TY - JOUR
T1 - USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase
AU - Fan, Yihui
AU - Mao, Renfang
AU - Yu, Yang
AU - Liu, Shangfeng
AU - Shi, Zhongcheng
AU - Cheng, Jin
AU - Zhang, Huiyuan
AU - An, Lei
AU - Zhao, Yanling
AU - Xu, Xin
AU - Chen, Zhenghu
AU - Kogiso, Mari
AU - Zhang, Dekai
AU - Zhang, Hong
AU - Zhang, Pumin
AU - Jung, Jae U.
AU - Li, Xiaonan
AU - Xu, Guotong
AU - Yang, Jianhua
PY - 2014/2/10
Y1 - 2014/2/10
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20122844
DO - 10.1084/jem.20122844
M3 - Article
C2 - 24493797
AN - SCOPUS:84893721948
SN - 0022-1007
VL - 211
SP - 313
EP - 328
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -