Cell reportsPub Date : 2025-05-14DOI: 10.1016/j.celrep.2025.115705
Joana R Costa, Yang Li, Nurkaiyisah Zaal Anuar, David O'Connor, Sunniyat Rahman, Tanya Rapoz-D'Silva, Kent T M Fung, Rachael Pocock, Zhaodong Li, Stephen Henderson, Lingyi Wang, Mateja E Krulik, Sara Hyseni, Nivedita Singh, George Morrow, Yanping Guo, Daisy O F Gresham, Javier Herrero, Richard G Jenner, A Thomas Look, Dennis Kappei, Marc R Mansour
{"title":"Transcription factor cooperativity at a GATA3 tandem DNA sequence determines oncogenic enhancer-mediated activation.","authors":"Joana R Costa, Yang Li, Nurkaiyisah Zaal Anuar, David O'Connor, Sunniyat Rahman, Tanya Rapoz-D'Silva, Kent T M Fung, Rachael Pocock, Zhaodong Li, Stephen Henderson, Lingyi Wang, Mateja E Krulik, Sara Hyseni, Nivedita Singh, George Morrow, Yanping Guo, Daisy O F Gresham, Javier Herrero, Richard G Jenner, A Thomas Look, Dennis Kappei, Marc R Mansour","doi":"10.1016/j.celrep.2025.115705","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115705","url":null,"abstract":"<p><p>The TAL1 oncogene driving T cell lymphoblastic leukemia is frequently activated through mutated cis-regulatory elements, whereby small insertions or deletions (indels) create a binding site for the transcription factor MYB. Unraveling how non-coding mutations create oncogenic enhancers is key to understanding cancer biology and can provide important insights into fundamental mechanisms of gene regulation. Utilizing a CRISPR-Cas9 screening approach, we identify GATA3 as the key transcriptional regulator of enhancer-mediated TAL1 overexpression. CRISPR-Cas9 engineering of the mutant enhancer reveals a tandem GATA3 site that is required for binding of GATA3, chromatin accessibility, and MYB recruitment. Reciprocally, MYB binding to its motif is required for GATA3 recruitment, consistent with a transcription factor cooperativity model. Importantly, we show that GATA3 stabilizes a TAL1-MYB interaction and that complex formation requires GATA3 binding to DNA. Our work sheds light on the mechanisms of enhancer-mediated oncogene activation, where key transcription factors cooperate to achieve maximal transcriptional output, thereby supporting leukemogenesis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115705"},"PeriodicalIF":7.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076287","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}
Cell reportsPub Date : 2025-05-14DOI: 10.1016/j.celrep.2025.115702
Yatao Chen, Yajie Wan, Xiaoying Pei, Ziqi Wei, Tan Wang, Jun Zhang, Liming Chen
{"title":"GATA3 differentially regulates the transcriptome via zinc finger 2-modulated phase separation.","authors":"Yatao Chen, Yajie Wan, Xiaoying Pei, Ziqi Wei, Tan Wang, Jun Zhang, Liming Chen","doi":"10.1016/j.celrep.2025.115702","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115702","url":null,"abstract":"<p><p>Phase separation (PS) underlies gene control by transcription factors. However, little is known about whether and how DNA-binding domains (DBDs) regulate the PS for transcription factors to differentially regulate the transcriptome. The transcription factor GATA3, a master immune regulator, is frequently mutated in breast cancer. Here, we report that GATA3 undergoes DBD-modulated PS to mediate the formation of chromatin condensates. We show that the DBD regulates the GATA3 PS through its zinc finger 2 (ZnF2) domain, which provides positive charges for multivalent electrostatic interactions mainly via two arginine amino acids, R329 and R330. Compared with breast-cancer-associated GATA3 without ZnF2-defective mutations, breast cancer GATA3 with ZnF2-defective mutations causes aberrant ZnF2-modulated PS and condensate formation to remodel the differentially regulated transcriptome, resulting in a favorable prognosis for patients and reduced tumor growth in mice. Therefore, GATA3 demonstrates a principle of how a transcription factor differentially regulates the transcriptome via DBD-modulated PS.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115702"},"PeriodicalIF":7.5,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076272","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}
Cell reportsPub Date : 2025-05-13DOI: 10.1016/j.celrep.2025.115714
Lara M Boyle, Wanhui Sheng, Andres Villegas, Rhea Sahai, Sarah Irfan, Heon-Jin Lee, W Scott Young, Felix Leroy, Steven A Siegelbaum
