ALBERT

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): David P. Nusinow, John Szpyt, Mahmoud Ghandi, Christopher M. Rose, E. Robert McDonald, Marian Kalocsay, Judit Jané-Valbuena, Ellen Gelfand, Devin K. Schweppe, Mark Jedrychowski, Javad Golji, Dale A. Porter, Tomas Rejtar, Y. Karen Wang, Gregory V. Kryukov, Frank Stegmeier, Brian K. Erickson, Levi A. Garraway, William R. Sellers, Steven P. Gygi〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Proteins are essential agents of biological processes. To date, large-scale profiling of cell line collections including the Cancer Cell Line Encyclopedia (CCLE) has focused primarily on genetic information whereas deep interrogation of the proteome has remained out of reach. Here, we expand the CCLE through quantitative profiling of thousands of proteins by mass spectrometry across 375 cell lines from diverse lineages to reveal information undiscovered by DNA and RNA methods. We observe unexpected correlations within and between pathways that are largely absent from RNA. An analysis of microsatellite instable (MSI) cell lines reveals the dysregulation of specific protein complexes associated with surveillance of mutation and translation. These and other protein complexes were associated with sensitivity to knockdown of several different genes. These data in conjunction with the wider CCLE are a broad resource to explore cellular behavior and facilitate cancer research.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313856-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Bo Xia, Yun Yan, Maayan Baron, Florian Wagner, Dalia Barkley, Marta Chiodin, Sang Y. Kim, David L. Keefe, Joseph P. Alukal, Jef D. Boeke, Itai Yanai〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The testis expresses the largest number of genes of any mammalian organ, a finding that has long puzzled molecular biologists. Our single-cell transcriptomic data of human and mouse spermatogenesis provide evidence that this widespread transcription maintains DNA sequence integrity in the male germline by correcting DNA damage through a mechanism we term transcriptional scanning. We find that genes expressed during spermatogenesis display lower mutation rates on the transcribed strand and have low diversity in the population. Moreover, this effect is fine-tuned by the level of gene expression during spermatogenesis. The unexpressed genes, which in our model do not benefit from transcriptional scanning, diverge faster over evolutionary timescales and are enriched for sensory and immune-defense functions. Collectively, we propose that transcriptional scanning shapes germline mutation signatures and modulates mutation rates in a gene-specific manner, maintaining DNA sequence integrity for the bulk of genes but allowing for faster evolution in a specific subset.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313777-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Yorick Post, Jens Puschhof, Joep Beumer, Harald M. Kerkkamp, Merijn A.G. de Bakker, Julien Slagboom, Buys de Barbanson, Nienke R. Wevers, Xandor M. Spijkers, Thomas Olivier, Taline D. Kazandjian, Stuart Ainsworth, Carmen Lopez Iglesias, Willine J. van de Wetering, Maria C. Heinz, Ravian L. van Ineveld, Regina G.D.M. van Kleef, Harry Begthel, Jeroen Korving, Yotam E. Bar-Ephraim〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Wnt dependency and Lgr5 expression define multiple mammalian epithelial stem cell types. Under defined growth factor conditions, such adult stem cells (ASCs) grow as 3D organoids that recapitulate essential features of the pertinent epithelium. Here, we establish long-term expanding venom gland organoids from several snake species. The newly assembled transcriptome of the Cape coral snake reveals that organoids express high levels of toxin transcripts. Single-cell RNA sequencing of both organoids and primary tissue identifies distinct venom-expressing cell types as well as proliferative cells expressing homologs of known mammalian stem cell markers. A hard-wired regional heterogeneity in the expression of individual venom components is maintained in organoid cultures. Harvested venom peptides reflect crude venom composition and display biological activity. This study extends organoid technology to reptilian tissues and describes an experimentally tractable model system representing the snake venom gland.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313236-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Casey E. Hughes, Troy K. Coody, Mi-Young Jeong, Jordan A. Berg, Dennis R. Winge, Adam L. Hughes〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mitochondria and lysosomes are functionally linked, and their interdependent decline is a hallmark of aging and disease. Despite the long-standing connection between these organelles, the function(s) of lysosomes required to sustain mitochondrial health remains unclear. Here, working in yeast, we show that the lysosome-like vacuole maintains mitochondrial respiration by spatially compartmentalizing amino acids. Defects in vacuole function result in a breakdown in intracellular amino acid homeostasis, which drives age-related mitochondrial decline. Among amino acids, we find that cysteine is most toxic for mitochondria and show that elevated non-vacuolar cysteine impairs mitochondrial respiration by limiting intracellular iron availability through an oxidant-based mechanism. Cysteine depletion or iron supplementation restores mitochondrial health in vacuole-impaired cells and prevents mitochondrial decline during aging. These results demonstrate that cysteine toxicity is a major driver of age-related mitochondrial deterioration and identify vacuolar amino acid compartmentation as a cellular strategy to minimize amino acid toxicity.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313972-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): International Multiple Sclerosis Genetics Consortium〈/p〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Henry R. Maun, Janet K. Jackman, David F. Choy, Kelly M. Loyet, Tracy L. Staton, Guiquan Jia, Amy Dressen, Jason A. Hackney, Meire Bremer, Benjamin T. Walters, Rajesh Vij, Xiaocheng Chen, Neil N. Trivedi, Ashley Morando, Michael T. Lipari, Yvonne Franke, Xiumin Wu, Juan Zhang, John Liu, Ping Wu〈/p〉

Description: 〈p〉Publication date: Available online 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): F. Kyle Satterstrom, Jack A. Kosmicki, Jiebiao Wang, Michael S. Breen, Silvia De Rubeis, Joon-Yong An, Minshi Peng, Ryan Collins, Jakob Grove, Lambertus Klei, Christine Stevens, Jennifer Reichert, Maureen S. Mulhern, Mykyta Artomov, Sherif Gerges, Brooke Sheppard, Xinyi Xu, Aparna Bhaduri, Utku Norman, Harrison Brand〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate 〈em〉de novo〈/em〉 and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive 〈em〉de novo〈/em〉 variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313984-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Jens Walter, Anissa M. Armet, B. Brett Finlay, Fergus Shanahan〈/p〉 〈div〉〈p〉Human diseases are increasingly linked with an altered or “dysbiotic” gut microbiota, but whether such changes are causal, consequential, or bystanders to disease is, for the most part, unresolved. Human microbiota-associated (HMA) rodents have become a cornerstone of microbiome science for addressing causal relationships between altered microbiomes and host pathology. In a systematic review, we found that 95% of published studies (36/38) on HMA rodents reported a transfer of pathological phenotypes to recipient animals, and many extrapolated the findings to make causal inferences to human diseases. We posit that this exceedingly high rate of inter-species transferable pathologies is implausible and overstates the role of the gut microbiome in human disease. We advocate for a more rigorous and critical approach for inferring causality to avoid false concepts and prevent unrealistic expectations that may undermine the credibility of microbiome science and delay its translation.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Maojin Yao, P. Britten Ventura, Ying Jiang, Fausto J. Rodriguez, Lixin Wang, Justin S.A. Perry, Yibo Yang, Kelsey Wahl, Rowena B. Crittenden, Mariko L. Bennett, Lin Qi, Cong-Cong Gong, Xiao-Nan Li, Ben A. Barres, Timothy P. Bender, Kodi S. Ravichandran, Kevin A. Janes, Charles G. Eberhart, Hui Zong〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were 〈em〉trans〈/em〉-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells 〈em〉trans〈/em〉-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313868-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Linlin Z. Fan, Simon Kheifets, Urs L. Böhm, Hao Wu, Kiryl D. Piatkevich, Michael E. Xie, Vicente Parot, Yooree Ha, Kathryn E. Evans, Edward S. Boyden, Anne E. Takesian, Adam E. Cohen〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cortical layer 1 (L1) interneurons have been proposed as a hub for attentional modulation of underlying cortex, but the transformations that this circuit implements are not known. We combined genetically targeted voltage imaging with optogenetic activation and silencing to study the mechanisms underlying sensory processing in mouse barrel cortex L1. Whisker stimuli evoked precisely timed single spikes in L1 interneurons, followed by strong lateral inhibition. A mild aversive stimulus activated cholinergic inputs and evoked a bimodal distribution of spiking responses in L1. A simple conductance-based model that only contained lateral inhibition within L1 recapitulated the sensory responses and the winner-takes-all cholinergic responses, and the model correctly predicted that the network would function as a spatial and temporal high-pass filter for excitatory inputs. Our results demonstrate that all-optical electrophysiology can reveal basic principles of neural circuit function 〈em〉in vivo〈/em〉 and suggest an intuitive picture for how L1 transforms sensory and modulatory inputs.