CellPub Date : 2024-12-31DOI: 10.1016/j.cell.2024.11.018
Skylar S. Wright, Puja Kumari, Víctor Fraile-Ágreda, Chengliang Wang, Sonia Shivcharan, Shirin Kappelhoff, Eleonora G. Margheritis, Alyssa Matz, Swathy O. Vasudevan, Ignacio Rubio, Michael Bauer, Beiyan Zhou, Sivapriya Kailasan Vanaja, Katia Cosentino, Jianbin Ruan, Vijay A. Rathinam
{"title":"Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells","authors":"Skylar S. Wright, Puja Kumari, Víctor Fraile-Ágreda, Chengliang Wang, Sonia Shivcharan, Shirin Kappelhoff, Eleonora G. Margheritis, Alyssa Matz, Swathy O. Vasudevan, Ignacio Rubio, Michael Bauer, Beiyan Zhou, Sivapriya Kailasan Vanaja, Katia Cosentino, Jianbin Ruan, Vijay A. Rathinam","doi":"10.1016/j.cell.2024.11.018","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.018","url":null,"abstract":"Pyroptosis mediated by gasdermins (GSDMs) plays crucial roles in infection and inflammation. Pyroptosis triggers the release of inflammatory molecules, including damage-associated molecular patterns (DAMPs). However, the consequences of pyroptosis—especially beyond interleukin (IL)-1 cytokines and DAMPs—that govern inflammation are poorly defined. Here, we show intercellular propagation of pyroptosis from dying cells to bystander cells <em>in vitro</em> and <em>in vivo</em>. We identified extracellular vesicles (EVs) released by pyroptotic cells as the propagator of lytic death to naive cells, promoting inflammation. DNA-PAINT super-resolution and immunoelectron microscopy revealed GSDMD pore structures on EVs released by pyroptotic cells. Importantly, pyroptotic EVs transplant GSDMD pores on the plasma membrane of bystander cells and kill them. Overall, we demonstrate that cell-to-cell vesicular transplantation of GSDMD pores disseminates pyroptosis, revealing a domino-like effect governing disease-associated bystander cell death.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"4 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-24DOI: 10.1016/j.cell.2024.11.026
Corinne L. Pender, Julian G. Dishart, Holly K. Gildea, Kelsie M. Nauta, Emily M. Page, Talha F. Siddiqi, Shannon S. Cheung, Larry Joe, Nicholas O. Burton, Andrew Dillin
{"title":"Perception of a pathogenic signature initiates intergenerational protection","authors":"Corinne L. Pender, Julian G. Dishart, Holly K. Gildea, Kelsie M. Nauta, Emily M. Page, Talha F. Siddiqi, Shannon S. Cheung, Larry Joe, Nicholas O. Burton, Andrew Dillin","doi":"10.1016/j.cell.2024.11.026","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.026","url":null,"abstract":"Transmission of immune responses from one generation to the next represents a powerful adaptive mechanism to protect an organism’s descendants. Parental infection by the natural <em>C. elegans</em> pathogen <em>Pseudomonas vranovensis</em> induces a protective response in progeny, but the bacterial cues and intergenerational signal driving this response were previously unknown. Here, we find that animals activate a protective stress response program upon exposure to <em>P. vranovensis</em>-derived cyanide and that a metabolic byproduct of cyanide detoxification, β-cyanoalanine, acts as an intergenerational signal to protect progeny from infection. Remarkably, this mechanism does not require direct parental infection; rather, exposure to pathogen-derived volatiles is sufficient to enhance the survival of the next generation, indicating that parental surveillance of environmental cues can activate a protective intergenerational response. Therefore, the mere perception of a pathogen-derived toxin, in this case cyanide, can protect an animal’s progeny from future pathogenic challenges.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-24DOI: 10.1016/j.cell.2024.11.033
Jinli Chen, Yanwei Duan, Yuanyuan Zhou, Qing Yang
