ALBERT

Description: Publication date: 19 July 2016 Source: Cell Reports, Volume 16, Issue 3 Author(s): Sandra Malmgren Hill, Xinxin Hao, Johan Grönvall, Stephanie Spikings-Nordby, Per O. Widlund, Triana Amen, Anna Jörhov, Rebecca Josefson, Daniel Kaganovich, Beidong Liu, Thomas Nyström Age can be reset during mitosis in both yeast and stem cells to generate a young daughter cell from an aged and deteriorated one. This phenomenon requires asymmetry-generating genes (AGGs) that govern the asymmetrical inheritance of aggregated proteins. Using a genome-wide imaging screen to identify AGGs in Saccharomyces cerevisiae , we discovered a previously unknown role for endocytosis, vacuole fusion, and the myosin-dependent adaptor protein Vac17 in asymmetrical inheritance of misfolded proteins. Overproduction of Vac17 increases deposition of aggregates into cytoprotective vacuole-associated sites, counteracts age-related breakdown of endocytosis and vacuole integrity, and extends replicative lifespan. The link between damage asymmetry and vesicle trafficking can be explained by a direct interaction between aggregates and vesicles. We also show that the protein disaggregase Hsp104 interacts physically with endocytic vesicle-associated proteins, such as the dynamin-like protein, Vps1, which was also shown to be required for Vac17-dependent sequestration of protein aggregates. These data demonstrate that two physiognomies of aging—reduced endocytosis and protein aggregation—are interconnected and regulated by Vac17. Graphical abstract Teaser Cellular rejuvenation is enabled by asymmetrical inheritance of damaged proteins. Using a genome-wide imaging screen to identify asymmetry-generating genes, Hill et al. demonstrate a role for vesicle trafficking, membrane fusion, and the myosin-dependent adaptor protein Vac17 in the asymmetric inheritance of misfolded proteins and consequently in the regulation of lifespan.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Mahesh S. Padanad, Georgia Konstantinidou, Niranjan Venkateswaran, Margherita Melegari, Smita Rindhe, Matthew Mitsche, Chendong Yang, Kimberly Batten, Kenneth E. Huffman, Jingwen Liu, Ximing Tang, Jaime Rodriguez-Canales, Neda Kalhor, Jerry W. Shay, John D. Minna, Jeffrey McDonald, Ignacio I. Wistuba, Ralph J. DeBerardinis, Pier Paolo Scaglioni KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A ( CoA ) synthetase long-chain family member 3 ( ACSL3 ), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β - oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3 -dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain. Graphical abstract Teaser In Brief: Padanad et al. find that ACSL3 is the critical enzyme required for viability of mutant KRAS lung cancer cells in vitro and for lung cancer initiation and progression in vivo. ACSL3 mediates survival and tumorigenesis of mutant KRAS lung cancer cells by promoting uptake, retention, and β-oxidation of fatty acids.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Junghee Jin, Seung-Nam Kim, Xuqing Liu, Haijun Zhang, Chao Zhang, Ji-Seon Seo, Yong Kim, Tao Sun Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors. Graphical abstract Teaser The molecular pathogenesis of anxiety and depression disorders is poorly understood. Jin et al. show that microRNA miR-17-92 plays a critical role in regulating adult hippocampal neurogenesis and anxiety- and depression-like behaviors by modifying expression of genes in the glucocorticoid pathway.