{"title":"The ventral CA2 region of the hippocampus and its differential contributions to social memory and social aggression.","authors":"Lara M Boyle, Wanhui Sheng, Andres Villegas, Rhea Sahai, Sarah Irfan, Heon-Jin Lee, W Scott Young, Felix Leroy, Steven A Siegelbaum","doi":"10.1016/j.celrep.2025.115714","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115714","url":null,"abstract":"<p><p>The dorsal and ventral regions of the CA1 field of the hippocampus play distinct roles in the encoding of cognitive vs. emotional behaviors, respectively. Whether this distinction applies to other hippocampal fields and other behaviors is unclear. Here, we focus on the hippocampal CA2 field and compare the properties and behavioral roles of its dorsal (dCA2) and ventral (vCA2) regions. Although dCA2 is known to be required for social memory and to promote social aggression, the role of vCA2 is unknown. We report that a defined CA2 region extends to the extreme ventral pole of the hippocampus, with certain distinctions to dCA2. Unlike dCA2, chemogenetic silencing of vCA2 pyramidal neurons did not impair social memory. Similar to dCA2, vCA2 was required to promote social aggression. Thus, consistent with the CA1 region, CA2 may be differentially tuned to support cognitive compared with emotional processes along its dorsal to ventral axis.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115714"},"PeriodicalIF":7.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076283","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}
Cell reportsPub Date : 2025-05-13DOI: 10.1016/j.celrep.2025.115684
Mohankumar Ramar, Rosana Wiscovitch-Russo, Naohiro Yano, Harinder Singh, Edward Lamere, Michael Short, Norberto Gonzalez-Juarbe, Alexey V Fedulov
{"title":"Live bacteria in gut microbiome dictate asthma onset triggered by environmental particles via modulation of DNA methylation in dendritic cells.","authors":"Mohankumar Ramar, Rosana Wiscovitch-Russo, Naohiro Yano, Harinder Singh, Edward Lamere, Michael Short, Norberto Gonzalez-Juarbe, Alexey V Fedulov","doi":"10.1016/j.celrep.2025.115684","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115684","url":null,"abstract":"<p><p>Despite broad knowledge of the pathogenesis, our understanding of the origin of allergy and asthma remains poor, preventing etiotropic treatments. The gut microbiome is seen to be altered in asthmatics; however, proof of causality of the microbiome alterations is lacking. We report on gut microbiome transplantation (GMT) from mice predisposed to asthma by maternal exposure to pro-allergy environmental particles into naive recipients. This GMT confers asthma predisposition, and the effect is abrogated by gamma sterilization of the transplant material or by co-administration of antibacterials, indicating that viable bacteria are mediating the effect. Metagenomics identifies key changes in the \"pro-asthma\" microbiome, and metabolomics links the identified species to altered production of butyrate known to act on immune cells and epigenetic mechanisms. We further show that transplant recipients develop DNA methylation alterations in dendritic cells. Finally, dendritic cells with an altered methylome present allergen to T cells, and this effect is abrogated by an epigenetically acting drug in vitro.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115684"},"PeriodicalIF":7.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076275","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}
Cell reportsPub Date : 2025-05-13DOI: 10.1016/j.celrep.2025.115709
Krishna Kumar Ganta, Margaret McManus, Ross Blanc, Qixin Wang, Wonyeong Jung, Robin Brody, Mary Carrington, Robert Paris, Sumana Chandramouli, Ryan P McNamara, Katherine Luzuriaga
{"title":"Acute infectious mononucleosis generates persistent, functional EBNA-1 antibodies with high cross-reactivity to alpha-crystalline beta.","authors":"Krishna Kumar Ganta, Margaret McManus, Ross Blanc, Qixin Wang, Wonyeong Jung, Robin Brody, Mary Carrington, Robert Paris, Sumana Chandramouli, Ryan P McNamara, Katherine Luzuriaga","doi":"10.1016/j.celrep.2025.115709","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115709","url":null,"abstract":"<p><p>We investigate the magnitude, specificity, and functional properties of Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1)-specific antibodies in young adults over the course of primary infection. EBNA-1-specific binding antibodies, as well as antibodies capable of antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent complement deposition (ADCD), are detected. These antibodies primarily target a region of EBNA-1 known to elicit cross-reactive antibodies to several self-peptides. Higher EBNA-1 binding and ADCD antibodies are observed in individuals with at least one HLA-DRB1<sup>∗</sup>15:01 allele. Alpha-crystallin beta (CRYAB) binding and complement-fixing antibodies are detected at 6 months and 1 year following infectious mononucleosis, and CRYAB antibodies are resistant to denaturation, consistent with an affinity-matured response. Blocking experiments show that CRYAB antibodies are cross-reactive with EBNA-1. Altogether, high levels of functional EBNA-1 antibodies are generated in primary EBV infection, some of which are cross-reactive with CRYAB. Further investigation is warranted to determine whether these responses contribute to autoimmunity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115709"},"PeriodicalIF":7.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076141","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}