{"title":"Squeeze pumping of lipids and insecticides by ABCH transporter","authors":"Jinli Chen, Yanwei Duan, Yuanyuan Zhou, Qing Yang","doi":"10.1016/j.cell.2024.11.033","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.033","url":null,"abstract":"ATP-binding cassette (ABC) transporter subfamily H is only identified in arthropods and zebrafish. It transports lipids and is related to insecticide resistance. However, the precise mechanisms of its functions remain elusive. Here, we report cryoelectron microscopy (cryo-EM) structures of an ABCH from <em>Tribolium castaneum</em>, a worldwide pest of stored grains, in complex with an HEK293 cell-ceramide lipid, a fluorescent-labeled ceramide, a carbamate insecticide, and a maltose detergent inhibitor. We revealed a narrow, long, and arched substrate-binding tunnel in the transmembrane domains of the transporter dimer with two arginine-gated cytoplasmic entries for the binding and transport of lipids or insecticides. A pair of glutamines above the tunnel acts as a gate for directing substrate to be extruded via a vent-like hydrophilic exit to the extracellular side of the membrane upon ATP binding. Our structures and biochemical data provide mechanistic understanding of lipid transport, insecticide detoxification, and the inhibition of transporter activity by branched maltose detergents.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"27 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-20DOI: 10.1016/j.cell.2024.11.013
Saurav Mallik, Johannes Venezian, Arseniy Lobov, Meta Heidenreich, Hector Garcia-Seisdedos, Todd O. Yeates, Ayala Shiber, Emmanuel D. Levy
{"title":"Structural determinants of co-translational protein complex assembly","authors":"Saurav Mallik, Johannes Venezian, Arseniy Lobov, Meta Heidenreich, Hector Garcia-Seisdedos, Todd O. Yeates, Ayala Shiber, Emmanuel D. Levy","doi":"10.1016/j.cell.2024.11.013","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.013","url":null,"abstract":"Protein assembly into functional complexes is critical to life’s processes. While complex assembly is classically described as occurring between fully synthesized proteins, recent work showed that co-translational assembly is prevalent in human cells. However, the biological basis for the existence of this process and the identity of protein pairs that assemble co-translationally remain unknown. We show that co-translational assembly is governed by structural characteristics of complexes and involves mutually stabilized subunits. Accordingly, co-translationally assembling subunits are unstable in isolation and exhibit synchronized proteostasis with their partner. By leveraging structural signatures and AlphaFold2-based predictions, we accurately predicted co-translational assembly, including pair identities, at proteome scale and across species. We validated our predictions by ribosome profiling, stoichiometry perturbations, and single-molecule RNA-fluorescence <em>in situ</em> hybridization (smFISH) experiments that revealed co-localized mRNAs. This work establishes a fundamental connection between protein structure and the translation process, highlighting the overarching impact of three-dimensional structure on gene expression, mRNA localization, and proteostasis.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-20DOI: 10.1016/j.cell.2024.11.031
Kevin Y. Chen, Marco De Giovanni, Ying Xu, Jinping An, Nikhita Kirthivasan, Erick Lu, Kan Jiang, Stephen Brooks, Serena Ranucci, Jiuling Yang, Shuto Kanameishi, Kenji Kabashima, Kevin Brulois, Michael Bscheider, Eugene C. Butcher, Jason G. Cyster
{"title":"Inflammation switches the chemoattractant requirements for naive lymphocyte entry into lymph nodes","authors":"Kevin Y. Chen, Marco De Giovanni, Ying Xu, Jinping An, Nikhita Kirthivasan, Erick Lu, Kan Jiang, Stephen Brooks, Serena Ranucci, Jiuling Yang, Shuto Kanameishi, Kenji Kabashima, Kevin Brulois, Michael Bscheider, Eugene C. Butcher, Jason G. Cyster","doi":"10.1016/j.cell.2024.11.031","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.031","url":null,"abstract":"Sustained lymphocyte migration from blood into lymph nodes (LNs) is important for immune responses. The CC-chemokine receptor-7 (CCR7) ligand CCL21 is required for LN entry but is downregulated during inflammation, and it has been unclear how recruitment is maintained. Here, we show that the oxysterol biosynthetic enzyme cholesterol-25-hydroxylase (Ch25h) is upregulated in LN high endothelial venules during viral infection. Lymphocytes become dependent on oxysterols, generated through a transcellular endothelial-fibroblast metabolic pathway, and the receptor EBI2 for inflamed LN entry. Additionally, Langerhans cells are an oxysterol source. Ch25h is also expressed in inflamed peripheral endothelium, and EBI2 mediates B cell recruitment in a tumor model. Finally, we demonstrate that LN CCL19 is critical in lymphocyte recruitment during inflammation. Thus, our work explains how naive precursor trafficking is sustained in responding LNs, identifies a role for oxysterols in cell recruitment into inflamed tissues, and establishes a logic for the CCR7 two-ligand system.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"113 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-20DOI: 10.1016/j.cell.2024.11.029
