USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase.
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.
Texas Children's Cancer Center, Department of Pediatrics, 2 Department of Pathology and Immunology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
Yihui
Y
Fan
Renfang
R
Mao
Yang
Y
Yu
Shangfeng
S
Liu
Zhongcheng
Z
Shi
Jin
J
Cheng
Huiyuan
H
Zhang
Lei
L
An
Yanling
Y
Zhao
Xin
X
Xu
Zhenghu
Z
Chen
Mari
M
Kogiso
Dekai
D
Zhang
Hong
H
Zhang
Pumin
P
Zhang
Jae U
JU
Jung
Xiaonan
X
Li
Guotong
G
Xu
Jianhua
J
Yang
D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D018353:Rhabdoviridae Infections / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D018116:Vesiculovirus / Q000276:immunology
D053468:CARD Signaling Adaptor Proteins; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D014157:Transcription Factors; C490034:Trim25 protein, mouse; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases