Apollo Stacy, Vinicius Andrade-Oliveira, John A McCulloch, Benedikt Hild, Ji Hoon Oh, P Juliana Perez-Chaparro, Choon K Sim, Ai Ing Lim, Verena M Link, Michel Enamorado, Giorgio Trinchieri, Julia A Segre, Barbara Rehermann, Yasmine Belkaid
The microbiota shields the host against infections in a process known as colonization resistance. How infections themselves shape this fundamental process remains largely unknown. Here, we show that gut microbiota from previously infected hosts display enhanced resistance to infection. This long-term functional remodeling is associated with altered bile acid metabolism leading to the expansion of taxa that utilize the sulfonic acid taurine. Notably, supplying exogenous taurine alone is sufficient to induce this alteration in microbiota function and enhance resistance...
January 14, 2021: Cell
Elizabeth A Bowling, Jarey H Wang, Fade Gong, William Wu, Nicholas J Neill, Ik Sun Kim, Siddhartha Tyagi, Mayra Orellana, Sarah J Kurley, Rocio Dominguez-Vidaña, Hsiang-Ching Chung, Tiffany Y-T Hsu, Julien Dubrulle, Alexander B Saltzman, Heyuan Li, Jitendra K Meena, Gino M Canlas, Srinivas Chamakuri, Swarnima Singh, Lukas M Simon, Calla M Olson, Lacey E Dobrolecki, Michael T Lewis, Bing Zhang, Ido Golding, Jeffrey M Rosen, Damian W Young, Anna Malovannaya, Fabio Stossi, George Miles, Matthew J Ellis, Lihua Yu, Silvia Buonamici, Charles Y Lin, Kristen L Karlin, Xiang H-F Zhang, Thomas F Westbrook
Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis...
January 13, 2021: Cell
Esther B Florsheim, Zuri A Sullivan, William Khoury-Hanold, Ruslan Medzhitov
Food is simultaneously a source of essential nutrients and a potential source of lethal toxins and pathogens. Consequently, multiple sensory mechanisms evolved to monitor the quality of food based on the presence and relative abundance of beneficial and harmful food substances. These include the olfactory, gustatory, and gut chemosensory systems. Here we argue that, in addition to these systems, allergic immunity plays a role in food quality control by mounting allergic defenses against food antigens associated with noxious substances...
January 11, 2021: Cell
Evan O Paull, Alvaro Aytes, Sunny J Jones, Prem S Subramaniam, Federico M Giorgi, Eugene F Douglass, Somnath Tagore, Brennan Chu, Alessandro Vasciaveo, Siyuan Zheng, Roel Verhaak, Cory Abate-Shen, Mariano J Alvarez, Andrea Califano
Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts...
January 8, 2021: Cell
Deepavali Chakravarti, Kyle A LaBella, Ronald A DePinho
The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer...
January 7, 2021: Cell
Fang Wang, Anna M Trier, Fengxian Li, Seonyoung Kim, Zhen Chen, Jiani N Chai, Madison R Mack, Stephanie A Morrison, Jennifer D Hamilton, Jinok Baek, Ting-Lin B Yang, Aaron M Ver Heul, Amy Z Xu, Zili Xie, Xintong Dong, Masato Kubo, Hongzhen Hu, Chyi-Song Hsieh, Xinzhong Dong, Qin Liu, David J Margolis, Marius Ardeleanu, Mark J Miller, Brian S Kim
Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked...
January 6, 2021: Cell
Rachael E Workman, Teja Pammi, Binh T K Nguyen, Leonardo W Graeff, Erika Smith, Suzanne M Sebald, Marie J Stoltzfus, Chad W Euler, Joshua W Modell
CRISPR-Cas systems provide prokaryotes with acquired immunity against viruses and plasmids, but how these systems are regulated to prevent autoimmunity is poorly understood. Here, we show that in the S. pyogenes CRISPR-Cas system, a long-form transactivating CRISPR RNA (tracr-L) folds into a natural single guide that directs Cas9 to transcriptionally repress its own promoter (Pcas ). Further, we demonstrate that Pcas serves as a critical regulatory node. De-repression causes a dramatic 3,000-fold increase in immunization rates against viruses; however, heightened immunity comes at the cost of increased autoimmune toxicity...