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Feng Jiang, Xia Wang, Bei Wang, Lihong Chen, Zhendong Zhao, Nicholas R. Waterfield, Guowei Yang, Qi Jin Pseudomonas aeruginosa is an opportunistic pathogen that regularly causes nosocomial infections in hospitalized patients. The type VI secretion system (T6SS) is responsible for the secretion of numerous virulence effector proteins that can both interfere with competing microbes and manipulate host cells. Here, we report a detailed investigation of a P. aeruginosa H2-T6SS-dependent phospholipase effector, TplE, which acts as a trans-kingdom toxin. Delivery of TplE to the periplasmic space of rival bacteria leads to growth inhibition. Importantly, TplE, also contains a eukaryotic PGAP1-like domain, which targets the host ER apparatus, ultimately leading to disruption of the ER. TplE activity leads to the activation of the unfolded protein response (UPR) through the IRE1α-XBP1 pathway, enhancing autophagic flux. These findings indicate that this T6SS-delivered phospholipase effector is active against both prokaryotic and eukaryotic cellular targets, highlighting the T6SS as a versatile weapon in the Pseudomonas arsenal. Graphical abstract Teaser Jiang et al. report that the P. aeruginosa T6SS PGAP1-like phospholipase effector (TplE) targets the periplasm of competing bacteria to inhibit their growth. TplE can also target and disrupt the ER of eukaryotic cells, leading to ER stress and autophagic flux in the host cells.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Seung-Hye Lee, Claire E. Le Pichon, Oskar Adolfsson, Valérie Gafner, Maria Pihlgren, Han Lin, Hilda Solanoy, Robert Brendza, Hai Ngu, Oded Foreman, Ruby Chan, James A. Ernst, Danielle DiCara, Isidro Hotzel, Karpagam Srinivasan, David V. Hansen, Jasvinder Atwal, Yanmei Lu, Daniela Bumbaca, Andrea Pfeifer, Ryan J. Watts, Andreas Muhs, Kimberly Scearce-Levie, Gai Ayalon The spread of tau pathology correlates with cognitive decline in Alzheimer’s disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau. Graphical abstract Teaser Lee et al. report that antibody effector function is not required for targeting tau with antibodies in vivo and in cultured neurons. The authors propose that reducing anti-tau effector function may offer a safer approach for targeting tau by avoiding engagement of microglia that may induce inflammatory responses.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Rotem Ben-Tov Perry, Ida Rishal, Ella Doron-Mandel, Ashley L. Kalinski, Katalin F. Medzihradszky, Marco Terenzio, Stefanie Alber, Sandip Koley, Albina Lin, Meir Rozenbaum, Dmitry Yudin, Pabitra K. Sahoo, Cynthia Gomes, Vera Shinder, Wasim Geraisy, Eric A. Huebner, Clifford J. Woolf, Avraham Yaron, Alma L. Burlingame, Jeffery L. Twiss, Mike Fainzilber How can cells sense their own size to coordinate biosynthesis and metabolism with their growth needs? We recently proposed a motor-dependent bidirectional transport mechanism for axon length and cell size sensing, but the nature of the motor-transported size signals remained elusive. Here, we show that motor-dependent mRNA localization regulates neuronal growth and cycling cell size. We found that the RNA-binding protein nucleolin is associated with importin β1 mRNA in axons. Perturbation of nucleolin association with kinesins reduces its levels in axons, with a concomitant reduction in axonal importin β1 mRNA and protein levels. Strikingly, subcellular sequestration of nucleolin or importin β1 enhances axonal growth and causes a subcellular shift in protein synthesis. Similar findings were obtained in fibroblasts. Thus, subcellular mRNA localization regulates size and growth in both neurons and cycling cells. Graphical abstract Teaser Perry et al. show that motor-dependent mRNA localization regulates neuronal growth and cycling cell size. They implicate the RNA-binding protein nucleolin in importin β1 mRNA transport to neuronal axons and to the cellular periphery in fibroblasts. Perturbation of this mechanism affects growth and shifts protein synthesis, regulating axon length and cell size.