Cell reportsPub Date : 2025-05-13DOI: 10.1016/j.celrep.2025.115691
Nancy Sue, Le May Thai, Ebru Boslem, Kwan Yi Chu, Chenxu Yan, Leanne Mackin, William E Hughes, Angela Fontaine-Titley, Deborah Barkauskas, Louise Cottle, Helen E Thomas, Carsten Schmitz-Peiffer, Yan-Chuan Shi, Paul Timpson, David Herrmann, Martin Whitham, Trevor J Biden
{"title":"ER stress disrupts insulin release in murine models of type 2 diabetes by impairing retromer action and constitutive secretion.","authors":"Nancy Sue, Le May Thai, Ebru Boslem, Kwan Yi Chu, Chenxu Yan, Leanne Mackin, William E Hughes, Angela Fontaine-Titley, Deborah Barkauskas, Louise Cottle, Helen E Thomas, Carsten Schmitz-Peiffer, Yan-Chuan Shi, Paul Timpson, David Herrmann, Martin Whitham, Trevor J Biden","doi":"10.1016/j.celrep.2025.115691","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115691","url":null,"abstract":"<p><p>Using in vitro models of lipotoxicity and islets from the db/db mouse model of type 2 diabetes (T2D), we show that endoplasmic reticulum (ER) stress impairs β cell function. This is unrelated to apoptosis or alterations in insulin content or proinsulin processing, despite expansion of the Golgi compartment. Instead, the constitutive secretory pathway and endocytic recycling are disrupted, as revealed by depletion of glycosylated proteins and syntaxins from the plasma membrane (PM) and accumulation of E-cadherin in the retromer. This involves the PERK arm of the unfolded protein response. Proteomics identified multiple PM proteins mislocalized by ER stress, notably axon-guidance and cell-adhesion proteins, and many with glycosylphosphatidylinositol linkages. A retromer chaperone attenuated defective insulin secretion from islets of both db/db and high-fat-fed mice. By identifying different endpoints and mechanisms, our results redefine the relevance of ER stress to β cell failure. They also implicate retromer chaperones as potential T2D therapeutics.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115691"},"PeriodicalIF":7.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076202","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}
Cell reportsPub Date : 2025-05-13DOI: 10.1016/j.celrep.2025.115708
Fan Yang, Anqi Li, Yuanyuan Zhu, Yan Zhou, Enming Tian, Mengxuan Yang, Qingtong Zhou, Dehua Yang, Ming-Wei Wang, Feng Mei, Di Zhu
{"title":"GATA1-mediated Notch signaling augment antitumor immunity of CD11b<sup>+</sup>CD27<sup>-</sup> natural killer cells maturation via BCL9/β-catenin signal.","authors":"Fan Yang, Anqi Li, Yuanyuan Zhu, Yan Zhou, Enming Tian, Mengxuan Yang, Qingtong Zhou, Dehua Yang, Ming-Wei Wang, Feng Mei, Di Zhu","doi":"10.1016/j.celrep.2025.115708","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115708","url":null,"abstract":"<p><p>The maturation process of natural killer (NK) cells is integral to their antitumor immune response. Despite the diverse effector properties exhibited during differentiation, targeting the fate of NK cells for immunotherapy remains challenging. Here, we demonstrate that deficiency of B cell lymphoma 9 (BCL9) induces transient expression of GATA1 in CD11b<sup>+</sup> CD27<sup>-</sup> NK cells upon activation of Notch and interleukin-18 receptor 1 (IL-18R1) signaling, which are crucial for their maturation and antitumor activity. Conversely, blocking Notch signaling impairs NK cell development and antitumor function. NK-specific Bcl9-deficiency enhances B16F10 tumor killing in vivo. Our findings underscore the intricate network interactions among transcription factors, signal transduction pathways in development, and cytokines modulated by BCL9 deficiency. Targeting BCL9 emerges as a promising strategy for melanoma therapy, bolstering NK cell maturation and cytotoxicity, and overcoming challenges in NK cell-based immunotherapies.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115708"},"PeriodicalIF":7.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076270","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}
Cell reportsPub Date : 2025-05-12DOI: 10.1016/j.celrep.2025.115699
Long V Nguyen, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Sarah Kronheim, Suet-Feung Chin, Raquel Manzano Garcia, Stephen-John Sammut, Giulia Lerda, Allan J W Lui, Helen A Bardwell, Wendy Greenwood, Hee Jin Shin, Riccardo Masina, Katarzyna Kania, Alejandra Bruna, Elham Esmaeilishirazifard, Emily A Kolyvas, Samuel Aparicio, Oscar M Rueda, Carlos Caldas
