CellPub Date : 2025-06-10DOI: 10.1016/j.cell.2025.05.019
Rajappa S. Kenchappa, Laszlo Radnai, Erica J. Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T. Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K.H. Nagaiah, Gavin Rumbaugh, Michael D. Cameron, Theodore M. Kamenecka, Patrick R. Griffin, Courtney A. Miller, Steven S. Rosenfeld
{"title":"MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma","authors":"Rajappa S. Kenchappa, Laszlo Radnai, Erica J. Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T. Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K.H. Nagaiah, Gavin Rumbaugh, Michael D. Cameron, Theodore M. Kamenecka, Patrick R. Griffin, Courtney A. Miller, Steven S. Rosenfeld","doi":"10.1016/j.cell.2025.05.019","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.019","url":null,"abstract":"Glioblastoma (GBM) is the most lethal of primary brain tumors. Here<u>,</u> we report our studies of MT-125, a small-molecule inhibitor of non-muscle myosin II. MT-125 has high brain penetrance and an excellent safety profile<u>,</u> blocks GBM invasion and cytokinesis<u>,</u> and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro<u>.</u> Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)<u>/</u>mTOR inhibitor<u>,</u> significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"63 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252670","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 : 2025-06-10DOI: 10.1016/j.cell.2025.05.015
Helena Mannochio-Russo, Vincent Charron-Lamoureux, Martijn van Faassen, Santosh Lamichhane, Wilhan D. Gonçalves Nunes, Victoria Deleray, Adriana V. Ayala, Yuichiro Tanaka, Abubaker Patan, Kyle Vittali, Prajit Rajkumar, Yasin El Abiead, Haoqi Nina Zhao, Paulo Wender Portal Gomes, Ipsita Mohanty, Carlynda Lee, Aidan Sund, Meera Sharma, Yuanhao Liu, David Pattynama, Pieter C. Dorrestein
{"title":"The microbiome diversifies long- to short-chain fatty acid-derived N-acyl lipids","authors":"Helena Mannochio-Russo, Vincent Charron-Lamoureux, Martijn van Faassen, Santosh Lamichhane, Wilhan D. Gonçalves Nunes, Victoria Deleray, Adriana V. Ayala, Yuichiro Tanaka, Abubaker Patan, Kyle Vittali, Prajit Rajkumar, Yasin El Abiead, Haoqi Nina Zhao, Paulo Wender Portal Gomes, Ipsita Mohanty, Carlynda Lee, Aidan Sund, Meera Sharma, Yuanhao Liu, David Pattynama, Pieter C. Dorrestein","doi":"10.1016/j.cell.2025.05.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.015","url":null,"abstract":"<em>N</em>-Acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of <em>N</em>-acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving <em>N</em>-acyl lipid patterns from 2,700 public datasets, identifying 851 <em>N</em>-acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet and microbial colonization and in people living with diabetes. We used the library to link microbial <em>N</em>-acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and to highlight the value of large-scale untargeted metabolomics data for metabolite discovery.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"19 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252671","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 : 2025-06-10DOI: 10.1016/j.cell.2025.05.009
Oszkár Schütz, Zoltán Maróti, Balázs Tihanyi, Attila P. Kiss, Emil Nyerki, Alexandra Gînguță, Petra Kiss, Gergely I.B. Varga, Bence Kovács, Kitti Maár, Bernadett Ny. Kovacsóczy, Nikoletta Lukács, István Major, Antónia Marcsik, Eszter Patyi, Anna Szigeti, Zoltán Tóth, Dorottya Walter, Gábor Wilhelm, Réka Cs. Andrási, Tibor Török
