Aerospace engineering

TANK-binding kinase 1

Receptor

Signal transducing adaptor protein

Autophagy

Sting

AMPK

Biology

BAG3

Golgi apparatus

Engineering

Endoplasmic reticulum

Innate immune system

Kinase

Apoptosis

Stimulator of interferon genes

ATG5

Signal transduction

Mitogen-activated protein kinase kinase

Cell biology

Protein kinase A

Biochemistry

ULK1

Nature

Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self&nbsp;DNA in the cytoplasm1. 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 cytokines2–6. Here we report that STING also activates autophagy through a mechanism that is&nbsp;independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic&nbsp;reticulum–Golgi intermediate compartment (ERGIC) and the Golgi in a process that is&nbsp;dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, which is&nbsp;a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway that is&nbsp;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, which&nbsp;suggests that induction of autophagy is a primordial function of the cGAS–STING pathway. The authors report that the cGAS–STING pathway drives a form of autophagy that is independent of interferon induction and distinct from the conventional autophagy.

Autophagy induction via STING trafficking is a primordial function of the cGAS pathway