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However, aberrant activation of MDA5 by viral infections or gain\u2010of\u2010function mutations leads to severe autoimmune diseases, for most of which effective treatment is limited. Here, it is shown that inactivation of ubiquitin\u2010specific protease 8 (USP8\/UBPy) degrades the MDA5 protein, suppressing antiviral signaling and autoimmunity. It is found that viral infection modulates the AKT\u2010dependent phosphorylation of USP8 at serine 718, which not only promotes the activation of USP8 but also enhances the association between USP8 and MDA5 and the consequent deubiquitination and stabilization of MDA5. Inactivation of USP8 specifically degrades the MDA5 protein regardless of the mutation pattern. Genetic deletion of\n                    <jats:italic>Usp8<\/jats:italic>\n                    in mice contributes to decreased levels of type I interferons and proinflammatory cytokines. Importantly, inhibition of USP8 or AKT can effectively suppress MDA5\u2010induced autoimmunity in Aicardi\u2013Gouti\u00e8res syndrome (AGS) mice and anti\u2010MDA5\u2010positive dermatomyositis (DM)\/systemic lupus erythematosus (SLE) patient cells. Therefore, these results highlight the critical roles of USP8 in innate antiviral immunity against RNA viruses and autoimmunity and provide a potential therapy for treating autoimmune diseases associated with MDA5.\n                  <\/jats:p>","DOI":"10.1002\/advs.202503865","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:10:51Z","timestamp":1751191851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["USP8\u2010Governed MDA5 Homeostasis Promotes Innate Immunity and Autoimmunity"],"prefix":"10.1002","volume":"12","author":[{"given":"Qimin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Personalized Drug Therapy Key Laboratory Sichuan Academy of Medical Sciences &amp; Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu 610072 China"},{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Huang","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial People's Hospital The First Affiliated Hospital of Nanchang Medical College  Nanchang 330006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology Union Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan 430022 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Tong","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengru","family":"Ma","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Yi","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Nanomedicine the Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and Technology Huazhong University of Science and Technology  Wuhan 430074 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus\u2010Peter","family":"Knobeloch","sequence":"additional","affiliation":[{"name":"Institute of Neuropathology University of Freiburg  79106 Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1586-8710","authenticated-orcid":false,"given":"Peijing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Personalized Drug Therapy Key Laboratory Sichuan Academy of Medical Sciences &amp; 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