期刊
JOURNAL OF IMMUNOLOGY
卷 202, 期 8, 页码 2397-2406出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801447
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资金
- National Key Research and Development Program of China [2018YFC1004601]
- Natural Science Foundation of China [31601131, 31671454, 31622036, 81501253]
- Natural Science Foundation of Hubei Province [2018CFA016]
- Health Commission of Hubei Province [WJ2018H0028]
- Wuhan University [2042017kf0199, 2042017kf0242]
- State Key Laboratory of Veterinary Etiological Biology [SKLVEB2017KFKT004]
Mediator of IRF3 activation ([MITA] also known as STING) is a direct sensor of cyclic dinucleotide and critically mediates cytoplasmic DNA-triggered innate immune signaling. The activity of MITA is extensively regulated by ubiquitination and deubiquitination. In this study, we report that USP20 interacts with and removes K48-linked ubiquitin chains from MITA after HSV-1 infection, thereby stabilizing MITA and promoting cellular antiviral responses. Deletion of USP20 accelerates HSV-1-induced degradation of MITA and impairs phosphorylation of IRF3 and IkBa as well as subsequent induction of type I IFNs and proinflammatory cytokines after HSV-1 infection or cytoplasmic DNA challenge. Consistently, Usp20(-/-) mice produce decreased type I IFNs and proinflammatory cytokines, exhibit increased susceptibility to lethal HSV-1 infection, and aggravated HSV-1 replication compared with Usp20(+/+) mice. In addition, complement of MITA into Usp20(-/-) cells fully restores HSV-1-triggered signaling and inhibits HSV-1 infection. These findings suggest a crucial role of USP20 in maintaining the stability of MITA and promoting innate antiviral signaling.
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