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867420300477-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): M. Zaeem Cader, Rodrigo Pereira de Almeida Rodrigues, James A. West, Gavin W. Sewell, Muhammad N. Md-Ibrahim, Stephanie Reikine, Giuseppe Sirago, Lukas W. Unger, Ana Belén Inglesias-Romero, Katharina Ramshorn, Lea-Maxie Haag, Svetlana Saveljeva, Jana-Fabienne Ebel, Philip Rosenstiel, Nicole C. Kaneider, James C. Lee, Trevor D. Lawley, Allan Bradley, Gordon Dougan, Yorgo Modis〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and 〈em〉S〈/em〉-methyl-5′-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H〈sup〉+〈/sup〉 and phosphate recycling.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313790-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): David W. Vredevoogd, Thomas Kuilman, Maarten A. Ligtenberg, Julia Boshuizen, Kelly E. Stecker, Beaunelle de Bruijn, Oscar Krijgsman, Xinyao Huang, Juliana C.N. Kenski, Ruben Lacroix, Riccardo Mezzadra, Raquel Gomez-Eerland, Mete Yildiz, Ilknur Dagidir, Georgi Apriamashvili, Nordin Zandhuis, Vincent van der Noort, Nils L. Visser, Christian U. Blank, Maarten Altelaar〈/p〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): The Cell Press Team〈/p〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Benjamin S. Waldman, Dominic Schwarz, Marc H. Wadsworth, Jeroen P. Saeij, Alex K. Shalek, Sebastian Lourido〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉〈em〉Toxoplasma gondii〈/em〉 chronically infects a quarter of the world’s population, and its recrudescence can cause life-threatening disease in immunocompromised individuals and recurrent ocular lesions in the immunocompetent. Acute-stage tachyzoites differentiate into chronic-stage bradyzoites, which form intracellular cysts resistant to immune clearance and existing therapies. The molecular basis of this differentiation is unknown, despite being efficiently triggered by stresses in culture. Through Cas9-mediated screening and single-cell profiling, we identify a Myb-like transcription factor (BFD1) necessary for differentiation in cell culture and in mice. BFD1 accumulates during stress and its synthetic expression is sufficient to drive differentiation. Consistent with its function as a transcription factor, BFD1 binds the promoters of many stage-specific genes and represents a counterpoint to the ApiAP2 factors that dominate our current view of parasite gene regulation. BFD1 provides a genetic switch to study and control 〈em〉Toxoplasma〈/em〉 differentiation and will inform prevention and treatment of chronic infections.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313753-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Qian Lin, Jason Manley, Magdalena Helmreich, Friederike Schlumm, Jennifer M. Li, Drew N. Robson, Florian Engert, Alexander Schier, Tobias Nöbauer, Alipasha Vaziri〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Goal-directed behavior requires the interaction of multiple brain regions. How these regions and their interactions with brain-wide activity drive action selection is less understood. We have investigated this question by combining whole-brain volumetric calcium imaging using light-field microscopy and an operant-conditioning task in larval zebrafish. We find global, recurring dynamics of brain states to exhibit pre-motor bifurcations toward mutually exclusive decision outcomes. These dynamics arise from a distributed network displaying trial-by-trial functional connectivity changes, especially between cerebellum and habenula, which correlate with decision outcome. Within this network the cerebellum shows particularly strong and predictive pre-motor activity (〉10 s before movement initiation), mainly within the granule cells. Turn directions are determined by the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the rate of bi-hemispheric population ramping quantitatively predicts decision time on the trial-by-trial level. Our results highlight a cognitive role of the cerebellum and its importance in motor planning.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313807-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Melody G. Campbell, Anthony Cormier, Saburo Ito, Robert I. Seed, Andrew J. Bondesson, Jianlong Lou, James D. Marks, Jody L. Baron, Yifan Cheng, Stephen L. Nishimura〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire αvβ8 ectodomain and its intact natural ligand, L-TGF-β, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies reveal a mechanism of TGF-β activation where mature TGF-β signals within the confines of L-TGF-β and the release and diffusion of TGF-β are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313923-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): George M. Burslem, Craig M. Crews〈/p〉 〈div〉〈p〉New biological tools provide new techniques to probe fundamental biological processes. Here we describe the burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system. We describe the PROTAC technology and its application to drug discovery and provide examples where PROTACs have enabled novel biological insights. Furthermore, we provide a workflow for PROTAC development and use and discuss the benefits and issues associated with PROTACs. Finally, we compare PROTAC-mediated protein-level modulation with other technologies, such as RNAi and genome editing.〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Daniel del Toro, Maria A. Carrasquero-Ordaz, Amy Chu, Tobias Ruff, Meriam Shahin, Verity A. Jackson, Matthieu Chavent, Miguel Berbeira-Santana, Goenuel Seyit-Bremer, Sara Brignani, Rainer Kaufmann, Edward Lowe, Rüdiger Klein, Elena Seiradake〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a 〈em〉trans〈/em〉-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and 〈em〉in utero〈/em〉 electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313765-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 19 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): 〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): David M. Walker, Peter L. Freddolino, Rasika M. Harshey〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Christopher G. Parker, Matthew R. Pratt〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Yongchao Dou, Emily A. Kawaler, Daniel Cui Zhou, Marina A. Gritsenko, Chen Huang, Lili Blumenberg, Alla Karpova, Vladislav A. Petyuk, Sara R. Savage, Shankha Satpathy, Wenke Liu, Yige Wu, Chia-Feng Tsai, Bo Wen, Zhi Li, Song Cao, Jamie Moon, Zhiao Shi, MacIntosh Cornwell, Matthew A. Wyczalkowski〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Joanna Kalucka, Laura P.M.H. de Rooij, Jermaine Goveia, Katerina Rohlenova, Sébastien J. Dumas, Elda Meta, Nadine V. Conchinha, Federico Taverna, Laure-Anne Teuwen, Koen Veys, Melissa García-Caballero, Shawez Khan, Vincent Geldhof, Liliana Sokol, Rongyuan Chen, Lucas Treps, Mila Borri, Pauline de Zeeuw, Charlotte Dubois, Tobias K. Karakach〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Shan Zhao, Mihail Ivilinov Todorov, Ruiyao Cai, Rami AI -Maskari, Hanno Steinke, Elisabeth Kemter, Hongcheng Mai, Zhouyi Rong, Martin Warmer, Karen Stanic, Oliver Schoppe, Johannes Christian Paetzold, Benno Gesierich, Milagros N. Wong, Tobias B. Huber, Marco Duering, Oliver Thomas Bruns, Bjoern Menze, Jan Lipfert, Victor G. Puelles〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Pranay Dogra, Chiara Rancan, Wenji Ma, Marta Toth, Takashi Senda, Dustin J. Carpenter, Masaru Kubota, Rei Matsumoto, Puspa Thapa, Peter A. Szabo, Maya Meimei Li Poon, Jacky Li, Janice Arakawa-Hoyt, Yufeng Shen, Lawrence Fong, Lewis L. Lanier, Donna L. Farber〈/p〉

Description: 〈p〉Publication date: 6 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 3〈/p〉 〈p〉Author(s): Feng Zhou, Aurélia Emonet, Valérie Dénervaud Tendon, Peter Marhavy, Dousheng Wu, Thomas Lahaye, Niko Geldner〈/p〉

Description: 〈p〉Publication date: 6 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 3〈/p〉 〈p〉Author(s): David Gokhman, Nadav Mishol, Marc de Manuel, David de Juan, Jonathan Shuqrun, Eran Meshorer, Tomas Marques-Bonet, Yoel Rak, Liran Carmel〈/p〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Jiefu Li, Shuo Han, Hongjie Li, Namrata D. Udeshi, Tanya Svinkina, D.R. Mani, Chuanyun Xu, Ricardo Guajardo, Qijing Xie, Tongchao Li, David J. Luginbuhl, Bing Wu, Colleen N. McLaughlin, Anthony Xie, Pornchai Kaewsapsak, Stephen R. Quake, Steven A. Carr, Alice Y. Ting, Liqun Luo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Molecular interactions at the cellular interface mediate organized assembly of single cells into tissues and, thus, govern the development and physiology of multicellular organisms. Here, we developed a cell-type-specific, spatiotemporally resolved approach to profile cell-surface proteomes in intact tissues. Quantitative profiling of cell-surface proteomes of 〈em〉Drosophila〈/em〉 olfactory projection neurons (PNs) in pupae and adults revealed global downregulation of wiring molecules and upregulation of synaptic molecules in the transition from developing to mature PNs. A proteome-instructed 〈em〉in vivo〈/em〉 screen identified 20 cell-surface molecules regulating neural circuit assembly, many of which belong to evolutionarily conserved protein families not previously linked to neural development. Genetic analysis further revealed that the lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting, contributing to the formation of a precise olfactory map. These findings highlight the power of temporally resolved 〈em〉in situ〈/em〉 cell-surface proteomic profiling in discovering regulators of brain wiring.