replication. RSC-dependent nucleosome positioning is pivotal in maintaining promoters of lowly expressed genes free from nucleosomes. In contrast, we observe that upon acute stress, the RSC is not necessary for the transcriptional response. Moreover, RSC-dependent nucleosome positions are tightly related to usage of specific transcription start sites. Our results suggest organizational principles that determine nucleosome positions with and without RSC and how these interact with the transcriptional process.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319314-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Zhichao Fan, William Bill Kiosses, Hao Sun, Marco Orecchioni, Yanal Ghosheh, Dirk M. Zajonc, M. Amin Arnaout, Edgar Gutierrez, Alex Groisman, Mark H. Ginsberg, Klaus Ley〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Leukocyte adhesion requires β〈sub〉2〈/sub〉-integrin activation. Resting integrins exist in a bent-closed conformation—i.e., not extended (E〈sup〉−〈/sup〉) and not high affinity (H〈sup〉−〈/sup〉)—unable to bind ligand. Fully activated E〈sup〉+〈/sup〉H〈sup〉+〈/sup〉 integrin binds intercellular adhesion molecules (ICAMs) expressed on the opposing cell in 〈em〉trans〈/em〉. E〈sup〉−〈/sup〉H〈sup〉−〈/sup〉 transitions to E〈sup〉+〈/sup〉H〈sup〉+〈/sup〉 through E〈sup〉+〈/sup〉H〈sup〉−〈/sup〉 or through E〈sup〉−〈/sup〉H〈sup〉+〈/sup〉, which binds to ICAMs on the same cell in 〈em〉cis〈/em〉. Spatial patterning of activated integrins is thought to be required for effective arrest, but no high-resolution cell surface localization maps of activated integrins exist. Here, we developed Super-STORM by combining super-resolution microscopy with molecular modeling to precisely localize activated integrin molecules and identify the molecular patterns of activated integrins on primary human neutrophils. At the time of neutrophil arrest, E〈sup〉−〈/sup〉H〈sup〉+〈/sup〉 integrins face each other to form oriented (non-random) nanoclusters. To address the mechanism causing this pattern, we blocked integrin binding to ICAMs in 〈em〉cis〈/em〉, which significantly relieved the face-to-face orientation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319685-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Maria A. Neginskaya, Maria E. Solesio, Elena V. Berezhnaya, Giuseppe F. Amodeo, Nelli Mnatsakanyan, Elizabeth A. Jonas, Evgeny V. Pavlov〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Permeability transition (PT) is an increase in mitochondrial inner membrane permeability that can lead to a disruption of mitochondrial function and cell death. PT is responsible for tissue damage in stroke and myocardial infarction. It is caused by the opening of a large conductance (∼1.5 nS) channel, the mitochondrial PT pore (mPTP). We directly tested the role of the c-subunit of ATP synthase in mPTP formation by measuring channel activity in c-subunit knockout mitochondria. We found that the classic mPTP conductance was lacking in c-subunit knockout mitochondria, but channels sensitive to the PT inhibitor cyclosporine A could be recorded. These channels had a significantly lower conductance compared with the cyclosporine A-sensitive channels detected in parental cells and were sensitive to the ATP/ADP translocase inhibitor bongkrekic acid. We propose that, in the absence of the c-subunit, mPTP cannot be formed, and a distinct cyclosporine A-sensitive low-conductance channel emerges.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319636-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Megan J. Agajanian, Matthew P. Walker, Alison D. Axtman, Roberta R. Ruela-de-Sousa, D. Stephen Serafin, Alex D. Rabinowitz, David M. Graham, Meagan B. Ryan, Tigist Tamir, Yuko Nakamichi, Melissa V. Gammons, James M. Bennett, Rafael M. Couñago, David H. Drewry, Jonathan M. Elkins, Carina Gileadi, Opher Gileadi, Paulo H. Godoi, Nirav Kapadia, Susanne Müller〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319533-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Krishna Jayant, Michael Wenzel, Yuki Bando, Jordan P. Hamm, Nicola Mandriota, Jake H. Rabinowitz, Ilan Jen-La Plante, Jonathan S. Owen, Ozgur Sahin, Kenneth L. Shepard, Rafael Yuste〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Intracellular recordings 〈em〉in vivo〈/em〉 remains the best technique to link single-neuron electrical properties to