{"title":"Unveiling the origins and genetic makeup of the “forgotten people”: A study of the Sarmatian-period population in the Carpathian Basin","authors":"Oszkár Schütz, Zoltán Maróti, Balázs Tihanyi, Attila P. Kiss, Emil Nyerki, Alexandra Gînguță, Petra Kiss, Gergely I.B. Varga, Bence Kovács, Kitti Maár, Bernadett Ny. Kovacsóczy, Nikoletta Lukács, István Major, Antónia Marcsik, Eszter Patyi, Anna Szigeti, Zoltán Tóth, Dorottya Walter, Gábor Wilhelm, Réka Cs. Andrási, Tibor Török","doi":"10.1016/j.cell.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.009","url":null,"abstract":"The nomadic Sarmatians dominated the Pontic Steppe from the 3rd century BCE and the Great Hungarian Plain from 50 CE until the Huns’ 4th-century expansion. In this study, we present a large-scale genetic analysis of 156 genomes from 1st- to 5th-century Hungary and the Carpathian foothills. Our findings reveal minor East Asian ancestry in the Carpathian Basin (CB) Sarmatians, distinguishing them from other regional populations. Using F4 statistics, qpAdm, and identity-by-descent (IBD) analysis, we show that CB Sarmatians descended from Steppe Sarmatians originating in the Ural and Kazakhstan regions, with Romanian Sarmatians serving as a possible genetic bridge between the two groups. We also identify two previously unknown migration waves during the Sarmatian era and a notable continuity of the Sarmatian population into the Hunnic period despite a smaller influx of Asian-origin individuals. These results shed new light on Sarmatian migrations and the genetic history of a key population neighboring the Roman Empire.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252673","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 : 2025-06-10DOI: 10.1016/j.cell.2025.05.020
Daniel A. Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu
{"title":"Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy","authors":"Daniel A. Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu","doi":"10.1016/j.cell.2025.05.020","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.020","url":null,"abstract":"Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"6 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252672","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 : 2025-06-09DOI: 10.1016/j.cell.2025.05.012
William Kong, Wan-Jin Lu, Megha Dubey, Rahul K. Suryawanshi, Sivakamasundari Vijayakumar, Youngtae Jeong, Saurabh Gombar, Maximilian Diehn, Kunyoo Shin, Melanie Ott, Yueh-hsiu Chien, Kavita Y. Sarin, Tushar J. Desai, Philip A. Beachy
{"title":"Neuroendocrine cells orchestrate regeneration through Desert hedgehog signaling","authors":"William Kong, Wan-Jin Lu, Megha Dubey, Rahul K. Suryawanshi, Sivakamasundari Vijayakumar, Youngtae Jeong, Saurabh Gombar, Maximilian Diehn, Kunyoo Shin, Melanie Ott, Yueh-hsiu Chien, Kavita Y. Sarin, Tushar J. Desai, Philip A. Beachy","doi":"10.1016/j.cell.2025.05.012","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.012","url":null,"abstract":"Understanding the mechanisms underlying mammalian regeneration may enable development of novel regenerative therapies. We present a mechanism wherein Desert hedgehog (Dhh), secreted from epithelial neuroendocrine cells, elicits a regenerative/protective response from mesenchymal cells. In mammalian airway, this mesenchymal response strikingly amplifies the initial signal from rare neuroendocrine cells to activate the entire tissue for survival and regeneration upon injury from SO<sub>2</sub> gas inhalation or following influenza or SARS-CoV-2 infection. Similar epithelial-mesenchymal feedback (EMF) signaling directed by Dhh from neuroendocrine β cells likewise protects mouse pancreatic islets from streptozotocin (STZ) injury. A role for EMF signaling in human pancreatic islets is suggested by higher incidence of diabetes in patients treated with Hedgehog pathway inhibitors. Remarkably, EMF augmentation by small-molecule Hedgehog pathway agonism protects against STZ injury of pancreatic β cells and shields against airway injury from SO<sub>2</sub> and influenza infection, with potential protective/therapeutic utility in chemical or infectious airway injury and in diabetes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"522 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237998","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 : 2025-06-09DOI: 10.1016/j.cell.2025.05.013
Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharaibeh, Laura Peterson, Shelby Steinmeyer, Emily M. Eshleman, Shikha Negi, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh