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313911-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 23 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 2〈/p〉 〈p〉Author(s): Sandra Catania, Phillip A. Dumesic, Harold Pimentel, Ammar Nasif, Caitlin I. Stoddard, Jordan E. Burke, Jolene K. Diedrich, Sophie Cook, Terrance Shea, Elizabeth Geinger, Robert Lintner, John R. Yates, Petra Hajkova, Geeta J. Narlikar, Christina A. Cuomo, Jonathan K. Pritchard, Hiten D. Madhani〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Cytosine methylation of DNA is a widespread modification of DNA that plays numerous critical roles. In the yeast 〈em〉Cryptococcus neoformans〈/em〉, CG methylation occurs in transposon-rich repeats and requires the DNA methyltransferase Dnmt5. We show that Dnmt5 displays exquisite maintenance-type specificity 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉 and utilizes similar 〈em〉in vivo〈/em〉 cofactors as the metazoan maintenance methylase Dnmt1. Remarkably, phylogenetic and functional analysis revealed that the ancestral species lost the gene for a 〈em〉de novo〈/em〉 methylase, DnmtX, between 50–150 mya. We examined how methylation has persisted since the ancient loss of DnmtX. Experimental and comparative studies reveal efficient replication of methylation patterns in 〈em〉C. neoformans〈/em〉, rare stochastic methylation loss and gain events, and the action of natural selection. We propose that an epigenome has been propagated for 〉50 million years through a process analogous to Darwinian evolution of the genome.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313741-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Fanny Matheis, Paul A. Muller, Christina L. Graves, Ilana Gabanyi, Zachary J. Kerner, Diego Costa-Borges, Tomasz Ahrends, Philip Rosenstiel, Daniel Mucida〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Enteric-associated neurons (EANs) are closely associated with immune cells and continuously monitor and modulate homeostatic intestinal functions, including motility and nutrient sensing. Bidirectional interactions between neuronal and immune cells are altered during disease processes such as neurodegeneration or irritable bowel syndrome. We investigated the effects of infection-induced inflammation on intrinsic EANs (iEANs) and the role of intestinal 〈em〉muscularis〈/em〉 macrophages (MMs) in this context. Using murine models of enteric infections, we observed long-term gastrointestinal symptoms, including reduced motility and loss of excitatory iEANs, which was mediated by a 〈em〉Nlrp6-〈/em〉 and 〈em〉Casp11-〈/em〉dependent mechanism, depended on infection history, and could be reversed by manipulation of the microbiota. MMs responded to luminal infection by upregulating a neuroprotective program via β〈sub〉2〈/sub〉-adrenergic receptor (β〈sub〉2〈/sub〉-AR) signaling and mediated neuronal protection through an arginase 1-polyamine axis. Our results identify a mechanism of neuronal death post-infection and point to a role for tissue-resident MMs in limiting neuronal damage.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313285-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Abigail Jarret, Ruaidhrí Jackson, Coco Duizer, Marc E. Healy, Jun Zhao, Joseph M. Rone, Piotr Bielecki, Esen Sefik, Manolis Roulis, Tyler Rice, Kisha N. Sivanathan, Ting Zhou, Angel G. Solis, Hanna Honcharova-Biletska, Karelia Vélez, Saskia Hartner, Jun Siong Low, Rihao Qu, Marcel R. de Zoete, Noah W. Palm〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence 〈em〉in situ〈/em〉 mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive 〈em〉Salmonella〈/em〉 typhimurium (〈em〉S.〈/em〉t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313789-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Devin Tauber, Gabriel Tauber, Anthony Khong, Briana Van Treeck, Jerry Pelletier, Roy Parker〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Stress granules are condensates of non-translating mRNAs and proteins involved in the stress response and neurodegenerative diseases. Stress granules form in part through intermolecular RNA-RNA interactions, and to better understand how RNA-based condensation occurs, we demonstrate that RNA is effectively recruited to the surfaces of RNA or RNP condensates 〈em〉in vitro〈/em〉. We demonstrate that, through ATP-dependent RNA binding, the DEAD-box protein eIF4A reduces RNA condensation 〈em〉in vitro〈/em〉 and limits stress granule formation in cells. This defines a function for eIF4A to limit intermolecular RNA-RNA interactions in cells. These results establish an important role for eIF4A, and potentially other DEAD-box proteins, as ATP-dependent RNA chaperones that limit the condensation of RNA, analogous to the function of proteins like HSP70 in combatting protein aggregates.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313935-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Zachary H. Harvey, Anupam K. Chakravarty, Raymond A. Futia, Daniel F. Jarosz〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Wenyan Jiang, Panos Oikonomou, Saeed Tavazoie〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Kun Wang, Qi Sun, Xiu Zhong, Mengxue Zeng, Huan Zeng, Xuyan Shi, Zilin Li, Yupeng Wang, Qiang Zhao, Feng Shao, Jingjin Ding〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Haopeng Xiao, Mark P. Jedrychowski, Devin K. Schweppe, Edward L. Huttlin, Qing Yu, David E. Heppner, Jiaming Li, Jiani Long, Evanna L. Mills, John Szpyt, Zhixiang He, Guangyan Du, Ryan Garrity, Anita Reddy, Laura Pontano Vaites, Joao A. Paulo, Tinghu Zhang, Nathanael S. Gray, Steven P. Gygi, Edward T. Chouchani〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Fan Hong, Duo Ma, Kaiyue Wu, Lida A. Mina, Rebecca C. Luiten, Yan Liu, Hao Yan, Alexander A. Green〈/p〉

Description: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Shuai Ma, Shuhui Sun, Lingling Geng, Moshi Song, Wei Wang, Yanxia Ye, Qianzhao Ji, Zhiran Zou, Si Wang, Xiaojuan He, Wei Li, Concepcion Rodriguez Esteban, Xiao Long, Guoji Guo, Piu Chan, Qi Zhou, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu〈/p〉

Description: 〈p〉Publication date: Available online 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Lou Beaulieu-Laroche, Marine Christin, Annmarie Donoghue, Francina Agosti, Noosha Yousefpour, Hugues Petitjean, Albena Davidova, Craig Stanton, Uzair Khan, Connor Dietz, Elise Faure, Tarheen Fatima, Amanda MacPherson, Stephanie Mouchbahani-Constance, Daniel G. Bisson, Lisbet Haglund, Jean A. Ouellet, Laura S. Stone, Jonathan Samson, Mary-Jo Smith〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Mototaka Suzuki, Matthew E. Larkum〈/p〉

Description: 〈p〉Publication date: Available online 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Sushant Kumar, Jonathan Warrell, Shantao Li, Patrick D. McGillivray, William Meyerson, Leonidas Salichos, Arif Harmanci, Alexander Martinez-Fundichely, Calvin W.Y. Chan, Morten Muhlig Nielsen, Lucas Lochovsky, Yan Zhang, Xiaotong Li, Shaoke Lou, Jakob Skou Pedersen, Carl Herrmann, Gad Getz, Ekta Khurana, Mark B. Gerstein〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Sandra Catania, Phillip A. Dumesic, Harold Pimentel, Ammar Nasif, Caitlin I. Stoddard, Jordan E. Burke, Jolene K. Diedrich, Sophie Cooke, Terrance Shea, Elizabeth Gienger, Robert Lintner, John R. Yates, Petra Hajkova, Geeta J. Narlikar, Christina A. Cuomo, Jonathan K. Pritchard, Hiten D. Madhani〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Jonathan M. Stokes, Kevin Yang, Kyle Swanson, Wengong Jin, Andres Cubillos-Ruiz, Nina M. Donghia, Craig R. MacNair, Shawn French, Lindsey A. Carfrae, Zohar Bloom-Ackerman, Victoria M. Tran, Anush Chiappino-Pepe, Ahmed H. Badran, Ian W. Andrews, Emma J. Chory, George M. Church, Eric D. Brown, Tommi S. Jaakkola, Regina Barzilay, James J. Collins〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Abigail Jarret, Ruaidhrí Jackson, Coco Duizer, Marc E. Healy, Jun Zhao, Joseph M. Rone, Piotr Bielecki, Esen Sefik, Manolis Roulis, Tyler Rice, Kisha N. Sivanathan, Ting Zhou, Angel G. Solis, Hanna Honcharova-Biletska, Karelia Vélez, Saskia Hartner, Jun Siong Low, Rihao Qu, Marcel R. de Zoete, Noah W. Palm〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Catherine S. Liou, Shannon J. Sirk, Camil A.C. Diaz, Andrew P. Klein, Curt R. Fischer, Steven K. Higginbottom, Amir Erez, Mohamed S. Donia, Justin L. Sonnenburg, Elizabeth S. Sattely〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Tamta Arakhamia, Christina E. Lee, Yari Carlomagno, Duc M. Duong, Sean R. Kundinger, Kevin Wang, Dewight Williams, Michael DeTure, Dennis W. Dickson, Casey N. Cook, Nicholas T. Seyfried, Leonard Petrucelli, Anthony W.P. Fitzpatrick〈/p〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Kimberly M. Cirelli, Diane G. Carnathan, Bartek Nogal, Jacob T. Martin, Oscar L. Rodriguez, Amit A. Upadhyay, Chiamaka A. Enemuo, Etse H. Gebru, Yury Choe, Federico Viviano, Catherine Nakao, Matthias G. Pauthner, Samantha Reiss, Christopher A. Cottrell, Melissa L. Smith, Raiza Bastidas, William Gibson, Amber N. Wolabaugh, Mariane B. Melo, Benjamin Cossette〈/p〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): David J. Clark, Saravana M. Dhanasekaran, Francesca Petralia, Jianbo Pan, Xiaoyu Song, Yingwei Hu, Felipe da Veiga Leprevost, Boris Reva, Tung-Shing M. Lih, Hui-Yin Chang, Weiping Ma, Chen Huang, Christopher J. Ricketts, Lijun Chen, Azra Krek, Yize Li, Dmitry Rykunov, Qing Kay Li, Lin S. Chen, Umut Ozbek〈/p〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Timothy J. Mitchison〈/p〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Michael D. Vahey, Daniel A. Fletcher〈/p〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Ju Eun Jeon, Jung-Gun Kim, Curt R. Fischer, Niraj Mehta, Cosima Dufour-Schroif, Kimberly Wemmer, Mary Beth Mudgett, Elizabeth Sattely〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉In response to biotic stress, plants produce suites of highly modified fatty acids that bear unusual chemical functionalities. Despite their chemical complexity and proposed roles in pathogen defense, little is known about the biosynthesis of decorated fatty acids in plants. Falcarindiol is a prototypical acetylenic lipid present in carrot, tomato, and celery that inhibits growth of fungi and human cancer cell lines. Using a combination of untargeted metabolomics and RNA sequencing, we discovered a biosynthetic gene cluster in tomato (〈em〉Solanum lycopersicum〈/em〉) required for falcarindiol production. By reconstituting initial biosynthetic steps in a heterologous host and generating transgenic pathway mutants in tomato, we demonstrate a direct role of the cluster in falcarindiol biosynthesis and resistance to fungal and bacterial pathogens in tomato leaves. This work reveals a mechanism by which plants sculpt their lipid pool in response to pathogens and provides critical insight into the complex biochemistry of alkynyl lipid production.