USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase

Yihui Fan, Renfang Mao, Yang Yu, Shangfeng Liu, Zhongcheng Shi, Jin Cheng, Huiyuan Zhang, Lei An, Yanling Zhao, Xin Xu, Zhenghu Chen, Mari Kogiso, Dekai Zhang, Hong Zhang, Pumin Zhang, Jae U. Jung, Xiaonan Li, Guotong Xu, Jianhua Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Scopus citations


Lys63-linked polyubiquitination of RIG-I is essential in antiviral immune defense, yet the molecular mechanism that negatively regulates this critical step is poorly understood. Here, we report that USP21 acts as a novel negative regulator in antiviral responses through its ability to bind to and deubiquitinate RIG-I. Overexpression of USP21 inhibited RNA virus-induced RIG-I polyubiquitination and RIG-I-mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-α/β production, and antiviral responses in MEFs in response to RNA virus infection. USP21 also restricted antiviral responses in peritoneal macrophages (PMs) and bone marrow-derived 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 ubiquitinediting complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I.

Original languageEnglish (US)
Pages (from-to)313-328
Number of pages16
JournalJournal of Experimental Medicine
Issue number2
StatePublished - Feb 10 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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