Michele Olivieri, Tiffany Cho, Alejandro Álvarez-Quilón, Kejiao Li, Matthew J Schellenberg, Michal Zimmermann, Nicole Hustedt, Silvia Emma Rossi, Salomé Adam, Henrique Melo, Anne Margriet Heijink, Guillermo Sastre-Moreno, Nathalie Moatti, Rachel K Szilard, Andrea McEwan, Alexanda K Ling, Almudena Serrano-Benitez, Tajinder Ubhi, Sumin Feng, Judy Pawling, Irene Delgado-Sainz, Michael W Ferguson, James W Dennis, Grant W Brown, Felipe Cortés-Ledesma, R Scott Williams, Alberto Martin, Dongyi Xu, Daniel Durocher
The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 31 CRISPR-Cas9 screens against 27 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 890 genes whose loss causes either sensitivity or resistance to DNA-damaging agents. Mining this dataset, we discovered that ERCC6L2 (which is mutated in a bone-marrow failure syndrome) codes for a canonical non-homologous end-joining pathway factor, that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents, and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA...
July 9, 2020: Cell
Tomohiro Yokota, Jackie McCourt, Feiyang Ma, Shuxun Ren, Shen Li, Tae-Hyung Kim, Yerbol Z Kurmangaliyev, Rohollah Nasiri, Samad Ahadian, Thang Nguyen, Xing Haw Marvin Tan, Yonggang Zhou, Rimao Wu, Abraham Rodriguez, Whitaker Cohn, Yibin Wang, Julian Whitelegge, Sergey Ryazantsev, Ali Khademhosseini, Michael A Teitell, Pei-Yu Chiou, David E Birk, Amy C Rowat, Rachelle H Crosbie, Matteo Pellegrini, Marcus Seldin, Aldons J Lusis, Arjun Deb
Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function...
July 2, 2020: Cell
Leandro Venturutti, Matt Teater, Andrew Zhai, Amy Chadburn, Leena Babiker, Daleum Kim, Wendy Béguelin, Tak C Lee, Youngjun Kim, Christopher R Chin, William T Yewdell, Brian Raught, Jude M Phillip, Yanwen Jiang, Louis M Staudt, Michael R Green, Jayanta Chaudhuri, Olivier Elemento, Pedro Farinha, Andrew P Weng, Michael D Nissen, Christian Steidl, Ryan D Morin, David W Scott, Gilbert G Privé, Ari M Melnick
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias...
July 2, 2020: Cell
Erika Sugisawa, Yasunori Takayama, Naoki Takemura, Takeshi Kondo, Shigetsugu Hatakeyama, Yutaro Kumagai, Masataka Sunagawa, Makoto Tominaga, Kenta Maruyama
Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels...
June 29, 2020: Cell
Longwen Huang, Justus M Kebschull, Daniel Fürth, Simon Musall, Matthew T Kaufman, Anne K Churchland, Anthony M Zador
Comprehensive analysis of neuronal networks requires brain-wide measurement of connectivity, activity, and gene expression. Although high-throughput methods are available for mapping brain-wide activity and transcriptomes, comparable methods for mapping region-to-region connectivity remain slow and expensive because they require averaging across hundreds of brains. Here we describe BRICseq (brain-wide individual animal connectome sequencing), which leverages DNA barcoding and sequencing to map connectivity from single individuals in a few weeks and at low cost...
June 29, 2020: Cell
Lianpan Dai, Tianyi Zheng, Kun Xu, Yuxuan Han, Lili Xu, Enqi Huang, Yaling An, Yingjie Cheng, Shihua Li, Mei Liu, Mi Yang, Yan Li, Huijun Cheng, Yuan Yuan, Wei Zhang, Changwen Ke, Gary Wong, Jianxun Qi, Chuan Qin, Jinghua Yan, George F Gao
Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs...