network function. Yet existing methods are limited in accuracy, throughput, and duration, primarily via washout, membrane damage, and movement-induced failure. Here, we introduce flexible quartz nanopipettes (inner diameters of 10–25 nm and spring constant of ∼0.08 N/m) as nanoscale analogs of traditional glass microelectrodes. Nanopipettes enable stable intracellular recordings (seal resistances of 500 to ∼800 MΩ, 5 to ∼10 cells/nanopipette, and duration of ∼1 hr) in anaesthetized and awake head-restrained mice, exhibit minimal diffusional flux, and facilitate precise recording and stimulation. When combined with quantum-dot labels and microprisms, nanopipettes enable two-photon targeted electrophysiology from both somata and dendrites, and even paired recordings from neighboring neurons, while permitting simultaneous population imaging across cortical layers. We demonstrate the versatility of this method by recording from parvalbumin-positive (Pv) interneurons while imaging seizure propagation, and we find that Pv depolarization block coincides with epileptic spread. Flexible nanopipettes present a simple method to procure stable intracellular recordings 〈em〉in vivo〈/em〉.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319302-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): David J. Cantor, Bryan King, Lili Blumenberg, Teresa DiMauro, Iannis Aifantis, Sergei B. Koralov, Jane A. Skok, Gregory David〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉B cell development is a highly regulated process that requires stepwise rearrangement of immunoglobulin genes to generate a functional B cell receptor (BCR). The polycomb group protein BMI1 is required for B cell development, but its function in developing B cells remains poorly defined. We demonstrate that BMI1 functions in a cell-autonomous manner at two stages during early B cell development. First, loss of BMI1 results in a differentiation block at the pro-B cell to pre-B cell transition due to the inability of BMI1-deficient cells to transcribe newly rearranged 〈em〉Igh〈/em〉 genes. Accordingly, introduction of a pre-rearranged 〈em〉Igh〈/em〉 allele partially restored B cell development in 〈em〉Bmi1〈/em〉〈sup〉−/−〈/sup〉 mice. In addition, BMI1 is required to prevent premature p53 signaling, and as a consequence, 〈em〉Bmi1〈/em〉〈sup〉−/−〈/sup〉 large pre-B cells fail to properly proliferate. Altogether, our results clarify the role of BMI1 in early B cell development and uncover an unexpected function of BMI1 during VDJ recombination.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319600-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Daniel Garcia, Kristina Hellberg, Amandine Chaix, Martina Wallace, Sébastien Herzig, Mehmet G. Badur, Terry Lin, Maxim N. Shokhirev, Antonio F.M. Pinto, Debbie S. Ross, Alan Saghatelian, Satchidananda Panda, Lukas E. Dow, Christian M. Metallo, Reuben J. Shaw〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The AMP-activated protein kinase (AMPK) is a highly conserved master regulator of metabolism, whose activation has been proposed to be therapeutically beneficial for the treatment of several metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). NAFLD, characterized by excessive accumulation of hepatic lipids, is the most common chronic liver disease and a major risk factor for development of nonalcoholic steatohepatitis, type 2 diabetes, and other metabolic conditions. To assess the therapeutic potential of AMPK activation, we have generated a genetically engineered mouse model, termed iAMPK〈sup〉CA〈/sup〉, where AMPK can be inducibly activated 〈em〉in vivo〈/em〉 in mice in a spatially and temporally restricted manner. Using this model, we show that liver-specific AMPK activation reprograms lipid metabolism, reduces liver steatosis, decreases expression of inflammation and fibrosis genes, and leads to significant therapeutic benefits in the context of diet-induced obesity. These findings further support AMPK as a target for the prevention and treatment of NAFLD.