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Cited by 1,269interferon and immune responsesAutophagy in Disease and TherapyCalcium signaling and nucleotide metabolism

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

Open access
Gui, Xiang, Yang, Hui, Li, Tuo, Tan, Xiaojun, Shi, Peiqing, Li, Minghao, Du, Fenghe, Chen, Zhijian J.·2019·Nature
DOI 10.1038/s41586-019-1006-9PMC PMC9417302
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Abstract

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.

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  • cGAS-STING signaling induces autophagy important for clearance of intracellular DNA and virus.

    “At the same time, cGAS-STING signaling induces autophagy which is important for the clearance of intracellular DNA and virus.398”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [398]

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Cited by

Sorted by citations

Authors
Gui, X., Yang, H., Li, T., Tan, X., Shi, P., Li, M., Du, F., & Chen, Z. J.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Chen, Zhijian J.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2019-03
Volume
567
Issue
7747
Pages
262-266
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-019-1006-9
PMC
PMC9417302
OpenAlex
W2919692138
Cited by
1,269
References
2
Citations by year
2026: 168 · 2025: 238 · 2024: 223 · 2023: 183 · 2022: 174 · 2021: 144 · 2020: 103 · 2019: 35
FWCI
45.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • University of Texas Southwestern Medical Center
  • National Institutes of Health (5t32ai005284-45)
  • National Institute of Allergy and Infectious Diseases (T32-AI005284)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
autophagy, STING, cGAS, cGAMP, STING trafficking, ERGIC, Golgi apparatus, Arf GTPases, LC3 lipidation, WIPI2, ATG5, cytosolic DNA sensing, Nematostella vectensis, innate immunity, viral clearance
MeSH terms
Autophagosomes, Beclin-1, Autophagy-Related Protein 5, Autophagy-Related Protein-1 Homolog, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Autophagy, Carrier Proteins, Cytosol, DNA Viruses, DNA, Viral, Endoplasmic Reticulum, Golgi Apparatus, Humans, Interferons, Membrane Proteins, Nucleotides, Cyclic, Nucleotidyltransferases, Sea Anemones, Signal Transduction, Protein Serine-Threonine Kinases, Evolution, Molecular, Monomeric GTP-Binding Proteins, Protein Transport, Phosphate-Binding Proteins, Vesicular Transport Proteins, Mice, HEK293 Cells, Class III Phosphatidylinositol 3-Kinases

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