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Severe COVID-19 has been reported to be associated with an impaired IFN response. However, the mechanisms of how SARS-CoV-2 antagonizes the host IFN response are poorly understood. In this study, we report that SARS-CoV-2 helicase NSP13 inhibits type I IFN production by directly targeting TANK-binding kinase 1 (TBK1) for degradation. Interestingly, inhibition of autophagy by genetic knockout of Beclin1 or pharmacological inhibition can rescue NSP13-mediated TBK1 degradation in HEK-293T cells. Subsequent studies revealed that NSP13 recruits TBK1 to p62, and the absence of p62 can also inhibit TBK1 degradation in HEK-293T and HeLa cells. Finally, TBK1 and p62 degradation and p62 aggregation were observed during SARS-CoV-2 infection in HeLa-ACE2 and Calu3 cells. Overall, our study shows that NSP13 inhibits type I IFN production by recruiting TBK1 to p62 for autophagic degradation, enabling it to evade the host innate immune response, which provides new insights into the transmission and pathogenesis of SARS-CoV-2 infection.<\/jats:p>","DOI":"10.4049\/jimmunol.2100684","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T17:05:19Z","timestamp":1641575119000},"page":"753-761","source":"Crossref","is-referenced-by-count":91,"title":["SARS-CoV-2 NSP13 Inhibits Type I IFN Production by Degradation of TBK1 via p62-Dependent Selective Autophagy"],"prefix":"10.1093","volume":"208","author":[{"given":"Chao","family":"Sui","sequence":"first","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University , Jinan, 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Shandong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Infection and Immunity of Shandong Province, Department of Immunology, School of Basic Medical Sciences, Shandong University , Jinan, Shandong,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0687-8108","authenticated-orcid":false,"given":"Gang","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital , Shenzhen, Guangdong Province,","place":["China"]},{"name":"The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong 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