Lorena Benedetti, Ruolin Fan, Aubrey V. Weigel, Andrew S. Moore, Patrick R. Houlihan, Mark Kittisopikul, Grace Park, Alyson Petruncio, Philip M. Hubbard, Song Pang, C. Shan Xu, Harald F. Hess, Stephan Saalfeld, Vidhya Rangaraju, David E. Clapham, Pietro De Camilli, Timothy A. Ryan, Jennifer Lippincott-Schwartz
{"title":"Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites","authors":"Lorena Benedetti, Ruolin Fan, Aubrey V. Weigel, Andrew S. Moore, Patrick R. Houlihan, Mark Kittisopikul, Grace Park, Alyson Petruncio, Philip M. Hubbard, Song Pang, C. Shan Xu, Harald F. Hess, Stephan Saalfeld, Vidhya Rangaraju, David E. Clapham, Pietro De Camilli, Timothy A. Ryan, Jennifer Lippincott-Schwartz","doi":"10.1016/j.cell.2024.11.029","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.029","url":null,"abstract":"Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca<sup>2+</sup> channels and ER Ca<sup>2+</sup>-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca<sup>2+</sup> homeostasis, and local activation of the Ca<sup>2+</sup>/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca<sup>2+</sup> modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca<sup>2+</sup> release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca<sup>2+</sup> release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"41 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-19DOI: 10.1016/j.cell.2024.11.020
Kyle Burrows, Louis Ngai, Pailin Chiaranunt, Jacqueline Watt, Sarah Popple, Brian Forde, Saven Denha, Vitoria M. Olyntho, Siu Ling Tai, Eric Yixiao Cao, Susana Tejeda-Garibay, Joshua F.E. Koenig, Katrin D. Mayer-Barber, Catherine J. Streutker, Katrina K. Hoyer, Lisa C. Osborne, Jun Liu, Liam O’Mahony, Arthur Mortha
{"title":"A gut commensal protozoan determines respiratory disease outcomes by shaping pulmonary immunity","authors":"Kyle Burrows, Louis Ngai, Pailin Chiaranunt, Jacqueline Watt, Sarah Popple, Brian Forde, Saven Denha, Vitoria M. Olyntho, Siu Ling Tai, Eric Yixiao Cao, Susana Tejeda-Garibay, Joshua F.E. Koenig, Katrin D. Mayer-Barber, Catherine J. Streutker, Katrina K. Hoyer, Lisa C. Osborne, Jun Liu, Liam O’Mahony, Arthur Mortha","doi":"10.1016/j.cell.2024.11.020","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.020","url":null,"abstract":"The underlying mechanisms used by the intestinal microbiota to shape disease outcomes of the host are poorly understood. Here, we show that the gut commensal protozoan, <em>Tritrichomonas musculis</em> (<em>T.mu</em>), remotely shapes the lung immune landscape to facilitate perivascular shielding of the airways by eosinophils. Lung-specific eosinophilia requires a tripartite immune network between gut-derived inflammatory group 2 innate lymphoid cells and lung-resident T cells and B cells. This network exacerbates the severity of allergic airway inflammation while hindering the systemic dissemination of pulmonary <em>Mycobacterium tuberculosis</em>. The identification of protozoan DNA sequences in the sputum of patients with severe allergic asthma further emphasizes the relevance of commensal protozoa in human disease. Collectively, these findings demonstrate that a commensal protozoan tunes pulmonary immunity via a gut-operated lung immune network, promoting both beneficial and detrimental disease outcomes in response to environmental airway allergens and pulmonary infections.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-19DOI: 10.1016/j.cell.2024.11.012
Jason J. Liu, Beatrice Borsari, Yunyang Li, Susanna X. Liu, Yuan Gao, Xin Xin, Shaoke Lou, Matthew Jensen, Diego Garrido-Martín, Terril L. Verplaetse, Garrett Ash, Jing Zhang, Matthew J. Girgenti, Walter Roberts, Mark Gerstein