June 28, 2020: Cell
Mehdi Bouhaddou, Danish Memon, Bjoern Meyer, Kris M White, Veronica V Rezelj, Miguel Correa Marrero, Benjamin J Polacco, James E Melnyk, Svenja Ulferts, Robyn M Kaake, Jyoti Batra, Alicia L Richards, Erica Stevenson, David E Gordon, Ajda Rojc, Kirsten Obernier, Jacqueline M Fabius, Margaret Soucheray, Lisa Miorin, Elena Moreno, Cassandra Koh, Quang Dinh Tran, Alexandra Hardy, Rémy Robinot, Thomas Vallet, Benjamin E Nilsson-Payant, Claudia Hernandez-Armenta, Alistair Dunham, Sebastian Weigang, Julian Knerr, Maya Modak, Diego Quintero, Yuan Zhou, Aurelien Dugourd, Alberto Valdeolivas, Trupti Patil, Qiongyu Li, Ruth Hüttenhain, Merve Cakir, Monita Muralidharan, Minkyu Kim, Gwendolyn Jang, Beril Tutuncuoglu, Joseph Hiatt, Jeffrey Z Guo, Jiewei Xu, Sophia Bouhaddou, Christopher J P Mathy, Anna Gaulton, Emma J Manners, Eloy Félix, Ying Shi, Marisa Goff, Jean K Lim, Timothy McBride, Michael C O'Neal, Yiming Cai, Jason C J Chang, David J Broadhurst, Saker Klippsten, Emmie De Wit, Andrew R Leach, Tanja Kortemme, Brian Shoichet, Melanie Ott, Julio Saez-Rodriguez, Benjamin R tenOever, R Dyche Mullins, Elizabeth R Fischer, Georg Kochs, Robert Grosse, Adolfo García-Sastre, Marco Vignuzzi, Jeffery R Johnson, Kevan M Shokat, Danielle L Swaney, Pedro Beltrao, Nevan J Krogan
The causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected millions and killed hundreds of thousands of people worldwide, highlighting an urgent need to develop antiviral therapies. Here we present a quantitative mass spectrometry-based phosphoproteomics survey of SARS-CoV-2 infection in Vero E6 cells, revealing dramatic rewiring of phosphorylation on host and viral proteins. SARS-CoV-2 infection promoted casein kinase II (CK2) and p38 MAPK activation, production of diverse cytokines, and shutdown of mitotic kinases, resulting in cell cycle arrest...
June 28, 2020: Cell
Marcin Maziarz, Jong-Chan Park, Anthony Leyme, Arthur Marivin, Alberto Garcia-Lopez, Prachi P Patel, Mikel Garcia-Marcos
Heterotrimeric G-proteins (Gαβγ) are the main transducers of signals from GPCRs, mediating the action of countless natural stimuli and therapeutic agents. However, there are currently no robust approaches to directly measure the activity of endogenous G-proteins in cells. Here, we describe a suite of optical biosensors that detect endogenous active G-proteins with sub-second resolution in live cells. Using a modular design principle, we developed genetically encoded, unimolecular biosensors for endogenous Gα-GTP and free Gβγ: the two active species of heterotrimeric G-proteins...
June 27, 2020: Cell
Hua Qing, Reina Desrouleaux, Kavita Israni-Winger, Yann S Mineur, Nia Fogelman, Cuiling Zhang, Saleh Rashed, Noah W Palm, Rajita Sinha, Marina R Picciotto, Rachel J Perry, Andrew Wang
Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling "fight or flight" responses...
June 27, 2020: Cell
Ilias Kounatidis, Megan L Stanifer, Michael A Phillips, Perrine Paul-Gilloteaux, Xavier Heiligenstein, Hongchang Wang, Chidinma A Okolo, Thomas M Fish, Matthew C Spink, David I Stuart, Ilan Davis, Steeve Boulant, Jonathan M Grimes, Ian M Dobbie, Maria Harkiolaki
Imaging of biological matter across resolution scales entails the challenge of preserving the direct and unambiguous correlation of subject features from the macroscopic to the microscopic level. Here, we present a correlative imaging platform developed specifically for imaging cells in 3D under cryogenic conditions by using X-rays and visible light. Rapid cryo-preservation of biological specimens is the current gold standard in sample preparation for ultrastructural analysis in X-ray imaging. However, cryogenic fluorescence localization methods are, in their majority, diffraction-limited and fail to deliver matching resolution...
June 27, 2020: Cell
Phi T Nguyen, Leah C Dorman, Simon Pan, Ilia D Vainchtein, Rafael T Han, Hiromi Nakao-Inoue, Sunrae E Taloma, Jerika J Barron, Ari B Molofsky, Mazen A Kheirbek, Anna V Molofsky
Synapse remodeling is essential to encode experiences into neuronal circuits. Here, we define a molecular interaction between neurons and microglia that drives experience-dependent synapse remodeling in the hippocampus. We find that the cytokine interleukin-33 (IL-33) is expressed by adult hippocampal neurons in an experience-dependent manner and defines a neuronal subset primed for synaptic plasticity. Loss of neuronal IL-33 or the microglial IL-33 receptor leads to impaired spine plasticity, reduced newborn neuron integration, and diminished precision of remote fear memories...
June 26, 2020: Cell
Yasuo Oguri, Kosaku Shinoda, Hyeonwoo Kim, Diana L Alba, W Reid Bolus, Qiang Wang, Zachary Brown, Rachana N Pradhan, Kazuki Tajima, Takeshi Yoneshiro, Kenji Ikeda, Yong Chen, Rachel T Cheang, Kazuyuki Tsujino, Caroline R Kim, Vanille Juliette Greiner, Ritwik Datta, Christopher D Yang, Kamran Atabai, Michael T McManus, Suneil K Koliwad, Bruce M Spiegelman, Shingo Kajimura
Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81...