{"title":"Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns","authors":"Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharaibeh, Laura Peterson, Shelby Steinmeyer, Emily M. Eshleman, Shikha Negi, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh","doi":"10.1016/j.cell.2025.05.013","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.013","url":null,"abstract":"Early-life susceptibility to respiratory viral infections remains a major public health concern, yet the underlying mechanisms are poorly understood. We demonstrate that antibiotic-induced dysbiosis impairs influenza-specific CD8<sup>+</sup> T cell immunity in infant mice and humans through the disruption of nuclear factor interleukin 3 (NFIL3)-dependent T cell programming. Mechanistically, we show that dysbiosis reduces intestinal and circulating inosine levels, disrupting NFIL3’s epigenetic regulation of T cell factor 1 (TCF1) expression. This leads to intrinsic defects in CD8<sup>+</sup> T cell proliferation and differentiation, diminished effector responses, and impaired formation of tissue-resident memory cells. <em>Bifidobacterium</em> colonization restores intestinal and pulmonary inosine levels, establishing a specific pathway of gut-lung metabolic communication. Notably, inosine supplementation rescues NFIL3-dependent regulation of TCF1, enhancing CD8<sup>+</sup> T cell responses and protection against influenza infection in dysbiotic infants. Our findings reveal how early-life microbial communities shape antiviral immunity and identify inosine as a therapeutic target for enhancing respiratory defenses in infants.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"9 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237996","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 : 2025-06-07DOI: 10.1016/j.cell.2025.05.043
Erika K. Williams, Rui B. Chang, David E. Strochlic, Benjamin D. Umans, Bradford B. Lowell, Stephen D. Liberles
{"title":"Sensory Neurons that Detect Stretch and Nutrients in the Digestive System","authors":"Erika K. Williams, Rui B. Chang, David E. Strochlic, Benjamin D. Umans, Bradford B. Lowell, Stephen D. Liberles","doi":"10.1016/j.cell.2025.05.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.043","url":null,"abstract":"(Cell <em>166</em>, 209–221; June 30, 2016)","PeriodicalId":9656,"journal":{"name":"Cell","volume":"11656 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237420","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 : 2025-06-06DOI: 10.1016/j.cell.2025.05.014
Orlando DeLeon, Mora Mocanu, Alan Tan, Ashley M. Sidebottom, Jason Koval, Hugo D. Ceccato, Sarah Kralicek, John J. Colgan, Marissa M. St. George, Joash M. Lake, Michael Cooper, Jingwen Xu, Julia Moore, Qi Su, Zhilu Xu, Siew C. Ng, Francis K.L. Chan, Hein M. Tun, Candace M. Cham, Cambrian Y. Liu, Eugene B. Chang
{"title":"Microbiome mismatches from microbiota transplants lead to persistent off-target metabolic and immunomodulatory effects","authors":"Orlando DeLeon, Mora Mocanu, Alan Tan, Ashley M. Sidebottom, Jason Koval, Hugo D. Ceccato, Sarah Kralicek, John J. Colgan, Marissa M. St. George, Joash M. Lake, Michael Cooper, Jingwen Xu, Julia Moore, Qi Su, Zhilu Xu, Siew C. Ng, Francis K.L. Chan, Hein M. Tun, Candace M. Cham, Cambrian Y. Liu, Eugene B. Chang","doi":"10.1016/j.cell.2025.05.014","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.014","url":null,"abstract":"Fecal microbiota transplant (FMT) is an increasingly used intervention, but its suitability to restore regional gut microbiota, particularly in the small bowel (SB), must be questioned because of its predominant anaerobic composition. In human subjects receiving FMT by upper endoscopy, duodenal engraftment of anaerobes was observed after 4 weeks. We hypothesized that peroral FMTs create host-microbe mismatches that impact SB homeostasis. To test this, antibiotic-treated specific-pathogen-free (SPF) mice were given jejunal, cecal, or fecal microbiota transplants (JMTs, CMTs, or FMTs, respectively) and studied 1 or 3 months later. JMT and FMT altered regional microbiota membership and function, energy balance, and intestinal and hepatic transcriptomes; JMT favored host metabolic pathways and FMT favored immune pathways. MTs drove regional intestinal identity (<em>Gata4</em>, <em>Gata6</em>, and <em>Satb2</em>) and downstream differentiation markers. RNA sequencing (RNA-seq) of metabolite-exposed human enteroids and duodenal biopsies post-FMT confirmed transcriptional changes in mice. Thus, regional microbial mismatches after FMTs can lead to unintended consequences and require rethinking of microbiome-based interventions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"62 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228851","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 : 2025-06-02DOI: 10.1016/j.cell.2025.05.007
