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

Xiang Gui, Hui Yang, Tuo Li, Xiaojun Tan, Peiqing Shi, Minghao Li, Fenghe Du and Zhijian J. Chen ()
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Xiang Gui: University of Texas Southwestern Medical Center
Hui Yang: University of Texas Southwestern Medical Center
Tuo Li: University of Texas Southwestern Medical Center
Xiaojun Tan: University of Texas Southwestern Medical Center
Peiqing Shi: University of Texas Southwestern Medical Center
Minghao Li: University of Texas Southwestern Medical Center
Fenghe Du: University of Texas Southwestern Medical Center
Zhijian J. Chen: University of Texas Southwestern Medical Center

Nature, 2019, vol. 567, issue 7747, 262-266

Abstract: Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self 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 independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum–Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases. STING-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis. cGAMP induced LC3 lipidation through a pathway that is 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 suggests that induction of autophagy is a primordial function of the cGAS–STING pathway.

Date: 2019
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DOI: 10.1038/s41586-019-1006-9

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