MARCH5 promotes STING pathway activation by suppressing polymer formation of oxidized STING

Stimulator of interferon genes (STING) is a core DNA sensing adaptor in innate immune signaling. STING activity is regulated by a variety of post-translational modifications (PTMs), including phosphorylation, ubiquitination, sumoylation, palmitoylation, and oxidation, as well as the balance between active and inactive polymer formation. It remains unclear, though, how different PTMs and higher order structures cooperate to regulate STING activity. Here, we report that the mitochondrial ubiquitin ligase MARCH5 (Membrane Associated Ring-CH-type Finger 5, also known as MITOL) ubiquitinates STING and enhances its activation. A long-term MARCH5 deficiency, in contrast, leads to the production of reactive oxygen species, which then facilitate the formation of inactive STING polymers by oxidizing mouse STING cysteine 205. We show that MARCH5-mediated ubiquitination of STING prevents the oxidation-induced STING polymer formation. Our findings highlight that MARCH5 balances STING ubiquitination and polymer formation and its control of STING activation is contingent on oxidative conditions.

干扰素基因刺激因子（Stimulator of interferon genes, STING）是先天免疫信号通路中的核心DNA感应接头蛋白。STING的活性受多种翻译后修饰（post-translational modifications, PTMs）调控，包括磷酸化、泛素化、类泛素化、棕榈酰化与氧化，同时也受活性与非活性聚合体形成之间的动态平衡调控。但目前尚不清楚不同的翻译后修饰与高级空间结构如何协同调控STING的活性。本研究发现，线粒体泛素连接酶MARCH5（膜相关环指-CH型结构域蛋白5，又名MITOL）可对STING进行泛素化修饰并增强其活化。与之相反，长期缺失MARCH5会导致活性氧的产生，后者通过氧化小鼠STING的第205位半胱氨酸残基，促进非活性STING聚合体的形成。本研究证实，MARCH5介导的STING泛素化修饰可阻断氧化诱导的STING聚合体形成。本研究揭示，MARCH5可平衡STING的泛素化修饰与聚合体形成，其对STING活化的调控作用依赖于氧化应激条件。