期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 2, 页码 313-328出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20122844
关键词
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资金
- National Institutes of Health-NINDS [1R01NS072420, 1R21NS085467]
- National Basic Research Program [2013CB967500]
- National Natural Science Foundation of China [31170824]
- Basic Research Project of Shanghai Science and Technology Commission [13JC1405400]
- Specialized Research Fund for the Doctoral Program of Higher Education [20120072110016]
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-alpha/beta 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.
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