The Mechanism and Function of Autophagy Induction by Cytosolic DNA

Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects pathogen infections or tissue damage by binding to microbial or self-DNA in the cytoplasm. Upon binding to DNA, cGAS produces cGAMP that binds and activates the adaptor protein stimulator of interferon genes (STING), which activates the kinases IKK and TBK1 to induce interferons and other inflammatory cytokines. Here, we report that STING also activates autophagy and induces cell death through a mechanism independent of TBK1 and IRF3 activation, which canonically triggers innate immunity signaling. Upon binding to cGAMP, STING translocates to the ER-Golgi intermediate compartments (ERGIC) and the Golgi in a process that depends on the COP-II complex and ARF GTPases. The STING-containing ERGIC serves as a membrane source for LC3 lipidation, a key step in autophagosome biogenesis. Interestingly, STING lacking its C tail for interferon signaling is still capable of membrane trafficking and autophagy induction. Through endosomes or autophagosomes, STING is further degraded in the lysosome to shut down its activation. Interestingly, we determined that cGAMP-induced autophagy is important for the clearance of DNA and viruses in the cytosol. Furthermore, sea anemone STING 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.