Autophagy Induction via STING Trafficking Is a Primordial Function of the cGAS Pathway

Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self-DNA in the cytoplasm(1). Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines(2–6). Here, we report that STING also activates autophagy through a mechanism independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the ER-Golgi intermediate compartment (ERGIC) and the Golgi in a process dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway dependent on WIPI2 and ATG5 but independent of the ULK and VPS34/BECLIN kinase complexes. Furthermore, we show that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Interestingly, STING from the sea anemone Nematostella vectensis induces autophagy but not interferons in response to stimulation by cGAMP, suggesting that induction of autophagy is a primordial function of the cGAS-STING pathway.