p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation.
p38 inhibition provides anti-DNA virus immunity by regulation of USP21 phosphorylation and STING activation.
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p38 抑制通过调节 USP21 磷酸化和 STING 激活提供抗 DNA 病毒免疫力
DOI：
10.1084/jem.20161387
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发表时间：
2017-04-03
期刊：
影响因子：
--
通讯作者：
Wang P
中科院分区：
文献类型：
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作者：
Chen Y;Wang L;Jin J;Luan Y;Chen C;Li Y;Chu H;Wang X;Liao G;Yu Y;Teng H;Wang Y;Pan W;Fang L;Liao L;Jiang Z;Ge X;Li B;Wang P
Chen等人结果表明，USP21是适配器蛋白刺突的去泛素酶，它负向调节DNA病毒诱导的I型干扰素的产生。HSV-1感染通过p38介导的SER538处USP21的磷酸化，使USP21在晚期被刺痛。干扰素基因刺激物(STING)是一种中枢接头蛋白，介导对DNA病毒感染的先天免疫反应。尽管泛素化对于刺痛功能是必不可少的，但病毒感染如何调节泛素化/去泛素化系统以控制刺痛活性仍不清楚。在本研究中，我们发现USP21是STING的一个重要的去泛素化酶，它通过降解STINK上K27/63连接的多泛素链来负性调节DNA病毒诱导的I型干扰素的产生。HSV-1感染通过p38介导的Ser538处USP21的磷酸化，使USP21在晚期被刺痛。抑制p38MAPK可增强病毒感染后干扰素的产生，保护小鼠免受致死性HSV-1感染。因此，我们的研究揭示了p38介导的USP21磷酸化在调节STIN介导的抗病毒功能中的关键作用，并确认p38-USP21轴是DNA病毒避免先天性免疫反应的重要途径。
Chen et al. show that USP21 is a deubiquitinating enzyme for the adaptor protein STING and that it negatively regulates the DNA virus–induced production of type I interferons. HSV-1 infection recruited USP21 to STING at a late stage by p38-mediated phosphorylation of USP21 at Ser538. Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus–induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.