January 6, 2021: Cell
David Fawkner-Corbett, Agne Antanaviciute, Kaushal Parikh, Marta Jagielowicz, Ana Sousa Gerós, Tarun Gupta, Neil Ashley, Doran Khamis, Darren Fowler, Edward Morrissey, Chris Cunningham, Paul R V Johnson, Hashem Koohy, Alison Simmons
Development of the human intestine is not well understood. Here, we link single-cell RNA sequencing and spatial transcriptomics to characterize intestinal morphogenesis through time. We identify 101 cell states including epithelial and mesenchymal progenitor populations and programs linked to key morphogenetic milestones. We describe principles of crypt-villus axis formation; neural, vascular, mesenchymal morphogenesis, and immune population of the developing gut. We identify the differentiation hierarchies of developing fibroblast and myofibroblast subtypes and describe diverse functions for these including as vascular niche cells...
January 4, 2021: Cell
Jasper S Phelps, David Grant Colburn Hildebrand, Brett J Graham, Aaron T Kuan, Logan A Thomas, Tri M Nguyen, Julia Buhmann, Anthony W Azevedo, Anne Sustar, Sweta Agrawal, Mingguan Liu, Brendan L Shanny, Jan Funke, John C Tuthill, Wei-Chung Allen Lee
To investigate circuit mechanisms underlying locomotor behavior, we used serial-section electron microscopy (EM) to acquire a synapse-resolution dataset containing the ventral nerve cord (VNC) of an adult female Drosophila melanogaster. To generate this dataset, we developed GridTape, a technology that combines automated serial-section collection with automated high-throughput transmission EM. Using this dataset, we studied neuronal networks that control leg and wing movements by reconstructing all 507 motor neurons that control the limbs...
January 4, 2021: Cell
Eviatar Yemini, Albert Lin, Amin Nejatbakhsh, Erdem Varol, Ruoxi Sun, Gonzalo E Mena, Aravinthan D T Samuel, Liam Paninski, Vivek Venkatachalam, Oliver Hobert
Comprehensively resolving neuronal identities in whole-brain images is a major challenge. We achieve this in C. elegans by engineering a multicolor transgene called NeuroPAL (a neuronal polychromatic atlas of landmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that resolves all neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics...
December 23, 2020: Cell
Hui Chiu, Eric D Hoopfer, Maeve L Coughlan, David J Anderson
Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We have identified three cell types that regulate aggression in Drosophila: one type is sexually shared, and the other two are sex specific. Shared common aggression-promoting (CAP) neurons mediate aggressive approach in both sexes, whereas functionally downstream dimorphic but homologous cell types, called male-specific aggression-promoting (MAP) neurons in males and fpC1 in females, control dimorphic attack...
December 22, 2020: Cell
Valentina Cappelletti, Thomas Hauser, Ilaria Piazza, Monika Pepelnjak, Liliana Malinovska, Tobias Fuhrer, Yaozong Li, Christian Dörig, Paul Boersema, Ludovic Gillet, Jan Grossbach, Aurelien Dugourd, Julio Saez-Rodriguez, Andreas Beyer, Nicola Zamboni, Amedeo Caflisch, Natalie de Souza, Paola Picotti
Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites...
December 22, 2020: Cell
Pablo Ávalos Prado, Stephanie Häfner, Yannick Comoglio, Brigitte Wdziekonski, Christophe Duranton, Bernard Attali, Jacques Barhanin, Guillaume Sandoz
Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily...
December 19, 2020: Cell
Jia Z Shen, Zhixin Qiu, Qiulian Wu, Darren Finlay, Guillermina Garcia, Dahui Sun, Juha Rantala, William Barshop, Jennifer L Hope, Ryan C Gimple, Olle Sangfelt, Linda M Bradley, James Wohlschlegel, Jeremy N Rich, Charles Spruck
Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response...
