{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:42:47Z","timestamp":1773769367103,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270970, 82241220"],"award-info":[{"award-number":["32270970, 82241220"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019065","name":"Tianjin Municipal Science and Technology Program","doi-asserted-by":"publisher","award":["22JCYBJC00440, 23JCZXJC00360, 24ZXZSSS00030"],"award-info":[{"award-number":["22JCYBJC00440, 23JCZXJC00360, 24ZXZSSS00030"]}],"id":[{"id":"10.13039\/501100019065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n \n Viral infection induces host cells to enter a state of \u201cvirus-induced senescence (VIS)\u201d, which provides a stable cellular environment for viral replication. However, it is unclear about the molecular mechanism of this process. Here, we identified cellular protein DAP5 and its N-terminal fragment DAP5\n 1\u2013451<\/jats:sub>\n as sensors to viral infection.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Upon SARS-CoV-2 infection, cellular apoptosis and senescence levels were assessed. This led to the identification of DAP5 as a pivotal proteolytic substrate that links viral protease activity to host cell fate determination. The specific cleavage site on DAP5 targeted by the non-structural protein 5 (NSP5) encoded by SARS-CoV-2 was mapped using Western Blot and Fluorescence Resonance Energy Transfer (FRET) analysis. The functional role of the resulting N-terminal fragment DAP5\n 1\u2013451<\/jats:sub>\n was then characterized through a series of molecular biology experiments, including ChIP-seq, dual-luciferase reporter assays, and co-immunoprecipitation (Co-IP). Furthermore, ubiquitination assays and protein stability analyses were conducted to delineate the degradation pathway responsible for clearing this N-terminal fragment DAP5\n 1-451<\/jats:sub>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Viral infection-activated caspase 3 cleaves DAP5, which contributed to positive feedback loops, reinforcing apoptotic process. NSP5 interrupted the apoptotic process by NSP5-specific cleavage of DAP5 that led to the production of the N-terminal fragment DAP5\n 1-451<\/jats:sub>\n , which initiated the cellular senescence program, achieving an \u201capoptosis\u2192senescence\u201d fate transformation and thereby promoting viral replication of SARS-CoV-2. Mechanistically, DAP5\n 1\u2013451<\/jats:sub>\n interacted with the transcription factor p53 to enter the nucleus and bind to\n CDKN1A<\/jats:italic>\n locus to increase its expression, thereby triggering cell cycle arrest. Additionally, DAP5\n 1\u2013451<\/jats:sub>\n activated the NF-\u03baB signaling pathway and promoted the production of senescence-associated secretory phenotype (SASP) factors. E3 ubiquitin ligase TRIM7 encoded by host cells degraded the N-terminal fragment DAP5\n 1\u2013451<\/jats:sub>\n by Glutamine C-degron-mediated ubiquitination and protein degradation, and restricted viral replication.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our findings clarify the mechanism of SARS-CoV-2 induced VIS and establish a model of host cells inhibiting VIS through protein degradation and limiting viral replication, which provides a basis for subsequent immunological studies of emergent pathogenic microbial infection.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1768183","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:38:42Z","timestamp":1773758322000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular sensor DAP5 decodes Betacoronaviral NSP5 to drive virus-induced senescence"],"prefix":"10.3389","volume":"17","author":[{"given":"Yao","family":"Lu","sequence":"first","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Xiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Tianjin Institute of Immunology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiale","family":"Wang","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zihan","family":"Meng","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyue","family":"Fan","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Zheng","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minghang","family":"Yu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Key Laboratory of Viral Infectious Diseases, Beijing Ditan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, Beijing Institute of Infectious Diseases, Beijing Key Laboratory of Viral Infectious Diseases, Beijing Ditan Hospital, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Immunology, Tianjin Medical University","place":["Tianjin, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor 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