Yi Wang, I-Ling Chiang, Takahiro E Ohara, Satoru Fujii, Jiye Cheng, Brian D Muegge, Aaron Ver Heul, Nathan D Han, Qiuhe Lu, Shanshan Xiong, Feidi Chen, Chin-Wen Lai, Hana Janova, Renee Wu, Charles E Whitehurst, Kelli L VanDussen, Ta-Chiang Liu, Jeffrey I Gordon, L David Sibley, Thaddeus S Stappenbeck
The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration...
November 5, 2019: Cell
Kuang Shen, Kacper B Rogala, Hui-Ting Chou, Rick K Huang, Zhiheng Yu, David M Sabatini
mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains...
November 5, 2019: Cell
Tatiana García-Muse, Andrés Aguilera
DNA-RNA hybrids play a physiological role in cellular processes, but often, they represent non-scheduled co-transcriptional structures with a negative impact on transcription, replication and DNA repair. Accumulating evidence suggests that they constitute a source of replication stress, DNA breaks and genome instability. Reciprocally, DNA breaks facilitate DNA-RNA hybrid formation by releasing the double helix torsional conformation. Cells avoid DNA-RNA accumulation by either preventing or removing hybrids directly or by DNA repair-coupled mechanisms...
October 8, 2019: Cell
Zhenda Shi, Jun Zou, Zhan Zhang, Xu Zhao, Juan Noriega, Benyue Zhang, Chunyu Zhao, Harshad Ingle, Kyle Bittinger, Lisa M Mattei, Andrea J Pruijssers, Richard K Plemper, Timothy J Nice, Megan T Baldridge, Terence S Dermody, Benoit Chassaing, Andrew T Gewirtz
Rotavirus (RV) encounters intestinal epithelial cells amidst diverse microbiota, opening possibilities of microbes influencing RV infection. Although RV clearance typically requires adaptive immunity, we unintentionally generated RV-resistant immunodeficient mice, which, we hypothesized, reflected select microbes protecting against RV. Accordingly, such RV resistance was transferred by co-housing and fecal transplant. RV-protecting microbiota were interrogated by heat, filtration, and antimicrobial agents, followed by limiting dilution transplant to germ-free mice and microbiome analysis...
October 8, 2019: Cell
Roseann E Peterson, Karoline Kuchenbaecker, Raymond K Walters, Chia-Yen Chen, Alice B Popejoy, Sathish Periyasamy, Max Lam, Conrad Iyegbe, Rona J Strawbridge, Leslie Brick, Caitlin E Carey, Alicia R Martin, Jacquelyn L Meyers, Jinni Su, Junfang Chen, Alexis C Edwards, Allan Kalungi, Nastassja Koen, Lerato Majara, Emanuel Schwarz, Jordan W Smoller, Eli A Stahl, Patrick F Sullivan, Evangelos Vassos, Bryan Mowry, Miguel L Prieto, Alfredo Cuellar-Barboza, Tim B Bigdeli, Howard J Edenberg, Hailiang Huang, Laramie E Duncan
Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development...
October 7, 2019: Cell
Alanna E McCarthy, Craig Yoshioka, Steven E Mansoor
P2X receptors are trimeric, non-selective cation channels activated by extracellular ATP. The P2X7 receptor subtype is a pharmacological target because of involvement in apoptotic, inflammatory, and tumor progression pathways. It is the most structurally and functionally distinct P2X subtype, containing a unique cytoplasmic domain critical for the receptor to initiate apoptosis and not undergo desensitization. However, lack of structural information about the cytoplasmic domain has hindered understanding of the molecular mechanisms underlying these processes...
October 2, 2019: Cell
Justin M Long, David M Holtzman
Alzheimer disease (AD) is a heterogeneous disease with a complex pathobiology. The presence of extracellular β-amyloid deposition as neuritic plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles remains the primary neuropathologic criteria for AD diagnosis. However, a number of recent fundamental discoveries highlight important pathological roles for other critical cellular and molecular processes. Despite this, no disease-modifying treatment currently exists, and numerous phase 3 clinical trials have failed to demonstrate benefits...
