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

• Published in: Nature (London) Vol. 567; no. 7747; pp. 262 - 266
• Main Authors: Gui, Xiang, Yang, Hui, Li, Tuo, Tan, Xiaojun, Shi, Peiqing, Li, Minghao, Du, Fenghe, Chen, Zhijian J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2019; Nature Publishing Group
• Subjects: 14/63; 631/250/262/2106; 631/80/39; 82; 82/83; Animals; Autophagosomes - metabolism; Autophagy; Autophagy (Cytology); Autophagy-Related Protein 5 - deficiency; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Autophagy-Related Protein-1 Homolog - deficiency; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Beclin-1 - deficiency; Beclin-1 - genetics; Beclin-1 - metabolism; Biological research; Biological response modifiers; Biosynthesis; Carrier Proteins - genetics; Carrier Proteins - metabolism; Class III Phosphatidylinositol 3-Kinases - metabolism; Cyclic guanosine monophosphate; Cytoplasm; Cytosol - virology; DNA; DNA Viruses - genetics; DNA Viruses - metabolism; DNA, Viral - metabolism; Endoplasmic Reticulum - metabolism; Enzymes; Evolution, Molecular; G proteins; Golgi Apparatus - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Infection; Interferon; Interferons - biosynthesis; Interferons - immunology; Letter; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Monomeric GTP-Binding Proteins - metabolism; multidisciplinary; Nucleotides, Cyclic - immunology; Nucleotides, Cyclic - metabolism; Nucleotidyltransferases - metabolism; Phosphate-Binding Proteins; Physiological aspects; Police officers; Protein binding; Protein Serine-Threonine Kinases - metabolism; Protein Transport; Science; Science (multidisciplinary); Sea Anemones; Signal Transduction; Vesicular Transport Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1006-9

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 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. 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.