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319661-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Juan Wang, Jian-Wei Hao, Xu Wang, Huiling Guo, Hui-Hui Sun, Xiao-Ying Lai, Li-Ying Liu, Mingxia Zhu, Hao-Yan Wang, Yi-Fan Li, Li-Yang Yu, Changchuan Xie, Hong-Rui Wang, Wei Mo, Hai-Meng Zhou, Shuai Chen, Guosheng Liang, Tong-Jin Zhao〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Fatty acid uptake is the first step in fatty acid utilization, but it remains unclear how the process is regulated. Protein palmitoylation is a fatty acyl modification that plays a key regulatory role in protein targeting and trafficking; however, its function in regulating fatty acid metabolism is unknown. Here, we show that two of the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases, DHHC4 and DHHC5, regulate fatty acid uptake. DHHC4 and DHHC5 function at different subcellular localizations to control the palmitoylation, plasma membrane localization, and fatty acid uptake activity of the scavenger receptor CD36. Depletion of either DHHC4 or DHHC5 in cells disrupts CD36-dependent fatty acid uptake. Furthermore, both 〈em〉Dhhc4〈/em〉〈sup〉−/−〈/sup〉 and adipose-specific 〈em〉Dhhc5〈/em〉 knockout mice show decreased fatty acid uptake activity in adipose tissues and develop severe hypothermia upon acute cold exposure. These findings demonstrate a critical role of DHHC4 and DHHC5 in regulating fatty acid uptake.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319338-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Kai Wang, Mingfang Liao, Nan Zhou, Li Bao, Ke Ma, Zhongyong Zheng, Yujing Wang, Chang Liu, Wenzhao Wang, Jun Wang, Shuang-Jiang Liu, Hongwei Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We demonstrated the metabolic benefits of 〈em〉Parabacteroides distasonis〈/em〉 (PD) on decreasing weight gain, hyperglycemia, and hepatic steatosis in 〈em〉ob/ob〈/em〉 and high-fat diet (HFD)-fed mice. Treatment with live 〈em〉P. distasonis〈/em〉 (LPD) dramatically altered the bile acid profile with elevated lithocholic acid (LCA) and ursodeoxycholic acid (UDCA) and increased the level of succinate in the gut. 〈em〉In vitro〈/em〉 cultivation of PD demonstrated its capacity to transform bile acids and production of succinate. Succinate supplementation in the diet decreased hyperglycemia in 〈em〉ob/ob〈/em〉 mice via the activation of intestinal gluconeogenesis (IGN). Gavage with a mixture of LCA and UDCA reduced hyperlipidemia by activating the FXR pathway and repairing gut barrier integrity. Co-treatment with succinate and LCA/UDCA mirrored the benefits of LPD. The binding target of succinate was identified as fructose-1,6-bisphosphatase, the rate-limiting enzyme in IGN. The succinate and secondary bile acids produced by 〈em〉P. distasonis〈/em〉 played key roles in the modulation of host metabolism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319582-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Un Seng Chio, SangYoon Chung, Shimon Weiss, Shu-ou Shan〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Molecular chaperones play key roles in maintaining cellular proteostasis. In addition to preventing client aggregation, chaperones often relay substrates within a network while preventing off-pathway chaperones from accessing the substrate. Here we show that a conserved lid motif lining the substrate-binding groove of the Get3 ATPase enables these important functions during the targeted delivery of tail-anchored membrane proteins (TAs) to the endoplasmic reticulum. The lid prevents promiscuous TA handoff to off-pathway chaperones, and more importantly, it cooperates with the Get4/5 scaffolding complex to enable rapid and privileged TA transfer from the upstream co-chaperone Sgt2 to Get3. These findings provide a molecular mechanism by which chaperones maintain the pathway specificity of client proteins in the crowded cytosolic environment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S221112471831965X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Sukyeong Lee, Soung Hun Roh, Jungsoon Lee, Nuri Sung, Jun Liu, Francis T.F. Tsai〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Hsp104 is a ring-forming, ATP-driven molecular machine that recovers functional protein from both stress-denatured and amyloid-forming aggregates. Although Hsp104 shares a common architecture with Clp/Hsp100 protein unfoldases, different and seemingly conflicting 3D structures have been reported. Examining the structure of Hsp104 poses considerable challenges because Hsp104 readily hydrolyzes ATP, whereas ATP analogs can be slowly turned over and are often contaminated with other nucleotide species. Here, we