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419313224-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 1〈/p〉 〈p〉Author(s): Vineet Augustine, Sangjun Lee, Yuki Oka〈/p〉 〈div〉〈p〉The function of central appetite neurons is instructing animals to ingest specific nutrient factors that the body needs. Emerging evidence suggests that individual appetite circuits for major nutrients—water, sodium, and food—operate on unique driving and quenching mechanisms. This review focuses on two aspects of appetite regulation. First, we describe the temporal relationship between appetite neuron activity and consumption behaviors. Second, we summarize ingestion-related satiation signals that differentially quench individual appetite circuits. We further discuss how distinct appetite and satiation systems for each factor may contribute to nutrient homeostasis from the functional and evolutional perspectives.〈/p〉〈/div〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): M. Zaeem Cader, Rodrigo Pereira de Almeida Rodrigues, James A. West, Gavin W. Sewell, Muhammad N. Md-Ibrahim, Stephanie Reikine, Giuseppe Sirago, Lukas W. Unger, Ana Belén Iglesias-Romero, Katharina Ramshorn, Lea-Maxie Haag, Svetlana Saveljeva, Jana-Fabienne Ebel, Philip Rosenstiel, Nicole C. Kaneider, James C. Lee, Trevor D. Lawley, Allan Bradley, Gordon Dougan, Yorgo Modis〈/p〉

Description: 〈p〉Publication date: 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 180, Issue 4〈/p〉 〈p〉Author(s): Christoph Kirst, Sophie Skriabine, Alba Vieites-Prado, Thomas Topilko, Paul Bertin, Gaspard Gerschenfeld, Florine Verny, Piotr Topilko, Nicolas Michalski, Marc Tessier-Lavigne, Nicolas Renier〈/p〉

Description: 〈p〉Publication date: Available online 13 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Mandeep Singh, Katherine J.L. Jackson, Jing J. Wang, Peter Schofield, Matt A. Field, David Koppstein, Timothy J. Peters, Deborah L. Burnett, Simone Rizzetto, Damien Nevoltris, Etienne Masle-Farquhar, Megan L. Faulks, Amanda Russell, Divya Gokal, Asami Hanioka, Keisuke Horikawa, Alexander D. Colella, Timothy K. Chataway, James Blackburn, Tim R. Mercer〈/p〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Meng Xu, Hong-Hai Xu, Yuan Lin, Xiangnan Sun, Li-Jing Wang, Zhe-Ping Fang, Xue-Han Su, Xiang-Jing Liang, Yang Hu, Zhi-Min Liu, Yuanxiong Cheng, Yuanyuan Wei, Jiabin Li, Li Li, Hong-Juan Liu, Zhiqiang Cheng, Na Tang, Chao Peng, Tingting Li, Tengfei Liu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Liver fibrosis is a very common condition seen in millions of patients with various liver diseases, and yet no effective treatments are available owing to poorly characterized molecular pathogenesis. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2) is a functional ligand of Tie1, a poorly characterized endothelial cell (EC)-specific orphan receptor. Upon binding to Tie1, LECT2 interrupts Tie1/Tie2 heterodimerization, facilitates Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits the migration and tube formations of EC. 〈em〉In vivo〈/em〉 studies showed that LECT2 overexpression inhibits portal angiogenesis, promotes sinusoid capillarization, and worsens fibrosis, whereas these changes were reversed in 〈em〉Lect2-KO〈/em〉 mice. Adeno-associated viral vector serotype 9 (AAV9)-LECT2 small hairpin RNA (shRNA) treatment significantly attenuates fibrosis. Upregulation of LECT2 is associated with advanced human liver fibrosis staging. We concluded that targeting LECT2/Tie1 signaling may represent a potential therapeutic target for liver fibrosis, and serum LECT2 level may be a potential biomarker for the screening and diagnosis of liver fibrosis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741930786X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Francisco J. Roca, Laura J. Whitworth, Sarah Redmond, Ana A. Jones, Lalita Ramakrishnan〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with 〈em〉Mycobacterium marinum〈/em〉 or 〈em〉Mycobacterium tuberculosis〈/em〉, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741930892X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Gorka Lasso, Sandra V. Mayer, Evandro R. Winkelmann, Tim Chu, Oliver Elliot, Juan Angel Patino-Galindo, Kernyu Park, Raul Rabadan, Barry Honig, Sagi D. Shapira〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉While knowledge of protein-protein interactions (PPIs) is critical for understanding virus-host relationships, limitations on the scalability of high-throughput methods have hampered their identification beyond a number of well-studied viruses. Here, we implement an 〈em〉in silico〈/em〉 computational framework (pathogen host interactome prediction using structure similarity [P-HIPSTer]) that employs structural information to predict ∼282,000 pan viral-human PPIs with an experimental validation rate of ∼76%. In addition to rediscovering known biology, P-HIPSTer has yielded a series of new findings: the discovery of shared and unique machinery employed across human-infecting viruses, a likely role for ZIKV-ESR1 interactions in modulating viral replication, the identification of PPIs that discriminate between human papilloma viruses (HPVs) with high and low oncogenic potential, and a structure-enabled history of evolutionary selective pressure imposed on the human proteome. Further, P-HIPSTer enables discovery of previously unappreciated cellular circuits that act on human-infecting viruses and provides insight into experimentally intractable viruses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419308931-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Sarah Canetta, Christoph Kellendonk〈/p〉 〈div〉〈p〉Can we one day prevent mental disorders? Mukherjee et al. (2019) use a genetic mouse model of schizophrenia-risk with established abnormalities in adult hippocampal-prefrontal circuit function and cognitive behaviors to identify circuit-specific treatments during adolescence that prevent the onset of the adult deficits.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 29 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Jianke Gong, Jinzhi Liu, Elizabeth A. Ronan, Feiteng He, Wei Cai, Mahar Fatima, Wenyuan Zhang, Hankyu Lee, Zhaoyu Li, Gun-Ho Kim, Kevin P. Pipe, Bo Duan, Jianfeng Liu, X.Z. Shawn Xu〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉In search of the molecular identities of cold-sensing receptors, we carried out an unbiased genetic screen for cold-sensing mutants in 〈em〉C. elegans〈/em〉 and isolated a mutant allele of 〈em〉glr-3〈/em〉 gene that encodes a kainate-type glutamate receptor. While glutamate receptors are best known to transmit chemical synaptic signals in the CNS, we show that GLR-3 senses cold in the peripheral sensory neuron ASER to trigger cold-avoidance behavior. GLR-3 transmits cold signals via G protein signaling independently of its glutamate-gated channel function, suggesting GLR-3 as a metabotropic cold receptor. The vertebrate GLR-3 homolog GluK2 from zebrafish, mouse, and human can all function as a cold receptor in heterologous systems. Mouse DRG sensory neurons express GluK2, and GluK2 knockdown in these neurons suppresses their sensitivity to cold but not cool temperatures. Our study identifies an evolutionarily conserved cold receptor, revealing that a central chemical receptor unexpectedly functions as a thermal receptor in the periphery.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419308335-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 22 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 5〈/p〉 〈p〉Author(s): Takashi Akera, Emily Trimm, Michael A. Lampson〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Asymmetric division in female meiosis creates selective pressure favoring selfish centromeres that bias their transmission to the egg. This centromere drive can explain the paradoxical rapid evolution of both centromere DNA and centromere-binding proteins despite conserved centromere function. Here, we define a molecular pathway linking expanded centromeres to histone phosphorylation and recruitment of microtubule destabilizing factors, leading to detachment of selfish centromeres from spindle microtubules that would direct them to the polar body. Exploiting centromere divergence between species, we show that selfish centromeres in two hybrid mouse models use the same molecular pathway but modulate it differently to enrich destabilizing factors. Our results indicate that increasing microtubule destabilizing activity is a general strategy for drive in both models, but centromeres have evolved distinct mechanisms to increase that activity. Furthermore, we show that drive depends on slowing meiotic progression, suggesting that selfish centromeres can be suppressed by regulating meiotic timing.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307408-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Erick Riquelme, Yu Zhang, Liangliang Zhang, Maria Montiel, Michelle Zoltan, Wenli Dong, Pompeyo Quesada, Ismet Sahin, Vidhi Chandra, Anthony San Lucas, Paul Scheet, Hanwen Xu, Samir M. Hanash, Lei Feng, Jared K. Burks, Kim-Anh Do, Christine B. Peterson, Deborah Nejman, Ching-Wei D. Tzeng, Michael P. Kim〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (〈em〉Pseudoxanthomonas〈/em〉-〈em〉Streptomyces〈/em〉-〈em〉Saccharopolyspora〈/em〉-〈em〉Bacillus clausii〈/em〉) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.〈/p〉〈/div〉 〈div〉 〈h6〉Video Abstract〈/h6〉 〈p〉〈/p〉 〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307731-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Nuria Domínguez-Iturza, Claudia Bagni〈/p〉 〈div〉〈p〉Autism spectrum disorder (ASD) is prevalent, complex, and heterogeneous, and currently there is no cure. Identifying shared mechanisms across the ASD spectrum is of utmost importance for therapeutic intervention. Orefice et al. show that tackling the GABA〈sub〉A〈/sub〉 receptor pathway in the peripheral somatosensory system in various ASD mouse models rescues core ASD-like phenotypes.〈/p〉〈/div〉