December 18, 2020: Cell
Rie Nygaard, Jia Yu, Jonathan Kim, Daniel R Ross, Giacomo Parisi, Oliver B Clarke, David M Virshup, Filippo Mancia
Wnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesis, cell fate, and stem cell renewal. The first and essential steps in Wnt secretion are their O-palmitoleation and subsequent loading onto the dedicated transporter Wntless/evenness interrupted (WLS/Evi). We report the 3.2 Å resolution cryogenic electron microscopy (cryo-EM) structure of palmitoleated human WNT8A in complex with WLS. This is accompanied by biochemical experiments to probe the physiological implications of the observed association...
December 18, 2020: Cell
Guanghui Yang, Rui Zhou, Xuefei Guo, Chuangye Yan, Jianlin Lei, Yigong Shi
Development of γ-secretase inhibitors (GSIs) and modulators (GSMs) represents an attractive therapeutic opportunity for Alzheimer's disease (AD) and cancers. However, how these GSIs and GSMs target γ-secretase has remained largely unknown. Here, we report the cryoelectron microscopy (cryo-EM) structures of human γ-secretase bound individually to two GSI clinical candidates, Semagacestat and Avagacestat, a transition state analog GSI L685,458, and a classic GSM E2012, at overall resolutions of 2.6-3.1 Å...
December 17, 2020: Cell
Yunfan Sun, Liang Wu, Yu Zhong, Kaiqian Zhou, Yong Hou, Zifei Wang, Zefan Zhang, Jiarui Xie, Chunqing Wang, Dandan Chen, Yaling Huang, Xiaochan Wei, Yinghong Shi, Zhikun Zhao, Yuehua Li, Ziwei Guo, Qichao Yu, Liqin Xu, Giacomo Volpe, Shuangjian Qiu, Jian Zhou, Carl Ward, Huichuan Sun, Ye Yin, Xun Xu, Xiangdong Wang, Miguel A Esteban, Huanming Yang, Jian Wang, Michael Dean, Yaguang Zhang, Shiping Liu, Xinrong Yang, Jia Fan
Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8+ T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8+ T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC...
December 17, 2020: Cell
Wilfredo F Garcia-Beltran, Evan C Lam, Michael G Astudillo, Diane Yang, Tyler E Miller, Jared Feldman, Blake M Hauser, Timothy M Caradonna, Kiera L Clayton, Adam D Nitido, Mandakolathur R Murali, Galit Alter, Richelle C Charles, Anand Dighe, John A Branda, Jochen K Lennerz, Daniel Lingwood, Aaron G Schmidt, A John Iafrate, Alejandro B Balazs
Coronavirus disease 2019 (COVID-19) exhibits variable symptom severity ranging from asymptomatic to life-threatening, yet the relationship between severity and the humoral immune response is poorly understood. We examined antibody responses in 113 COVID-19 patients and found that severe cases resulting in intubation or death exhibited increased inflammatory markers, lymphopenia, pro-inflammatory cytokines, and high anti-receptor binding domain (RBD) antibody levels. Although anti-RBD immunoglobulin G (IgG) levels generally correlated with neutralization titer, quantitation of neutralization potency revealed that high potency was a predictor of survival...
December 15, 2020: Cell
Carlos López-Otín, Guido Kroemer
Health is usually defined as the absence of pathology. Here, we endeavor to define health as a compendium of organizational and dynamic features that maintain physiology. The biological causes or hallmarks of health include features of spatial compartmentalization (integrity of barriers and containment of local perturbations), maintenance of homeostasis over time (recycling and turnover, integration of circuitries, and rhythmic oscillations), and an array of adequate responses to stress (homeostatic resilience, hormetic regulation, and repair and regeneration)...
December 15, 2020: Cell
Adam L Bailey, Michael S Diamond
Complementary genome-wide CRISPR-Cas9 screens performed by multiple groups reveal new insights into SARS-CoV-2 biology including aspects of viral entry, translation, replication, egress, and the genes regulating these processes. Comparisons with other coronaviruses enhances our understanding of the cellular life cycle of this medically important family of emerging viruses.
December 15, 2020: Cell
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