September 25, 2019: Cell
Tianxiong Yu, Birgit S Koppetsch, Sara Pagliarani, Stephen Johnston, Noah J Silverstein, Jeremy Luban, Keith Chappell, Zhiping Weng, William E Theurkauf
Antisense Piwi-interacting RNAs (piRNAs) guide silencing of established transposons during germline development, and sense piRNAs drive ping-pong amplification of the antisense pool, but how the germline responds to genome invasion is not understood. The KoRV-A gammaretrovirus infects the soma and germline and is sweeping through wild koalas by a combination of horizontal and vertical transfer, allowing direct analysis of retroviral invasion of the germline genome. Gammaretroviruses produce spliced Env mRNAs and unspliced transcripts encoding Gag, Pol, and the viral genome, but KoRV-A piRNAs are almost exclusively derived from unspliced genomic transcripts and are strongly sense-strand biased...
September 23, 2019: Cell
Yinan Wan, Ziqiang Wei, Loren L Looger, Minoru Koyama, Shaul Druckmann, Philipp J Keller
Animal survival requires a functioning nervous system to develop during embryogenesis. Newborn neurons must assemble into circuits producing activity patterns capable of instructing behaviors. Elucidating how this process is coordinated requires new methods that follow maturation and activity of all cells across a developing circuit. We present an imaging method for comprehensively tracking neuron lineages, movements, molecular identities, and activity in the entire developing zebrafish spinal cord, from neurogenesis until the emergence of patterned activity instructing the earliest spontaneous motor behavior...
September 23, 2019: Cell
DeAnna C Bublitz, Grayson L Chadwick, John S Magyar, Kelsi M Sandoz, Diane M Brooks, Stéphane Mesnage, Mark S Ladinsky, Arkadiy I Garber, Pamela J Bjorkman, Victoria J Orphan, John P McCutcheon
Peptidoglycan (PG) is a defining feature of bacteria, involved in cell division, shape, and integrity. We previously reported that several genes related to PG biosynthesis were horizontally transferred from bacteria to the nuclear genome of mealybugs. Mealybugs are notable for containing a nested bacteria-within-bacterium endosymbiotic structure in specialized insect cells, where one bacterium, Moranella, lives in the cytoplasm of another bacterium, Tremblaya. Here we show that horizontally transferred genes on the mealybug genome work together with genes retained on the Moranella genome to produce a PG layer exclusively at the Moranella cell periphery...
September 21, 2019: Cell
Yuvaraj Bhoobalan-Chitty, Thomas Baek Johansen, Nadia Di Cianni, Xu Peng
Bacteria and archaea possess a striking diversity of CRISPR-Cas systems divided into six types, posing a significant barrier to viral infection. As part of the virus-host arms race, viruses encode protein inhibitors of type I, II, and V CRISPR-Cas systems, but whether there are natural inhibitors of the other, mechanistically distinct CRISPR-Cas types is unknown. Here, we present the discovery of a type III CRISPR-Cas inhibitor, AcrIIIB1, encoded by the Sulfolobus virus SIRV2. AcrIIIB1 exclusively inhibits CRISPR-Cas subtype III-B immunity mediated by the RNase activity of the accessory protein Csx1...
September 19, 2019: Cell
Mikael B L Winkler, Rune T Kidmose, Maria Szomek, Katja Thaysen, Shaun Rawson, Stephen P Muench, Daniel Wüstner, Bjørn Panyella Pedersen
Niemann-Pick type C (NPC) proteins are essential for sterol homeostasis, believed to drive sterol integration into the lysosomal membrane before redistribution to other cellular membranes. Here, using a combination of crystallography, cryo-electron microscopy, and biochemical and in vivo studies on the Saccharomyces cerevisiae NPC system (NCR1 and NPC2), we present a framework for sterol membrane integration. Sterols are transferred between hydrophobic pockets of vacuolar NPC2 and membrane-protein NCR1. NCR1 has its N-terminal domain (NTD) positioned to deliver a sterol to a tunnel connecting NTD to the luminal membrane leaflet 50 Å away...
September 13, 2019: Cell
Bryan A Gibson, Lynda K Doolittle, Maximillian W G Schneider, Liv E Jensen, Nathan Gamarra, Lisa Henry, Daniel W Gerlich, Sy Redding, Michael K Rosen
Eukaryotic chromatin is highly condensed but dynamically accessible to regulation and organized into subdomains. We demonstrate that reconstituted chromatin undergoes histone tail-driven liquid-liquid phase separation (LLPS) in physiologic salt and when microinjected into cell nuclei, producing dense and dynamic droplets. Linker histone H1 and internucleosome linker lengths shared across eukaryotes promote phase separation of chromatin, tune droplet properties, and coordinate to form condensates of consistent density in manners that parallel chromatin behavior in cells...
