TY - JOUR
T1 - Autophagy induction via STING trafficking is a primordial function of the cGAS pathway
AU - Gui, Xiang
AU - Yang, Hui
AU - Li, Tuo
AU - Tan, Xiaojun
AU - Shi, Peiqing
AU - Li, Minghao
AU - Du, Fenghe
AU - Chen, Zhijian J.
N1 - Funding Information:
Acknowledgements We thank C. Roy (Yale University) for providing the RavZ expression plasmids, B. Levine (UT Southwestern) for providing tissues from beclin 1-knockout mice, and A. Darehshouri at UT Southwestern Electron Microscopy Core Facility for training in electron microscopy sample preparation and image processing. We are grateful for suggestions and technical supports from Chen Laboratory members, especially L. Sun, Y. Wu and S. Hu. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP120718 and RP150498) and the Welch Foundation (I-1389). M.L. was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (T32AI005284). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. T. L. and X.T. are Cancer Research Institute Irvington Postdoctoral Fellows. Z.J.C. is an Investigator of Howard Hughes Medical Institute.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/14
Y1 - 2019/3/14
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-1006-9
DO - 10.1038/s41586-019-1006-9
M3 - Article
C2 - 30842662
AN - SCOPUS:85062871501
SN - 0028-0836
VL - 567
SP - 262
EP - 266
JO - Nature
JF - Nature
IS - 7747
ER -