USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA
USP20 Promotes Cellular Antiviral Responses via Deconjugating K48-Linked Ubiquitination of MITA
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USP20 通过解偶联 MITA 的 K48 泛素化促进细胞抗病毒反应
DOI：
10.4049/jimmunol.1801447
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发表时间：
2019-04-15
影响因子：
4.4
通讯作者：
Lin, Dandan
中科院分区：
文献类型：
--
作者：
Zhang, Meng-Xin;Cai, Zeng;Lin, Dandan
IRF3激活介质（Mediator of IRF3 activation, [MITA]，也称为STING）是环二核苷酸的直接传感器，并介导细胞质dna触发的先天免疫信号。MITA的活性受到泛素化和去泛素化的广泛调控。在这项研究中，我们报道了USP20在HSV-1感染后与MITA相互作用并去除k48连接的泛素链，从而稳定MITA并促进细胞抗病毒反应。USP20的缺失加速了HSV-1诱导的MITA降解，损害了IRF3和IkBa的磷酸化，以及随后在HSV-1感染或细胞质DNA挑战后诱导I型ifn和促炎细胞因子。与Usp20（+/+）小鼠相比，Usp20（-/-）小鼠产生I型ifn和促炎细胞因子减少，对致死性HSV-1感染的易感性增加，HSV-1复制加剧。此外，MITA补体进入Usp20（-/-）细胞完全恢复HSV-1触发的信号并抑制HSV-1感染。这些发现表明USP20在维持MITA的稳定性和促进先天抗病毒信号传导中起关键作用。
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.