present the single-particle electron cryo-microscopy (cryo-EM) structures of a catalytically inactive Hsp104 variant (Hsp104〈sub〉DWB〈/sub〉) in the ATP-bound state determined between 7.7 Å and 9.3 Å resolution. Surprisingly, we observe that the Hsp104〈sub〉DWB〈/sub〉 hexamer adopts distinct ring conformations (closed, extended, and open) despite being in the same nucleotide state. The latter underscores the structural plasticity of Hsp104 in solution, with different conformations stabilized by nucleotide binding. Our findings suggest that, in addition to ATP hydrolysis-driven conformational changes, Hsp104 uses stochastic motions to translocate unfolded polypeptides.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319673-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Stefanie Ritter-Makinson, Alexandra Clemente-Perez, Bryan Higashikubo, Frances S. Cho, Stephanie S. Holden, Eric Bennett, Ana Chkaidze, Oscar H.J. Eelkman Rooda, Marie-Coralie Cornet, Freek E. Hoebeek, Kazuhiro Yamakawa, Maria Roberta Cilio, Bruno Delord, Jeanne T. Paz〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Loss of function in the 〈em〉Scn1a〈/em〉 gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in 〈em〉Scn1a〈/em〉, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319296-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Arne Battefeld, Marko A. Popovic, Sharon I. de Vries, Maarten H.P. Kole〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Ensheathment of axons by myelin is a highly complex and multi-cellular process. Cytosolic calcium (Ca〈sup〉2+〈/sup〉) changes in the myelin sheath have been implicated in myelin synthesis, but the source of this Ca〈sup〉2+〈/sup〉 and the role of neuronal activity is not well understood. Using one-photon Ca〈sup〉2+〈/sup〉 imaging, we investigated myelin sheath formation in the mouse somatosensory cortex and found a high rate of spontaneous microdomain Ca〈sup〉2+〈/sup〉 transients and large-amplitude Ca〈sup〉2+〈/sup〉 waves propagating along the internode. The frequency of Ca〈sup〉2+〈/sup〉 transients and waves rapidly declines with maturation and reactivates during remyelination. Unexpectedly, myelin microdomain Ca〈sup〉2+〈/sup〉 transients occur independent of neuronal action potential generation or network activity but are nearly completely abolished when the mitochondrial permeability transition pores are blocked. These findings are supported by the discovery of mitochondria organelles in non-compacted myelin. Together, the results suggest that myelin microdomain Ca〈sup〉2+〈/sup〉 signals are cell-autonomously driven by high activity of mitochondria during myelin remodeling.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319697-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Frauke Liebelt, Rebecca M. Sebastian, Christopher L. Moore, Monique P.C. Mulder, Huib Ovaa, Matthew D. Shoulders, Alfred C.O. Vertegaal〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The role of stress-induced increases in SUMO2/3 conjugation during the heat shock response (HSR) has remained enigmatic. We investigated SUMO signal transduction at the proteomic and functional level during the HSR in cells depleted of proteostasis network components via chronic heat shock factor 1 inhibition. In the recovery phase post heat shock, high SUMO2/3 conjugation was prolonged in cells lacking sufficient chaperones. Similar results were obtained upon inhibiting HSP90, indicating that increased chaperone activity during the HSR is critical for recovery to normal SUMO2/3 levels post-heat shock. Proteasome inhibition likewise prolonged SUMO2/3 conjugation, indicating that stress-induced SUMO2/3 targets are subsequently degraded by the ubiquitin-proteasome system. Functionally, we suggest that SUMOylation can enhance the solubility of target proteins upon heat shock, a phenomenon that we experimentally observed 〈em〉in vitro〈/em〉. Collectively, our results implicate SUMO2/3 as a rapid response factor that coordinates proteome degradation and assists the maintenance of proteostasis upon proteotoxic stress.