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

J Exp Med. 2014 Feb 10;211(2):313-28. doi: 10.1084/jem.20122844. Epub 2014 Feb 3.


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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism*
  • DNA-Binding Proteins / metabolism
  • Female
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Rhabdoviridae Infections / immunology
  • Transcription Factors / metabolism
  • Ubiquitin Thiolesterase / deficiency
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / immunology*
  • Ubiquitin-Specific Proteases / metabolism*
  • Vesiculovirus / immunology


  • CARD Signaling Adaptor Proteins
  • DNA-Binding Proteins
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Transcription Factors
  • Trim25 protein, mouse
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Ddx58 protein, mouse
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases