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.