USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. Academic Article uri icon


  • 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-/ 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 ubiquitin-editing complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I.

published proceedings

  • J Exp Med

author list (cited authors)

  • Fan, Y., Mao, R., Yu, Y., Liu, S., Shi, Z., Cheng, J., ... Yang, J.

citation count

  • 122

complete list of authors

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

publication date

  • February 2014