Description: 〈p〉Publication date: 22 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 5〈/p〉 〈p〉Author(s): Hila Sberro, Brayon J. Fremin, Soumaya Zlitni, Fredrik Edfors, Nicholas Greenfield, Michael P. Snyder, Georgios A. Pavlopoulos, Nikos C. Kyrpides, Ami S. Bhatt〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Small proteins are traditionally overlooked due to computational and experimental difficulties in detecting them. To systematically identify small proteins, we carried out a comparative genomics study on 1,773 human-associated metagenomes from four different body sites. We describe 〉4,000 conserved protein families, the majority of which are novel; ∼30% of these protein families are predicted to be secreted or transmembrane. Over 90% of the small protein families have no known domain and almost half are not represented in reference genomes. We identify putative housekeeping, mammalian-specific, defense-related, and protein families that are likely to be horizontally transferred. We provide evidence of transcription and translation for a subset of these families. Our study suggests that small proteins are highly abundant and those of the human microbiome, in particular, may perform diverse functions that have not been previously reported.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307810-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Sergey Stolyar, Christopher J. Marx〈/p〉 〈div〉〈p〉Microbes in the same community but with distinct niches can have unique long stretches of perfect sequence identity due to recent genetic exchange. Arevalo et al. (2019) use this as a starting point for defining ecologically-relevant populations within a community and to identify the genes that appear to be driving divergence between populations.〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Tomasz Kula, Mohammad H. Dezfulian, Charlotte I. Wang, Nouran S. Abdelfattah, Zachary C. Hartman, Kai W. Wucherpfennig, Herbert Kim Lyerly, Stephen J. Elledge〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307743-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Sujatha Jagannathan, Srinivas Ramachandran, Olivia S. Rissland〈/p〉 〈div〉〈p〉In this issue of 〈em〉Cell〈/em〉, Cassidy et al. (2019) show that, in 〈em〉Drosophila melanogaster〈/em〉, developmental abnormalities resulting from loss of repressors such as microRNAs can be suppressed by slow metabolism. They additionally provide insight into the underlying mechanism that connects metabolic state with developmental outcomes.〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Patrick-Simon Welz, Valentina M. Zinna, Aikaterini Symeonidi, Kevin B. Koronowski, Kenichiro Kinouchi, Jacob G. Smith, Inés Marín Guillén, Andrés Castellanos, Stephen Furrow, Ferrán Aragón, Georgiana Crainiciuc, Neus Prats, Juan Martín Caballero, Andrés Hidalgo, Paolo Sassone-Corsi, Salvador Aznar Benitah〈/p〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Elizabeth K. Ruzzo, Laura Pérez-Cano, Jae-Yoon Jung, Lee-kai Wang, Dorna Kashef-Haghighi, Chris Hartl, Chanpreet Singh, Jin Xu, Jackson N. Hoekstra, Olivia Leventhal, Virpi M. Leppä, Michael J. Gandal, Kelley Paskov, Nate Stockham, Damon Polioudakis, Jennifer K. Lowe, David A. Prober, Daniel H. Geschwind, Dennis P. Wall〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the 〈em〉de novo〈/em〉 and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of 〈em〉DLG2〈/em〉 and 〈em〉NR3C2〈/em〉. Loss of 〈em〉nr3c2〈/em〉 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307809-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 22 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 5〈/p〉 〈p〉Author(s): Laila El Khattabi, Haiyan Zhao, Jens Kalchschmidt, Natalie Young, Seolkyoung Jung, Peter Van Blerkom, Philippe Kieffer-Kwon, Kyong-Rim Kieffer-Kwon, Solji Park, Xiang Wang, Jordan Krebs, Subhash Tripathi, Noboru Sakabe, Débora R. Sobreira, Su-Chen Huang, Suhas S.P. Rao, Nathanael Pruett, Daniel Chauss, Erica Sadler, Andrea Lopez〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉While Mediator plays a key role in eukaryotic transcription, little is known about its mechanism of action. This study combines CRISPR-Cas9 genetic screens, degron assays, Hi-C, and cryoelectron microscopy (cryo-EM) to dissect the function and structure of mammalian Mediator (mMED). Deletion analyses in B, T, and embryonic stem cells (ESC) identified a core of essential subunits required for Pol II recruitment genome-wide. Conversely, loss of non-essential subunits mostly affects promoters linked to multiple enhancers. Contrary to current models, however, mMED and Pol II are dispensable to physically tether regulatory DNA, a topological activity requiring architectural proteins. Cryo-EM analysis revealed a conserved core, with non-essential subunits increasing structural complexity of the tail module, a primary transcription factor target. Changes in tail structure markedly increase Pol II and kinase module interactions. We propose that Mediator’s structural pliability enables it to integrate and transmit regulatory signals and act as a functional, rather than an architectural bridge, between promoters and enhancers.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307767-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Lara Szewczak〈/p〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Viraj R. Sanghvi, Josef Leibold, Marco Mina, Prathibha Mohan, Marjan Berishaj, Zhuoning Li, Matthew M. Miele, Nathalie Lailler, Chunying Zhao, Elisa de Stanchina, Agnes Viale, Leila Akkari, Scott W. Lowe, Giovanni Ciriello, Ronald C. Hendrickson, Hans-Guido Wendel〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)—a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and 〈em〉Keap1〈/em〉 inactivation depends on FN3K 〈em〉in vivo〈/em〉. N-acetyl cysteine treatment partially rescues the effects of 〈em〉FN3K〈/em〉 loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741930830X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Joseph L. Benci, Lexus R. Johnson, Ruth Choa, Yuanming Xu, Jingya Qiu, Zilu Zhou, Bihui Xu, Darwin Ye, Katherine L. Nathanson, Carl H. June, E. John Wherry, Nancy R. Zhang, Hemant Ishwaran, Matthew D. Hellmann, Jedd D. Wolchok, Taku Kambayashi, Andy J. Minn〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (T〈sub〉EX〈/sub〉). In tumors with favorable antigenicity, these T〈sub〉EX〈/sub〉 mediate rejection. In tumors with neoantigen or MHC-I loss, T〈sub〉EX〈/sub〉 instead utilize IFNG to drive maturation of innate immune cells, including a PD1〈sup〉+〈/sup〉TRAIL〈sup〉+〈/sup〉 ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307846-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Lauren L. Orefice, Jacqueline R. Mosko, Danielle T. Morency, Michael F. Wells, Aniqa Tasnim, Shawn M. Mozeika, Mengchen Ye, Anda M. Chirila, Alan J. Emanuel, Genelle Rankin, Ryann M. Fame, Maria K. Lehtinen, Guoping Feng, David D. Ginty〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Somatosensory over-reactivity is common among patients with autism spectrum disorders (ASDs) and is hypothesized to contribute to core ASD behaviors. However, effective treatments for sensory over-reactivity and ASDs are lacking. We found distinct somatosensory neuron pathophysiological mechanisms underlie tactile abnormalities in different ASD mouse models and contribute to some ASD-related behaviors. Developmental loss of ASD-associated genes 〈em〉Shank3〈/em〉 or 〈em〉Mecp2〈/em〉 in peripheral mechanosensory neurons leads to region-specific brain abnormalities, revealing links between developmental somatosensory over-reactivity and the genesis of aberrant behaviors. Moreover, acute treatment with a peripherally restricted GABA〈sub〉A〈/sub〉 receptor agonist that acts directly on mechanosensory neurons reduced tactile over-reactivity in six distinct ASD models. Chronic treatment of 〈em〉Mecp2〈/em〉 and 〈em〉Shank3〈/em〉 mutant mice improved body condition, some brain abnormalities, anxiety-like behaviors, and some social impairments but not memory impairments, motor deficits, or overgrooming. Our findings reveal a potential therapeutic strategy targeting peripheral mechanosensory neurons to treat tactile over-reactivity and select ASD-related behaviors.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307913-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Philip Arevalo, David VanInsberghe, Joseph Elsherbini, Jeff Gore, Martin F. Polz〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Delineating ecologically meaningful populations among microbes is important for identifying their roles in environmental and host-associated microbiomes. Here, we introduce a metric of recent gene flow, which when applied to co-existing microbes, identifies congruent genetic and ecological units separated by strong gene flow discontinuities from their next of kin. We then develop a pipeline to identify genome regions within these units that show differential adaptation and allow mapping of populations onto environmental variables or host associations. Using this reverse ecology approach, we show that the human commensal bacterium 〈em〉Ruminococcus gnavus〈/em〉 breaks up into sharply delineated populations that show different associations with health and disease. Defining populations by recent gene flow in this way will facilitate the analysis of bacterial and archaeal genomes using ecological and evolutionary theory developed for plants and animals, thus allowing for testing unifying principles across all biology.