USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA

The Journal of Immunology : Official Journal of the American Association of Immunologists
Meng-Xin ZhangDandan Lin

Abstract

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 IκBα 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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Citations

Dec 5, 2019·Annual Review of Immunology·Ming-Ming Hu, Hong-Bing Shu
Jun 14, 2020·Signal Transduction and Targeted Therapy·Zhangliang ChengFangfang Zhou
Oct 27, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Hui SuTianjun Xu

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