Pantetheinase Vanin-1 potentiates agonist-induced STING activation via S-cysteaminylation.

Stimulator of interferon genes (STING) is a key player in innate immunity, and its dysregulation has been implicated in autoimmune and inflammatory diseases. The activation of STING is regulated by multiple factors, including post-translational modifications (PTMs), but the regulatory network of these PTMs remains incompletely characterized. Here, we report that vascular non-inflammatory molecule-1 (Vanin-1) facilitates STING activation and provide evidence supporting S-cysteaminylation as a previously unrecognized modification of STING. Mechanistically, Vanin-1 hydrolyzes pantetheine to pantothenic acid (vitamin B5) and cysteamine, an aminothiol that promotes S-cysteaminylation of STING at three conserved cysteine residues within the transmembrane domain and potentiates agonist-induced STING activation without directly activating STING. Genetic and pharmacological inhibition of Vanin-1 attenuated STING signaling induced by STING agonists and ameliorated DSS-induced colitis in vivo. Together, our findings reveal a novel regulatory role for Vanin-1 in the cGAS-STING pathway and suggest that Vanin-1 may represent a potential therapeutic target for inflammatory diseases characterized by aberrant cGAS-STING activation.