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319570-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Kevin T. Beier, Xiaojing J. Gao, Stanley Xie, Katherine E. DeLoach, Robert C. Malenka, Liqun Luo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Viral-genetic tracing techniques have enabled mesoscale mapping of neuronal connectivity by teasing apart inputs to defined neuronal populations in regions with heterogeneous cell types. We previously observed input biases to output-defined ventral tegmental area dopamine (VTA-DA) neurons. Here, we further dissect connectivity in the VTA by defining input-output relations of neurochemically and output-defined neuronal populations. By expanding our analysis to include input patterns to subtypes of excitatory (vGluT2-expressing) or inhibitory (GAD2-expressing) populations, we find that the output site, rather than neurochemical phenotype, correlates with whole-brain inputs of each subpopulation. Lastly, we find that biases in input maps to different VTA neurons can be generated using publicly available whole-brain output mapping datasets. Our comprehensive dataset and detailed spatial analysis suggest that connection specificity in the VTA is largely a function of the spatial location of the cells within the VTA.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319703-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Fang Hu, Jingheng Zhou, Yanxin Lu, Lizhao Guan, Ning-Ning Wei, Yi-Quan Tang, KeWei Wang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesis of epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319624-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 2 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 26, Issue 1〈/p〉 〈p〉Author(s): Frank Adolf, Manuel Rhiel, Bernd Hessling, Qi Gao, Andrea Hellwig, Julien Béthune, Felix T. Wieland〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Intracellular transport and homeostasis of the endomembrane system in eukaryotic cells depend on the formation and fusion of vesicular carriers. Coat protein complex (COP) II vesicles export newly synthesized secretory proteins from the endoplasmic reticulum (ER), whereas COPI vesicles facilitate traffic from the Golgi to the ER and intra-Golgi transport. Mammalian cells express various isoforms of COPII and COPI coat proteins. To investigate the roles of coat protein paralogs, we have combined 〈em〉in vitro〈/em〉 vesicle reconstitution from semi-intact cells with SILAC-based mass spectrometric analysis. Here, we describe the core proteomes of mammalian COPII and COPI vesicles. Whereas the compositions of COPII vesicles reconstituted with various isoforms of the cargo-binding subunit Sec24 differ depending on the paralog used, all of the isoforms of the COPI coat produce COPI-coated vesicles with strikingly similar protein compositions.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124718319715-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 September 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell Reports, Volume 28, Issue 11〈/p〉 〈p〉Author(s): Masamichi Yamamoto, Minsoo Kim, Hirohiko Imai, Yamato Itakura, Gen Ohtsuki〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cerebellar dysfunction relates to various psychiatric disorders, including autism spectrum and depressive disorders. However, the physiological aspect is less advanced. Here, we investigate the immune-triggered hyperexcitability in the cerebellum on a wider scope. Activated microglia via exposure to bacterial endotoxin lipopolysaccharide or heat-killed Gram-negative bacteria induce a potentiation of the intrinsic excitability in Purkinje neurons, which is suppressed by microglia-activity inhibitor and microglia depletion. An inflammatory cytokine, tumor necrosis factor alpha (TNF-α), released from microglia via toll-like receptor 4, triggers this plasticity. Our two-photon FRET ATP imaging shows an increase in ATP concentration following endotoxin exposure. Both TNF-α and ATP secretion facilitate synaptic transmission. Region-specific inflammation in the cerebellum 〈em〉in vivo〈/em〉 shows depression- and autistic-like behaviors. Furthermore, both TNF-α inhibition and microglia depletion revert such behavioral abnormality. Resting-state functional MRI reveals overconnectivity between the inflamed cerebellum and the prefrontal neocortical regions. Thus, immune activity in the cerebellum induces neuronal hyperexcitability and disruption of psychomotor behaviors in animals.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S2211124719309829-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