{"title":"Digital phenotyping from wearables using AI characterizes psychiatric disorders and identifies genetic associations","authors":"Jason J. Liu, Beatrice Borsari, Yunyang Li, Susanna X. Liu, Yuan Gao, Xin Xin, Shaoke Lou, Matthew Jensen, Diego Garrido-Martín, Terril L. Verplaetse, Garrett Ash, Jing Zhang, Matthew J. Girgenti, Walter Roberts, Mark Gerstein","doi":"10.1016/j.cell.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.012","url":null,"abstract":"Psychiatric disorders are influenced by genetic and environmental factors. However, their study is hindered by limitations on precisely characterizing human behavior. New technologies such as wearable sensors show promise in surmounting these limitations in that they measure heterogeneous behavior in a quantitative and unbiased fashion. Here, we analyze wearable and genetic data from the Adolescent Brain Cognitive Development (ABCD) study. Leveraging >250 wearable-derived features as digital phenotypes, we show that an interpretable AI framework can objectively classify adolescents with psychiatric disorders more accurately than previously possible. To relate digital phenotypes to the underlying genetics, we show how they can be employed in univariate and multivariate genome-wide association studies (GWASs). Doing so, we identify 16 significant genetic loci and 37 psychiatric-associated genes, including <em>ELFN1</em> and <em>ADORA3</em>, demonstrating that continuous, wearable-derived features give greater detection power than traditional case-control GWASs. Overall, we show how wearable technology can help uncover new linkages between behavior and genetics.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-19DOI: 10.1016/j.cell.2024.11.017
Toshimichi Yamada, Coralie Trentesaux, Jonathan M. Brunger, Yini Xiao, Adam J. Stevens, Iain Martyn, Petr Kasparek, Neha P. Shroff, Angelica Aguilar, Benoit G. Bruneau, Dario Boffelli, Ophir D. Klein, Wendell A. Lim
{"title":"Synthetic organizer cells guide development via spatial and biochemical instructions","authors":"Toshimichi Yamada, Coralie Trentesaux, Jonathan M. Brunger, Yini Xiao, Adam J. Stevens, Iain Martyn, Petr Kasparek, Neha P. Shroff, Angelica Aguilar, Benoit G. Bruneau, Dario Boffelli, Ophir D. Klein, Wendell A. Lim","doi":"10.1016/j.cell.2024.11.017","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.017","url":null,"abstract":"<em>In vitro</em> development relies primarily on treating progenitor cells with media-borne morphogens and thus lacks native-like spatial information. Here, we engineer morphogen-secreting organizer cells programmed to self-assemble, via cell adhesion, around mouse embryonic stem (ES) cells in defined architectures. By inducing the morphogen WNT3A and its antagonist DKK1 from organizer cells, we generated diverse morphogen gradients, varying in range and steepness. These gradients were strongly correlated with morphogenetic outcomes: the range of minimum-maximum WNT activity determined the resulting range of anterior-to-posterior (A-P) axis cell lineages. Strikingly, shallow WNT activity gradients, despite showing truncated A-P lineages, yielded higher-resolution tissue morphologies, such as a beating, chambered cardiac-like structure associated with an endothelial network. Thus, synthetic organizer cells, which integrate spatial, temporal, and biochemical information, provide a powerful way to systematically and flexibly direct the development of ES or other progenitor cells in different directions within the morphogenetic landscape.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"53 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellPub Date : 2024-12-18DOI: 10.1016/j.cell.2024.11.010
Mark Zucker, Maria A. Perry, Samuel I. Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A. Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T.A. Donoghue, Yonina R. Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, Chaitanya Bandlamudi
{"title":"Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer","authors":"Mark Zucker, Maria A. Perry, Samuel I. Gould, Arielle Elkrief, Anton Safonov, Rohit Thummalapalli, Miika Mehine, Debyani Chakravarty, A. Rose Brannon, Marc Ladanyi, Pedram Razavi, Mark T.A. Donoghue, Yonina R. Murciano-Goroff, Kristiana Grigoriadis, Nicholas McGranahan, Mariam Jamal-Hanjani, Charles Swanton, Yuan Chen, Ronglai Shen, Sarat Chandarlapaty, Chaitanya Bandlamudi","doi":"10.1016/j.cell.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.cell.2024.11.010","url":null,"abstract":"The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as <em>KEAP1</em>. Genomic, functional, and clinical data collectively indicate that <em>KEAP1</em> VUSs phenocopy established <em>KEAP1</em> oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"258 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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