Timothy A. Currier, Thomas R. Clandinin
{"title":"Infrequent strong connections constrain connectomic predictions of neuronal function","authors":"Timothy A. Currier, Thomas R. Clandinin","doi":"10.1016/j.cell.2025.05.007","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.007","url":null,"abstract":"How does circuit wiring constrain neural computation? Recent work has leveraged connectomic datasets to predict the functions of cells and circuits in the brains of multiple species. However, many of these hypotheses have not been compared with physiological measurements, obscuring the limits of connectome-based functional predictions. To explore these limits, we characterized the visual responses of 43 cell types in the fruit fly and quantitatively compared them with connectomic predictions. We show that these predictions are accurate for some response properties, such as orientation tuning, but are surprisingly poor for other properties, such as receptive field size. Importantly, strong synaptic inputs are more functionally homogeneous than expected by chance and exert a disproportionately large influence on postsynaptic responses. Finally, we quantitatively define the subset of connections that best describe the functional differences between cell types. Our results establish a powerful set of constraints for improving the accuracy of connectomic predictions.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"129 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192780","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 : 2025-06-02DOI: 10.1016/j.cell.2025.05.008
Xavier Lahaye, Patrick Tran Van, Camellia Chakraborty, Anna Shmakova, Ngoc Tran Bich Cao, Hermine Ferran, Ouardia Ait-Mohamed, Mathieu Maurin, Joshua J. Waterfall, Benedikt B. Kaufer, Patrick Fischer, Thomas Hennig, Lars Dölken, Patrick Lomonte, Daniele Fachinetti, Nicolas Manel
{"title":"Centromeric DNA amplification triggered by viral proteins activates nuclear cGAS","authors":"Xavier Lahaye, Patrick Tran Van, Camellia Chakraborty, Anna Shmakova, Ngoc Tran Bich Cao, Hermine Ferran, Ouardia Ait-Mohamed, Mathieu Maurin, Joshua J. Waterfall, Benedikt B. Kaufer, Patrick Fischer, Thomas Hennig, Lars Dölken, Patrick Lomonte, Daniele Fachinetti, Nicolas Manel","doi":"10.1016/j.cell.2025.05.008","DOIUrl":"https://doi.org/10.1016/j.cell.2025.05.008","url":null,"abstract":"The cGAS-cGAMP-STING pathway is crucial for antiviral immunity. While cytosolic cGAS detects viral DNA, most DNA viruses shield their genome and invade the nucleus, where chromatin restricts cGAS activation. How viruses may activate nuclear cGAS is not well understood. Here, we show that several herpesvirus proteins trigger nuclear cGAS activation by perturbing centromeres, where cGAS is enriched. The herpes simplex virus type 1 (HSV-1) ubiquitin ligase infected cell protein 0 (ICP0), which degrades centromeric proteins, promotes centromeric DNA amplification through the translesion DNA synthesis (TLS) pathway in quiescent monocyte-derived cells, thereby activating nuclear cGAS. During infection, HSV-1 evades this detection by also expressing UL36USP, a suppressor of TLS. Similarly to ICP0, the cytomegalovirus IE1 protein causes centromeric DNA amplification and cGAS activation. We define this mechanism as viral-induced centromeric DNA amplification and recognition (VICAR), uncovering a non-mitotic, immune-activating role of centromeres.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"37 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192783","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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