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307366-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 15 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Xiaoliang Sunney Xie〈/p〉 〈div〉〈p〉In response to recent anti-Chinese sentiment in the US, Sunney Xie uses his own experiences to assert that American ideals should not be replaced by nationalism and populism and that everybody wins in Sino-US scientific collaborations, contrary to what Americans are led to believe: that China is the sole beneficiary.〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Justin G. English, Reid H.J. Olsen, Katherine Lansu, Michael Patel, Karoline White, Adam S. Cockrell, Darshan Singh, Ryan T. Strachan, Daniel Wacker, Bryan L. Roth〈/p〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Kathryn M. Hastie, Robert W. Cross, Stephanie S. Harkins, Michelle A. Zandonatti, Anatoliy P. Koval, Megan L. Heinrich, Megan M. Rowland, James E. Robinson, Thomas W. Geisbert, Robert F. Garry, Luis M. Branco, Erica Ollmann Saphire〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Lassa virus (LASV) causes hemorrhagic fever and is endemic in West Africa. Protective antibody responses primarily target the LASV surface glycoprotein (GPC), and GPC-B competition group antibodies often show potent neutralizing activity in humans. However, which features confer potent and broadly neutralizing antibody responses is unclear. Here, we compared three crystal structures of LASV GPC complexed with GPC-B antibodies of varying neutralization potency. Each GPC-B antibody recognized an overlapping epitope involved in binding of two adjacent GPC monomers and preserved the prefusion trimeric conformation. Differences among GPC-antibody interactions highlighted specific residues that enhance neutralization. Using structure-guided amino acid substitutions, we increased the neutralization potency and breadth of these antibodies to include all major LASV lineages. The ability to define antibody residues that allow potent and broad neutralizing activity, together with findings from analyses of inferred germline precursors, is critical to develop potent therapeutics and for vaccine design and assessment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307858-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Bruno Hudry, Eva de Goeij, Alessandro Mineo, Pedro Gaspar, Dafni Hadjieconomou, Chris Studd, Joao B. Mokochinski, Holger B. Kramer, Pierre-Yves Plaçais, Thomas Preat, Irene Miguel-Aliaga〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of 〈em〉Drosophila melanogaster〈/em〉 to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419307962-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 8 August 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 178, Issue 4〈/p〉 〈p〉Author(s): Simon H. Ye, Katherine J. Siddle, Daniel J. Park, Pardis C. Sabeti〈/p〉 〈div〉〈p〉Metagenomic sequencing is revolutionizing the detection and characterization of microbial species, and a wide variety of software tools are available to perform taxonomic classification of these data. The fast pace of development of these tools and the complexity of metagenomic data make it important that researchers are able to benchmark their performance. Here, we review current approaches for metagenomic analysis and evaluate the performance of 20 metagenomic classifiers using simulated and experimental datasets. We describe the key metrics used to assess performance, offer a framework for the comparison of additional classifiers, and discuss the future of metagenomic data analysis.〈/p〉〈/div〉

Description: 〈p〉Publication date: Available online 28 March 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell〈/p〉 〈p〉Author(s): Kristine Werling, W. Robert Shaw, Maurice A. Itoe, Kathleen A. Westervelt, Perrine Marcenac, Douglas G. Paton, Duo Peng, Naresh Singh, Andrea L. Smidler, Adam South, Amy A. Deik, Liliana Mancio-Silva, Allison R. Demas, Sandra March, Eric Calvo, Sangeeta N. Bhatia, Clary B. Clish, Flaminia Catteruccia〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transmission of malaria parasites occurs when a female 〈em〉Anopheles〈/em〉 mosquito feeds on an infected host to acquire nutrients for egg development. How parasites are affected by oogenetic processes, principally orchestrated by the steroid hormone 20-hydroxyecdysone (20E), remains largely unknown. Here we show that 〈em〉Plasmodium falciparum〈/em〉 development is intimately but not competitively linked to processes shaping 〈em〉Anopheles gambiae〈/em〉 reproduction. We unveil a 20E-mediated positive correlation between egg and oocyst numbers; impairing oogenesis by multiple 20E manipulations decreases parasite intensities. These manipulations, however, accelerate 〈em〉Plasmodium〈/em〉 growth rates, allowing sporozoites to become infectious sooner. Parasites exploit mosquito lipids for faster growth, but they do so without further affecting egg development. These results suggest that 〈em〉P. falciparum〈/em〉 has adopted a non-competitive evolutionary strategy of resource exploitation to optimize transmission while minimizing fitness costs to its mosquito vector. Our findings have profound implications for currently proposed control strategies aimed at suppressing mosquito populations.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419302193-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〈/p〉 〈p〉Author(s): Ben Zhou, Johannes Kreuzer, Caroline Kumsta, Lianfeng Wu, Kimberli J. Kamer, Lucydalila Cedillo, Yuyao Zhang, Sainan Li, Michael C. Kacergis, Christopher M. Webster, Geza Fejes-Toth, Aniko Naray-Fejes-Toth, Sudeshna Das, Malene Hansen, Wilhelm Haas, Alexander A. Soukas〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Autophagy is required in diverse paradigms of lifespan extension, leading to the prevailing notion that autophagy is beneficial for longevity. However, why autophagy is harmful in certain contexts remains unexplained. Here, we show that mitochondrial permeability defines the impact of autophagy on aging. Elevated autophagy unexpectedly shortens lifespan in 〈em〉C. elegans〈/em〉 lacking serum/glucocorticoid regulated kinase-1 (〈em〉sgk-1〈/em〉) because of increased mitochondrial permeability. In 〈em〉sgk-1〈/em〉 mutants, reducing levels of autophagy or mitochondrial permeability transition pore (mPTP) opening restores normal lifespan. Remarkably, low mitochondrial permeability is required across all paradigms examined of autophagy-dependent lifespan extension. Genetically induced mPTP opening blocks autophagy-dependent lifespan extension resulting from caloric restriction or loss of germline stem cells. Mitochondrial permeability similarly transforms autophagy into a destructive force in mammals, as liver-specific 〈em〉Sgk〈/em〉 knockout mice demonstrate marked enhancement of hepatocyte autophagy, mPTP opening, and death with ischemia/reperfusion injury. Targeting mitochondrial permeability may maximize benefits of autophagy in aging.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741930162X-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〈/p〉 〈p〉Author(s): Jared A.M. Bard, Charlene Bashore, Ken C. Dong, Andreas Martin〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉The 26S proteasome is the principal macromolecular machine responsible for protein degradation in eukaryotes. However, little is known about the detailed kinetics and coordination of the underlying substrate-processing steps of the proteasome, and their correlation with observed conformational states. Here, we used reconstituted 26S proteasomes with unnatural amino-acid-attached fluorophores in a series of FRET- and anisotropy-based assays to probe substrate-proteasome interactions, the individual steps of the processing pathway, and the conformational state of the proteasome itself. We develop a complete kinetic picture of proteasomal degradation, which reveals that the engagement steps prior to substrate commitment are fast relative to subsequent deubiquitination, translocation, and unfolding. Furthermore, we find that non-ideal substrates are rapidly rejected by the proteasome, which thus employs a kinetic proofreading mechanism to ensure degradation fidelity and substrate prioritization.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419302144-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〈/p〉 〈p〉Author(s): Summer B. Thyme, Lindsey M. Pieper, Eric H. Li, Shristi Pandey, Yiqun Wang, Nathan S. Morris, Carrie Sha, Joo Won Choi, Kristian J. Herrera, Edward R. Soucy, Steve Zimmerman, Owen Randlett, Joel Greenwood, Steven A. McCarroll, Alexander F. Schier〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter 〈em〉cnnm2〈/em〉 and the translational repressor 〈em〉gigyf2〈/em〉, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor 〈em〉znf536〈/em〉 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419301114-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〈/p〉 〈p〉Author(s): Daniel A. Berg, Yijing Su, Dennisse Jimenez-Cyrus, Aneek Patel, Nancy Huang, David Morizet, Stephanie Lee, Reeti Shah, Francisca Rojas Ringeling, Rajan Jain, Jonathan A. Epstein, Qing-Feng Wu, Stefan Canzar, Guo-Li Ming, Hongjun Song, Allison M. Bond〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉New neurons arise from quiescent adult neural progenitors throughout life in specific regions of the mammalian brain. Little is known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx〈sup〉+〈/sup〉 precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give rise to proliferative Hopx〈sup〉+〈/sup〉 neural progenitors in the primitive dentate region, and they, in turn, generate granule neurons, but not other neurons, throughout development and then transition into Hopx〈sup〉+〈/sup〉 quiescent radial glial-like neural progenitors during an early postnatal period. RNA-seq and ATAC-seq analyses of Hopx〈sup〉+〈/sup〉 embryonic, early postnatal, and adult dentate neural progenitors further reveal common molecular and epigenetic signatures and developmental dynamics. Together, our findings support a “continuous” model wherein a common neural progenitor population exclusively contributes to dentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelong extension of development that maintains heightened plasticity in the mammalian hippocampus.