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

Abstract

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 211 Issue 2 Pg. 313-28 (Feb 10 2014) ISSN: 1540-9538 [Electronic] United States
• PMID: 24493797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, genetics, immunology)
• Ubiquitin-Specific Proteases (metabolism)
• Vesiculovirus (immunology)