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Ectopic expression of NLRC4 facilitates the activation of the IFN\u2010\u03b2 promoter, the mRNA levels of <jats:italic>IFN\u2010\u03b2<\/jats:italic>, <jats:italic>ISG54<\/jats:italic>, and <jats:italic>ISG56<\/jats:italic>, and the nuclear translocation of interferon regulatory factor 3 induced by cGAS and STING. Consistently, under herpes simplex virus\u20101 (HSV\u20101) infection, knockdown or knockout of NLRC4 in BJ cells and primary peritoneal macrophages from <jats:italic>Nlrc4<\/jats:italic>\u2010deficient (<jats:italic>Nlrc4<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) mice show attenuated <jats:italic>Ifn\u2010\u03b2<\/jats:italic>, <jats:italic>Isg54<\/jats:italic>, and <jats:italic>Isg56<\/jats:italic> mRNA transcription, TBK1 phosphorylation, and augmented viral replications. Moreover, <jats:italic>Nlrc4<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice show higher mortality upon HSV\u20101 infection. Mechanistically, NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance the K63\u2010linked polyubiquitination of TBK1. Our study elucidates a previously uncharacterized function for NLRC4 in upregulating the cGAS\u2010STING signaling pathway and antiviral innate immunity.<\/jats:p>","DOI":"10.1002\/jmv.29013","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T05:34:51Z","timestamp":1691127291000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["NLRC4 promotes the cGAS\u2010STING signaling pathway by facilitating CBL\u2010mediated K63\u2010linked polyubiquitination of TBK1"],"prefix":"10.1002","volume":"95","author":[{"given":"Rongzhao","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medical Sciences Fujian Medical University Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxian","family":"Yang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute 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