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Overexpression of USP21 inhibited RNA virus\u2013induced RIG-I polyubiquitination and RIG-I\u2013mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-\u03b1\/\u03b2 production, and antiviral responses in MEFs in response to RNA virus infection. USP21 also restricted antiviral responses in peritoneal macrophages (PMs) and bone marrow\u2013derived dendritic cells (BMDCs). USP21-deficient mice spontaneously developed splenomegaly and were more resistant to VSV infection with elevated production of IFNs. Chimeric mice with USP21-deficient hematopoietic cells developed virus-induced splenomegaly and were more resistant to VSV infection. Functional comparison of three deubiquitinases (USP21, A20, and CYLD) demonstrated that USP21 acts as a bona fide RIG-I deubiquitinase to down-regulate antiviral response independent of the A20 ubiquitin-editing complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I.<\/jats:p>","DOI":"10.1084\/jem.20122844","type":"journal-article","created":{"date-parts":[[2014,2,4]],"date-time":"2014-02-04T01:51:40Z","timestamp":1391478700000},"page":"313-328","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":173,"title":["USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase"],"prefix":"10.1084","volume":"211","author":[{"given":"Yihui","family":"Fan","sequence":"first","affiliation":[{"name":"Texas Children\u2019s Cancer Center, Department of Pediatrics 1 , 2"},{"name":"Department of Pathology and Immunology, Dan L. 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