June 26, 2020: Cell
Tsung-Han Chou, Nami Tajima, Annabel Romero-Hernandez, Hiro Furukawa
Excitatory neurotransmission meditated by glutamate receptors including N-methyl-D-aspartate receptors (NMDARs) is pivotal to brain development and function. NMDARs are heterotetramers composed of GluN1 and GluN2 subunits, which bind glycine and glutamate, respectively, to activate their ion channels. Despite importance in brain physiology, the precise mechanisms by which activation and inhibition occur via subunit-specific binding of agonists and antagonists remain largely unknown. Here, we show the detailed patterns of conformational changes and inter-subunit and -domain reorientation leading to agonist-gating and subunit-dependent competitive inhibition by providing multiple structures in distinct ligand states at 4 Å or better...
June 26, 2020: Cell
Adrienne M Luoma, Shengbao Suo, Hannah L Williams, Tatyana Sharova, Keri Sullivan, Michael Manos, Peter Bowling, F Stephen Hodi, Osama Rahma, Ryan J Sullivan, Genevieve M Boland, Jonathan A Nowak, Stephanie K Dougan, Michael Dougan, Guo-Cheng Yuan, Kai W Wucherpfennig
Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion...
June 25, 2020: Cell
Kafui Dzirasa
I have tried to live in a world that does not see color but have only succeeded in living in a world that does not see me.
June 25, 2020: Cell
Christopher O Barnes, Anthony P West, Kathryn E Huey-Tubman, Magnus A G Hoffmann, Naima G Sharaf, Pauline R Hoffman, Nicholas Koranda, Harry B Gristick, Christian Gaebler, Frauke Muecksch, Julio C Cetrulo Lorenzi, Shlomo Finkin, Thomas Hägglöf, Arlene Hurley, Katrina G Millard, Yiska Weisblum, Fabian Schmidt, Theodora Hatziioannou, Paul D Bieniasz, Marina Caskey, Davide F Robbiani, Michel C Nussenzweig, Pamela J Bjorkman
Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike...
June 24, 2020: Cell
Lin Wu, Kate E R Hollinshead, Yuhan Hao, Christy Au, Lina Kroehling, Charles Ng, Woan-Yu Lin, Dayi Li, Hernandez Moura Silva, Jong Shin, Juan J Lafaille, Richard Possemato, Michael E Pacold, Thales Papagiannakopoulos, Alec C Kimmelman, Rahul Satija, Dan R Littman
Targeting glycolysis has been considered therapeutically intractable owing to its essential housekeeping role. However, the context-dependent requirement for individual glycolytic steps has not been fully explored. We show that CRISPR-mediated targeting of glycolysis in T cells in mice results in global loss of Th17 cells, whereas deficiency of the glycolytic enzyme glucose phosphate isomerase (Gpi1) selectively eliminates inflammatory encephalitogenic and colitogenic Th17 cells, without substantially affecting homeostatic microbiota-specific Th17 cells...
June 24, 2020: Cell
Eirene Markenscoff-Papadimitriou, Sean Whalen, Pawel Przytycki, Reuben Thomas, Fadya Binyameen, Tomasz J Nowakowski, Arnold R Kriegstein, Stephan J Sanders, Matthew W State, Katherine S Pollard, John L Rubenstein
To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages...
June 24, 2020: Cell
Colin Chih-Chien Wu, Amy Peterson, Boris Zinshteyn, Sergi Regot, Rachel Green
Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Using translation elongation inhibitors and general cellular stress conditions, including amino acid starvation and UV irradiation, we show that ribosome collisions activate the stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways...
June 23, 2020: Cell
Erik Verschueren, Bushra Husain, Kobe Yuen, Yi Sun, Sairupa Paduchuri, Yasin Senbabaoglu, Isabelle Lehoux, Tia A Arena, Blair Wilson, Steve Lianoglou, Corey Bakalarski, Yvonne Franke, Pamela Chan, Athena W Wong, Lino C Gonzalez, Sanjeev Mariathasan, Shannon J Turley, Jennie R Lill, Nadia Martinez-Martin
Cell surface receptors and their interactions play a central role in physiological and pathological signaling. Despite its clinical relevance, the immunoglobulin superfamily (IgSF) remains uncharacterized and underrepresented in databases. Here, we present a systematic extracellular protein map, the IgSF interactome. Using a high-throughput technology to interrogate most single transmembrane receptors for binding to 445 IgSF proteins, we identify over 500 interactions, 82% previously undocumented, and confirm more than 60 receptor-ligand pairs using orthogonal assays...
June 23, 2020: Cell
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