September 13, 2019: Cell
(no author information available yet)
To celebrate this year's Peer Review Week theme, "Quality in Peer Review," we asked editors across Cell Press to nominate some of their best reviewers to give their philosophies on peer reviewing.
September 11, 2019: Cell
Elias Zerhouni
This year's Lasker-Bloomberg Public Service Award goes to GAVI, the Vaccine Alliance, for providing sustained access to childhood vaccines around the globe, saving millions of lives, and highlighting the power of immunization to prevent disease.
September 10, 2019: Cell
Victor A Lopez, Brenden C Park, Dominika Nowak, Anju Sreelatha, Patrycja Zembek, Jessie Fernandez, Kelly A Servage, Marcin Gradowski, Jacek Hennig, Diana R Tomchick, Krzysztof Pawłowski, Magdalena Krzymowska, Vincent S Tagliabracci
The molecular chaperone HSP90 facilitates the folding of several client proteins, including innate immune receptors and protein kinases. HSP90 is an essential component of plant and animal immunity, yet pathogenic strategies that directly target the chaperone have not been described. Here, we identify the HopBF1 family of bacterial effectors as eukaryotic-specific HSP90 protein kinases. HopBF1 adopts a minimal protein kinase fold that is recognized by HSP90 as a host client. As a result, HopBF1 phosphorylates HSP90 to completely inhibit the chaperone's ATPase activity...
September 7, 2019: Cell
Meng-Meng Fu, Thomas S McAlear, Huy Nguyen, Juan A Oses-Prieto, Alex Valenzuela, Rebecca D Shi, John J Perrino, Ting-Ting Huang, Alma L Burlingame, Susanne Bechstedt, Ben A Barres
Oligodendrocytes extend elaborate microtubule arbors that contact up to 50 axon segments per cell, then spiral around myelin sheaths, penetrating from outer to inner layers. However, how they establish this complex cytoarchitecture is unclear. Here, we show that oligodendrocytes contain Golgi outposts, an organelle that can function as an acentrosomal microtubule-organizing center (MTOC). We identify a specific marker for Golgi outposts-TPPP (tubulin polymerization promoting protein)-that we use to purify this organelle and characterize its proteome...
September 7, 2019: Cell
Jin Zhang, Hao Jin, Wenyi Zhang, Cheng Ding, Sean O'Keeffe, Mingyu Ye, Charles S Zuker
The ability to sense sour provides an important sensory signal to prevent the ingestion of unripe, spoiled, or fermented foods. Taste and somatosensory receptors in the oral cavity trigger aversive behaviors in response to acid stimuli. Here, we show that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system. We demonstrate that knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs)...
September 6, 2019: Cell
Yochai Wolf, Osnat Bartok, Sushant Patkar, Gitit Bar Eli, Sapir Cohen, Kevin Litchfield, Ronen Levy, Alejandro Jiménez-Sánchez, Sophie Trabish, Joo Sang Lee, Hiren Karathia, Eilon Barnea, Chi-Ping Day, Einat Cinnamon, Ilan Stein, Adam Solomon, Lital Bitton, Eva Pérez-Guijarro, Tania Dubovik, Shai S Shen-Orr, Martin L Miller, Glenn Merlino, Yishai Levin, Eli Pikarsky, Lea Eisenbach, Arie Admon, Charles Swanton, Eytan Ruppin, Yardena Samuels
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected...
September 4, 2019: Cell
Vasant Shinde, Vagheesh M Narasimhan, Nadin Rohland, Swapan Mallick, Matthew Mah, Mark Lipson, Nathan Nakatsuka, Nicole Adamski, Nasreen Broomandkhoshbacht, Matthew Ferry, Ann Marie Lawson, Megan Michel, Jonas Oppenheimer, Kristin Stewardson, Nilesh Jadhav, Yong Jun Kim, Malavika Chatterjee, Avradeep Munshi, Amrithavalli Panyam, Pranjali Waghmare, Yogesh Yadav, Himani Patel, Amit Kaushik, Kumarasamy Thangaraj, Matthias Meyer, Nick Patterson, Niraj Rai, David Reich
We report an ancient genome from the Indus Valley Civilization (IVC). The individual we sequenced fits as a mixture of people related to ancient Iranians (the largest component) and Southeast Asian hunter-gatherers, a unique profile that matches ancient DNA from 11 genetic outliers from sites in Iran and Turkmenistan in cultural communication with the IVC. These individuals had little if any Steppe pastoralist-derived ancestry, showing that it was not ubiquitous in northwest South Asia during the IVC as it is today...
September 4, 2019: Cell
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