Abstract：
Optimal activation of stimulator of interferon genes (STING) protein is crucial for host defenses against pathogens and avoiding detrimental effects. Various post-translational modifications control STING activity. However, the function of interferon (IFN)-stimulated gene (ISG) 15 modification (ISGylation) in controlling STING stability and activation is unclear. Here, we show that the E3 ISGylation ligases HECT domain- and RCC1-like domain-containing proteins (HERCs; HERC5 in humans and HERC6 in mice) facilitate STING activation by mediating ISGylation of STING at K150, preventing its K48-linked ubiquitination and degradation. Concordantly, Herc6 deficiency suppresses herpes simplex virus 1 infection-induced type I IFN responses and facilitates viral replication both in vitro and in vivo. Notably, severe acute respiratory syndrome coronavirus 2 protein papain-like protease cleaves HERC5-mediated ISGylation of STING, suppressing host antiviral responses. These data identify a mechanism by which HERCs-mediated ISGylation controls STING stability and activation and uncover the correlations and interactions of ISGylation and ubiquitination during STING activation.
摘要：
干扰素基因刺激因子（STING）蛋白的最佳激活对于宿主防御病原体和避免有害作用至关重要。各种翻译后修饰控制STING活性。然而,干扰素（IFN）刺激基因（ISG）15修饰（ISGylation）在控制STING稳定性和激活中的功能尚不清楚。这里,我们显示E3ISGylation连接酶HECT域和RCC1样结构域包含蛋白(HERCs;人HERC5和小鼠HERC6)通过在K150介导STING的ISGylation,防止其K48连接的泛素化和降解,促进STING激活.和谐地，Herc6缺乏抑制单纯疱疹病毒1感染诱导的I型IFN反应，并促进病毒在体外和体内复制。值得注意的是,严重急性呼吸综合征冠状病毒2蛋白木瓜蛋白酶样蛋白酶裂解HERC5介导的STING，抑制宿主抗病毒反应。这些数据确定了HERCs介导的ISGylation控制STING稳定性和激活的机制，并揭示了STING激活过程中ISGylation和泛素化的相关性和相互作用。