Description: Publication date: Available online 28 July 2016 Source: Cell Reports Author(s): Anna Prudova, Vasilena Gocheva, Ulrich auf dem Keller, Ulrich Eckhard, Oakley C. Olson, Leila Akkari, Georgina S. Butler, Nikolaus Fortelny, Philipp F. Lange, Jennifer C. Mark, Johanna A. Joyce, Christopher M. Overall Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N-terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%–44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%–83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer. Graphical abstract Teaser Cathepsin proteases play a significant role in carcinogenesis, yet their in vivo substrates remain ill-defined. By using systems-level 8-plex TAILS proteomics, Prudova et al. demonstrate that, in the Rip1-Tag2 model of pancreatic cancer, degradation roles for cathepsins predominate, yet many proteins, mostly extracellular ones, are processed to produce stable cleavage products.

Description: Publication date: Available online 29 July 2016 Source: Cell Reports Author(s): Kimberly A. Dowd, Christina R. DeMaso, Rebecca S. Pelc, Scott D. Speer, Alexander R.Y. Smith, Leslie Goo, Derek J. Platt, John R. Mascola, Barney S. Graham, Mark J. Mulligan, Michael S. Diamond, Julie E. Ledgerwood, Theodore C. Pierson Recent epidemics of Zika virus (ZIKV) have been associated with congenital malformation during pregnancy and Guillain-Barré syndrome. There are two ZIKV lineages (African and Asian) that share >95% amino acid identity. Little is known regarding the ability of neutralizing antibodies elicited against one lineage to protect against the other. We investigated the breadth of the neutralizing antibody response following ZIKV infection by measuring the sensitivity of six ZIKV strains to neutralization by ZIKV-confirmed convalescent human serum or plasma samples. Contemporary Asian and early African ZIKV strains were similarly sensitive to neutralization regardless of the cellular source of virus. Furthermore, mouse immune serum generated after infection with African or Asian ZIKV strains was capable of neutralizing homologous and heterologous ZIKV strains equivalently. Because our study only defines a single ZIKV serotype, vaccine candidates eliciting robust neutralizing antibody responses should inhibit infection of both ZIKV lineages, including strains circulating in the Americas. Graphical abstract Teaser Dowd et al. investigate the breadth of the neutralizing antibody response to ZIKV. They demonstrate that contemporary South American, Asian, and early African ZIKV strains are similarly sensitive to neutralization by ZIKV-confirmed convalescent human serum.

Description: Publication date: 2 August 2016 Source: Cell Reports, Volume 16, Issue 5 Author(s): Megan Chastain, Qing Zhou, Olga Shiva, Leanne Whitmore, Pingping Jia, Xueyu Dai, Chenhui Huang, Maria Fadri-Moskwik, Ping Ye, Weihang Chai The telomeric CTC1/STN1/TEN1 (CST) complex has been implicated in promoting replication recovery under replication stress at genomic regions, yet its precise role is unclear. Here, we report that STN1 is enriched at GC-rich repetitive sequences genome-wide in response to hydroxyurea (HU)-induced replication stress. STN1 deficiency exacerbates the fragility of these sequences under replication stress, resulting in chromosome fragmentation. We find that upon fork stalling, CST proteins form distinct nuclear foci that colocalize with RAD51. Furthermore, replication stress induces physical association of CST with RAD51 in an ATR-dependent manner. Strikingly, CST deficiency diminishes HU-induced RAD51 foci formation and reduces RAD51 recruitment to telomeres and non-telomeric GC-rich fragile sequences. Collectively, our findings establish that CST promotes RAD51 recruitment to GC-rich repetitive sequences in response to replication stress to facilitate replication restart, thereby providing insights into the mechanism underlying genome stability maintenance. Graphical abstract Teaser Chastain et al. find that under replication stress, the telomeric complex CST interacts with RAD51 and is enriched at GC-rich repetitive fragile sites. CST suppression inhibits RAD51 recruitment to fragile sites, resulting in genome instability.

Description: Publication date: Available online 14 July 2016 Source: Cell Reports Author(s): Niloufar Monhasery, Jens Moll, Carly Cuman, Manuel Franke, Larissa Lamertz, Rebecca Nitz, Boris Görg, Dieter Häussinger, Juliane Lokau, Doreen M. Floss, Roland Piekorz, Eva Dimitriadis, Christoph Garbers, Jürgen Scheller Interleukin (IL)-11 signaling is involved in various processes, including epithelial intestinal cell regeneration and embryo implantation. IL-11 signaling is initiated upon binding of IL-11 to IL-11R1 or IL-11R2, two IL-11α-receptor splice variants, and gp130. Here, we show that IL-11 signaling via IL-11R1/2:gp130 complexes occurs on both the apical and basolateral sides of polarized cells, whereas IL-6 signaling via IL-6R:gp130 complexes is restricted to the basolateral side. We show that basolaterally supplied IL-11 is transported and released to the apical extracellular space via transcytosis in an IL-11R1-dependent manner. By contrast, IL-6R and IL-11R2 do not promote transcytosis. In addition, we show that transcytosis of IL-11 is dependent on the intracellular domain of IL-11R1 and that synthetic transfer of the intracellular domain of IL-11R1 to IL-6R promotes transcytosis of IL-6. Our data define IL-11R as a cytokine receptor with transcytotic activity by which IL-11 and IL-6:soluble IL-6R complexes are transported across cellular barriers. Graphical abstract Teaser Monhasery et al. show that interleukin 11 (IL-11) signaling via IL-11 receptor:gp130 complexes occurs on both the apical and basolateral sides of polarized cells. The transcytotic activity of the IL-11 receptor allows IL-11 and interleukin-6:soluble interleukin-6 receptor complexes to be transported across cellular barriers.