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However, whether host restricts its replication and the underlying mechanisms remain incompletely delineated. Here, we identify the E3 ubiquitin ligase RNF138 as an intrinsic restriction factor targeting the viral RNA\u2010dependent RNA polymerase (RdRp) NS5. Mechanistically, RNF138 directly interacts with the RdRp domain of NS5 through its ubiquitin\u2010interacting motif, catalyzes K48\u2010linked polyubiquitination and induces degradation of TBEV NS5. Ubiquitin\u2010remnant profiling and mutational analyses identify K372, K462, and K470 within NS5 as the ubiquitination sites, and mutating these residues leads to NS5 resistant to RNF138\u2010induced degradation. Functionally, RNF138 suppresses the replication of TBEV as well as Zika virus, a representative mosquito\u2010borne flavivirus, through recognizing and degrading NS5 proteins. Ectopic RNF138 reduces viral RNA levels in the brain and peripheral tissues of TBEV\u2010infected mice, mitigates neuroinflammatory responses, and improves survival. Notably, the antiviral activity is conserved among several mammalian RNF138 orthologs but absent in the arthropod homologs, highlighting a host\u2010specific antiviral adaptation. Together, these findings reveal RNF138\u2010mediated ubiquitination and degradation of NS5 as a mechanism of intrinsic defense against TBEV and provide a framework for exploring targeted destabilization of conserved flaviviral replicases.<\/jats:p>","DOI":"10.1002\/advs.75991","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:48:38Z","timestamp":1781084918000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RNF138\u2010Mediated Ubiquitination and Degradation of NS5 Restricts Tick\u2010Borne Encephalitis Virus Infection"],"prefix":"10.1002","volume":"13","author":[{"given":"Jialiang","family":"Sun","sequence":"first","affiliation":[{"name":"Institute of Virology and AIDS Research Centre of Infectious Diseases and Pathogen Biology Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases the First Hospital of Jilin University Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijing","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research Centre of Infectious Diseases and Pathogen Biology Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases the First Hospital of Jilin University Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Virology and AIDS Research Centre of Infectious Diseases and Pathogen Biology Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases the First Hospital of Jilin University Changchun 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