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741930159X-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〈/p〉 〈p〉Author(s): Ritesh Ranjan Pal, Amit K. Baidya, Gideon Mamou, Saurabh Bhattacharya, Yaakov Socol, Simi Kobi, Naama Katsowich, Sigal Ben-Yehuda, Ilan Rosenshine〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Microbiota and intestinal epithelium restrict pathogen growth by rapid nutrient consumption. We investigated how pathogens circumvent this obstacle to colonize the host. Utilizing enteropathogenic 〈em〉E. coli〈/em〉 (EPEC), we show that host-attached bacteria obtain nutrients from infected host cell in a process we termed host nutrient extraction (HNE). We identified an inner-membrane protein complex, henceforth termed CORE, as necessary and sufficient for HNE. The CORE is a key component of the EPEC injectisome, however, here we show that it supports the formation of an alternative structure, composed of membranous nanotubes, protruding from the EPEC surface to directly contact the host. The injectisome and flagellum are evolutionarily related, both containing conserved COREs. Remarkably, CORE complexes of diverse ancestries, including distant flagellar COREs, could rescue HNE capacity of EPEC lacking its native CORE. Our results support the notion that HNE is a widespread virulence strategy, enabling pathogens to thrive in competitive niches.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419302041-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〈/p〉 〈p〉Author(s): Mark J. Wagner, Tony Hyun Kim, Jonathan Kadmon, Nghia D. Nguyen, Surya Ganguli, Mark J. Schnitzer, Liqun Luo〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Throughout mammalian neocortex, layer 5 pyramidal (L5) cells project via the pons to a vast number of cerebellar granule cells (GrCs), forming a fundamental pathway. Yet, it is unknown how neuronal dynamics are transformed through the L5→GrC pathway. Here, by directly comparing premotor L5 and GrC activity during a forelimb movement task using dual-site two-photon Ca〈sup〉2+〈/sup〉 imaging, we found that in expert mice, L5 and GrC dynamics were highly similar. L5 cells and GrCs shared a common set of task-encoding activity patterns, possessed similar diversity of responses, and exhibited high correlations comparable to local correlations among L5 cells. Chronic imaging revealed that these dynamics co-emerged in cortex and cerebellum over learning: as behavioral performance improved, initially dissimilar L5 cells and GrCs converged onto a shared, low-dimensional, task-encoding set of neural activity patterns. Thus, a key function of cortico-cerebellar communication is the propagation of shared dynamics that emerge during learning.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867419301680-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Lilan You, Jun Ma, Jiuyu Wang, Daria Artamonova, Min Wang, Liang Liu, Hua Xiang, Konstantin Severinov, Xinzheng Zhang, Yanli Wang〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Csm, a type III-A CRISPR-Cas interference complex, is a CRISPR RNA (crRNA)-guided RNase that also possesses target RNA-dependent DNase and cyclic oligoadenylate (cOA) synthetase activities. However, the structural features allowing target RNA-binding-dependent activation of DNA cleavage and cOA generation remain unknown. Here, we report the structure of Csm in complex with crRNA together with structures of cognate or non-cognate target RNA bound Csm complexes. We show that depending on complementarity with the 5′ tag of crRNA, the 3′ anti-tag region of target RNA binds at two distinct sites of the Csm complex. Importantly, the interaction between the non-complementary anti-tag region of cognate target RNA and Csm1 induces a conformational change at the Csm1 subunit that allosterically activates DNA cleavage and cOA generation. Together, our structural studies provide crucial insights into the mechanistic processes required for crRNA-meditated sequence-specific RNA cleavage, RNA target-dependent non-specific DNA cleavage, and cOA generation.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741831451X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Julien Boudet, Jean-Christophe Devillier, Thomas Wiegand, Loic Salmon, Beat H. Meier, Georg Lipps, Frédéric H.-T. Allain〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Primases have a fundamental role in DNA replication. They synthesize a primer that is then extended by DNA polymerases. Archaeoeukaryotic primases require for synthesis a catalytic and an accessory domain, the exact contribution of the latter being unresolved. For the pRN1 archaeal primase, this domain is a 115-amino acid helix bundle domain (HBD). Our structural investigations of this small HBD by liquid- and solid-state nuclear magnetic resonance (NMR) revealed that only the HBD binds the DNA template. DNA binding becomes sequence-specific after a major allosteric change in the HBD, triggered by the binding of two nucleotide triphosphates. The spatial proximity of the two nucleotides and the DNA template in the quaternary structure of the HBD strongly suggests that this small domain brings together the substrates to prepare the first catalytic step of primer synthesis. This efficient mechanism is likely general for all archaeoeukaryotic primases.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315563-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Kareem N. Mohni, Sarah R. Wessel, Runxiang Zhao, Andrea C. Wojciechowski, Jessica W. Luzwick, Hillary Layden, Brandt F. Eichman, Petria S. Thompson, Kavi P.M. Mehta, David Cortez〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Abasic sites are one of the most common DNA lesions. All known abasic site repair mechanisms operate only when the damage is in double-stranded DNA. Here, we report the discovery of 5-hydroxymethylcytosine (5hmC) binding, ESC-specific (HMCES) as a sensor of abasic sites in single-stranded DNA. HMCES acts at replication forks, binds PCNA and single-stranded DNA, and generates a DNA-protein crosslink to shield abasic sites from error-prone processing. This unusual HMCES DNA-protein crosslink intermediate is resolved by proteasome-mediated degradation. Acting as a suicide enzyme, HMCES prevents translesion DNA synthesis and the action of endonucleases that would otherwise generate mutations and double-strand breaks. HMCES is evolutionarily conserved in all domains of life, and its biochemical properties are shared with its 〈em〉E. coli〈/em〉 ortholog. Thus, HMCES is an ancient DNA lesion recognition protein that preserves genome integrity by promoting error-free repair of abasic sites in single-stranded DNA.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418314545-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Justin E. Silpe, Bonnie L. Bassler〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉〈em〉Vibrio cholerae〈/em〉 uses a quorum-sensing (QS) system composed of the autoinducer 3,5-dimethylpyrazin-2-ol (DPO) and receptor VqmA (VqmA〈sub〉Vc〈/sub〉), which together repress genes for virulence and biofilm formation. 〈em〉vqmA〈/em〉 genes exist in 〈em〉Vibrio〈/em〉 and in one vibriophage, VP882. Phage-encoded VqmA (VqmA〈sub〉Phage〈/sub〉) binds to host-produced DPO, launching the phage lysis program via an antirepressor that inactivates the phage repressor by sequestration. The antirepressor interferes with repressors from related phages. Like phage VP882, these phages encode DNA-binding proteins and partner antirepressors, suggesting that they, too, integrate host-derived information into their lysis-lysogeny decisions. VqmA〈sub〉Phage〈/sub〉 activates the host VqmA〈sub〉Vc〈/sub〉 regulon, whereas VqmA〈sub〉Vc〈/sub〉 cannot induce phage-mediated lysis, suggesting an asymmetry whereby the phage influences host QS while enacting its own lytic-lysogeny program without interference. We reprogram phages to activate lysis in response to user-defined cues. Our work shows that a phage, causing bacterial infections, and 〈em〉V. cholerae〈/em〉, causing human infections, rely on the same signal molecule for pathogenesis.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418314582-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Joseph Rodriguez, Gang Ren, Christopher R. Day, Keji Zhao, Carson C. Chow, Daniel R. Larson〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Transcriptional regulation in metazoans occurs through long-range genomic contacts between enhancers and promoters, and most genes are transcribed in episodic “bursts” of RNA synthesis. To understand the relationship between these two phenomena and the dynamic regulation of genes in response to upstream signals, we describe the use of live-cell RNA imaging coupled with Hi-C measurements and dissect the endogenous regulation of the estrogen-responsive 〈em〉TFF1〈/em〉 gene. Although 〈em〉TFF1〈/em〉 is highly induced, we observe short active periods and variable inactive periods ranging from minutes to days. The heterogeneity in inactive times gives rise to the widely observed “noise” in human gene expression and explains the distribution of protein levels in human tissue. We derive a mathematical model of regulation that relates transcription, chromosome structure, and the cell’s ability to sense changes in estrogen and predicts that hypervariability is largely dynamic and does not reflect a stable biological state.