{"title":"Fitness and transcriptional plasticity of human breast cancer single-cell-derived clones.","authors":"Long V Nguyen, Yaniv Eyal-Lubling, Daniel Guerrero-Romero, Sarah Kronheim, Suet-Feung Chin, Raquel Manzano Garcia, Stephen-John Sammut, Giulia Lerda, Allan J W Lui, Helen A Bardwell, Wendy Greenwood, Hee Jin Shin, Riccardo Masina, Katarzyna Kania, Alejandra Bruna, Elham Esmaeilishirazifard, Emily A Kolyvas, Samuel Aparicio, Oscar M Rueda, Carlos Caldas","doi":"10.1016/j.celrep.2025.115699","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115699","url":null,"abstract":"<p><p>Clonal fitness and plasticity drive cancer heterogeneity. We used expressed lentiviral-based cellular barcodes combined with single-cell RNA sequencing to associate single-cell profiles with in vivo clonal growth. This generated a significant resource of growth measurements from over 20,000 single-cell-derived clones in 110 xenografts from 26 patient-derived breast cancer xenograft models. 167,375 single-cell RNA profiles were obtained from 5 models and revealed that rare propagating clones display a highly conserved model-specific differentiation program with reproducible regeneration of the entire transcriptomic landscape of the original xenograft. In 2 models of basal breast cancer, propagating clones demonstrated remarkable transcriptional plasticity at single-cell resolution. Dichotomous cell populations with different clonal growth properties, signaling pathways, and metabolic programs were characterized. By directly linking clonal growth with single-cell transcriptomes, these findings provide a profound understanding of clonal fitness and plasticity with implications for cancer biology and therapy.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115699"},"PeriodicalIF":7.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984430","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}
Cell reportsPub Date : 2025-05-12DOI: 10.1016/j.celrep.2025.115683
Raffaele Nicastro, Marie-Pierre Péli-Gulli, Marco Caligaris, Malika Jaquenoud, Ladislav Dokládal, Josephine Alba, Farida Tripodi, Benjamin Pillet, Melanie Brunner, Michael Stumpe, Kenji Muneshige, Riko Hatakeyama, Jörn Dengjel, Claudio De Virgilio
{"title":"TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.","authors":"Raffaele Nicastro, Marie-Pierre Péli-Gulli, Marco Caligaris, Malika Jaquenoud, Ladislav Dokládal, Josephine Alba, Farida Tripodi, Benjamin Pillet, Melanie Brunner, Michael Stumpe, Kenji Muneshige, Riko Hatakeyama, Jörn Dengjel, Claudio De Virgilio","doi":"10.1016/j.celrep.2025.115683","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115683","url":null,"abstract":"<p><p>The eukaryotic target of rapamycin complex 1 (TORC1) kinase is a homeostatic regulator of growth, integrating nutritional cues at the endolysosomal compartment. Amino acids activate mammalian TORC1 (mTORC1) through the Rag GTPases that recruit it to lysosomes via a short domain within the mTORC1 subunit Raptor. Intriguingly, this \"Raptor claw\" domain is absent in Kog1, the Raptor ortholog in yeast. Instead, as we show here, yeast utilizes the fungal-specific Tco89 to tether TORC1 to active Rag GTPases. This interaction enables TORC1 to precisely calibrate the activity of the S6K1-related effector kinase Sch9 in response to amino acid availability. TORC1 stabilizes Tco89 by phosphorylation, and its inactivation causes swift Tco89 proteolysis, provoking a redistribution of TORC1 from the vacuole to signaling endosomes and its spatial separation from Sch9. Thus, TORC1 not only operates in spatially distinct subcellular pools but also controls its own quantitative distribution between these pools to economize energy resources under fluctuating nutrient conditions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115683"},"PeriodicalIF":7.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975293","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}
Cell reportsPub Date : 2025-05-12DOI: 10.1016/j.celrep.2025.115696
Risako Gen, Amin Addetia, Daniel Asarnow, Young-Jun Park, Joel Quispe, Matthew C Chan, Jack T Brown, Jimin Lee, Melody G Campbell, Christopher P Lapointe, David Veesler
{"title":"SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.","authors":"Risako Gen, Amin Addetia, Daniel Asarnow, Young-Jun Park, Joel Quispe, Matthew C Chan, Jack T Brown, Jimin Lee, Melody G Campbell, Christopher P Lapointe, David Veesler","doi":"10.1016/j.celrep.2025.115696","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115696","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats-natural reservoirs of sarbecoviruses with a markedly different innate immune system than humans. We reveal that nsp1 potently inhibits translation in Rhinolophus lepidus bat cells, which belong to the same genus as known sarbecovirus reservoir hosts. We determined a cryoelectron microscopy structure of nsp1 bound to the R. lepidus 40S ribosomal subunit, showing that it blocks the mRNA entry channel by targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cells from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity, providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillover.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 5","pages":"115696"},"PeriodicalIF":7.5,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960595","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