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315186-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Jan Jakub Żylicz, Aurélie Bousard, Kristina Žumer, Francois Dossin, Eusra Mohammad, Simão Teixeira da Rocha, Björn Schwalb, Laurène Syx, Florent Dingli, Damarys Loew, Patrick Cramer, Edith Heard〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉During development, the precise relationships between transcription and chromatin modifications often remain unclear. We use the X chromosome inactivation (XCI) paradigm to explore the implication of chromatin changes in gene silencing. Using female mouse embryonic stem cells, we initiate XCI by inducing 〈em〉Xist〈/em〉 and then monitor the temporal changes in transcription and chromatin by allele-specific profiling. This reveals histone deacetylation and H2AK119 ubiquitination as the earliest chromatin alterations during XCI. We show that HDAC3 is pre-bound on the X chromosome and that, upon 〈em〉Xist〈/em〉 coating, its activity is required for efficient gene silencing. We also reveal that first PRC1-associated H2AK119Ub and then PRC2-associated H3K27me3 accumulate initially at large intergenic domains that can then spread into genes only in the context of histone deacetylation and gene silencing. Our results reveal the hierarchy of chromatin events during the initiation of XCI and identify key roles for chromatin in the early steps of transcriptional silencing.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315666-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 7 February 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issue 4〈/p〉 〈p〉Author(s): Hanjie Li, Anne M. van der Leun, Ido Yofe, Yaniv Lubling, Dikla Gelbard-Solodkin, Alexander C.J. van Akkooi, Marlous van den Braber, Elisa A. Rozeman, John B.A.G. Haanen, Christian U. Blank, Hugo M. Horlings, Eyal David, Yael Baran, Akhiad Bercovich, Aviezer Lifshitz, Ton N. Schumacher, Amos Tanay, Ido Amit〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Tumor immune cell compositions play a major role in response to immunotherapy, but the heterogeneity and dynamics of immune infiltrates in human cancer lesions remain poorly characterized. Here, we identify conserved intratumoral CD4 and CD8 T cell behaviors in scRNA-seq data from 25 melanoma patients. We discover a large population of CD8 T cells showing continuous progression from an early effector “transitional” into a dysfunctional T cell state. CD8 T cells that express a complete cytotoxic gene set are rare, and TCR sharing data suggest their independence from the transitional and dysfunctional cell states. Notably, we demonstrate that dysfunctional T cells are the major intratumoral proliferating immune cell compartment and that the intensity of the dysfunctional signature is associated with tumor reactivity. Our data demonstrate that CD8 T cells previously defined as exhausted are in fact a highly proliferating, clonal, and dynamically differentiating cell population within the human tumor microenvironment.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S009286741831568X-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 24 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issue 3〈/p〉 〈p〉Author(s): Jonathan J. Ruprecht, Martin S. King, Thomas Zögg, Antoniya A. Aleksandrova, Els Pardon, Paul G. Crichton, Jan Steyaert, Edmund R.S. Kunji〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family.〈/p〉〈/div〉 〈div〉 〈h6〉Video Abstract〈/h6〉 〈p〉〈/p〉 〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315174-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Justin L. Sparks, Gheorghe Chistol, Alan O. Gao, Markus Räschle, Nicolai B. Larsen, Matthias Mann, Julien P. Duxin, Johannes C. Walter〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Covalent DNA-protein cross-links (DPCs) impede replication fork progression and threaten genome integrity. Using 〈em〉Xenopus〈/em〉 egg extracts, we previously showed that replication fork collision with DPCs causes their proteolysis, followed by translesion DNA synthesis. We show here that when DPC proteolysis is blocked, the replicative DNA helicase CMG (CDC45, MCM2-7, GINS), which travels on the leading strand template, bypasses an intact leading strand DPC. Single-molecule imaging reveals that GINS does not dissociate from CMG during bypass and that CMG slows dramatically after bypass, likely due to uncoupling from the stalled leading strand. The DNA helicase RTEL1 facilitates bypass, apparently by generating single-stranded DNA beyond the DPC. The absence of RTEL1 impairs DPC proteolysis, suggesting that CMG must bypass the DPC to enable proteolysis. Our results suggest a mechanism that prevents inadvertent CMG destruction by DPC proteases, and they reveal CMG’s remarkable capacity to overcome obstacles on its translocation strand.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418314521-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Jun Wang, Miguel F. Sanmamed, Ila Datar, Tina Tianjiao Su, Lan Ji, Jingwei Sun, Ling Chen, Yusheng Chen, Gefeng Zhu, Weiwei Yin, Linghua Zheng, Ting Zhou, Ti Badri, Sheng Yao, Shu Zhu, Agedi Boto, Mario Sznol, Ignacio Melero, Dario A.A. Vignali, Kurt Schalper〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315022-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Jeffrey L. Rhoades, Jessica C. Nelson, Ijeoma Nwabudike, Stephanie K. Yu, Ian G. McLachlan, Gurrein K. Madan, Eden Abebe, Joshua R. Powers, Daniel A. Colón-Ramos, Steven W. Flavell〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Animals must respond to the ingestion of food by generating adaptive behaviors, but the role of gut-brain signaling in behavioral regulation is poorly understood. Here, we identify conserved ion channels in an enteric serotonergic neuron that mediate its responses to food ingestion and decipher how these responses drive changes in foraging behavior. We show that the 〈em〉C. elegans〈/em〉 serotonergic neuron NSM acts as an enteric sensory neuron that acutely detects food ingestion. We identify the novel and conserved acid-sensing ion channels (ASICs) DEL-7 and DEL-3 as NSM-enriched channels required for feeding-dependent NSM activity, which in turn drives slow locomotion while animals feed. Point mutations that alter the DEL-7 channel change NSM dynamics and associated behavioral dynamics of the organism. This study provides causal links between food ingestion, molecular and physiological properties of an enteric serotonergic neuron, and adaptive feeding behaviors, yielding a new view of how enteric neurons control behavior.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315150-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 10 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issues 1–2〈/p〉 〈p〉Author(s): Adam J. Rubin, Kevin R. Parker, Ansuman T. Satpathy, Yanyan Qi, Beijing Wu, Alvin J. Ong, Maxwell R. Mumbach, Andrew L. Ji, Daniel S. Kim, Seung Woo Cho, Brian J. Zarnegar, William J. Greenleaf, Howard Y. Chang, Paul A. Khavari〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉Here, we present Perturb-ATAC, a method that combines multiplexed CRISPR interference or knockout with genome-wide chromatin accessibility profiling in single cells based on the simultaneous detection of CRISPR guide RNAs and open chromatin sites by assay of transposase-accessible chromatin with sequencing (ATAC-seq). We applied Perturb-ATAC to transcription factors (TFs), chromatin-modifying factors, and noncoding RNAs (ncRNAs) in ∼4,300 single cells, encompassing more than 63 genotype-phenotype relationships. Perturb-ATAC in human B lymphocytes uncovered regulators of chromatin accessibility, TF occupancy, and nucleosome positioning and identified a hierarchy of TFs that govern B cell state, variation, and disease-associated 〈em〉cis〈/em〉-regulatory elements. Perturb-ATAC in primary human epidermal cells revealed three sequential modules of 〈em〉cis〈/em〉-elements that specify keratinocyte fate. Combinatorial deletion of all pairs of these TFs uncovered their epistatic relationships and highlighted genomic co-localization as a basis for synergistic interactions. Thus, Perturb-ATAC is a powerful strategy to dissect gene regulatory networks in development and disease.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315149-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉

Description: 〈p〉Publication date: 24 January 2019〈/p〉 〈p〉〈b〉Source:〈/b〉 Cell, Volume 176, Issue 3〈/p〉 〈p〉Author(s): Sung-Hwan Moon, Chun-Hao Huang, Shauna L. Houlihan, Kausik Regunath, William A. Freed-Pastor, John P. Morris, Darjus F. Tschaharganeh, Edward R. Kastenhuber, Anthony M. Barsotti, Rachel Culp-Hill, Wen Xue, Yu-Jui Ho, Timour Baslan, Xiang Li, Allison Mayle, Elisa de Stanchina, Lars Zender, David R. Tong, Angelo D’Alessandro, Scott W. Lowe〈/p〉 〈h5〉Summary〈/h5〉 〈div〉〈p〉There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the 〈em〉ABCA1〈/em〉 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis. Furthermore, pharmacological or RNAi inhibition of the mevalonate pathway restricts the development of murine hepatocellular carcinomas driven by p53 loss. Like p53 loss, ablation of ABCA1 promotes murine liver tumorigenesis and is associated with increased SREBP-2 maturation. Our findings demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated liver tumor suppression and outline the mechanism by which this occurs.〈/p〉〈/div〉 〈h5〉Graphical Abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0092867418315034-fx1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