Autophagy Induction via STING Trafficking Is a Primordial Function of the cGAS Pathway

By Xiang Gui, Hui Yang, Tuo Li, Xiaojun Tan, Peiqing Shi, Minghao Li, Fenghe Du, Zhijian J. Chen. Nature, 2019

1,109 citations recorded by the source corpus.

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.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.

Subfields: Immunology, Parasitology, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/c4f4e443a48e9ce465f8ef4bab65513c78bae7f2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Guido Kroemer
2. R. Kang
3. V. Deretic
4. D. Tang
5. L. Zitvogel

In Parasitology

1. Guido Kroemer
2. V. Deretic
3. R. Kang
4. D. Tang
5. Beth Levine
6. G. Hotamışlıgil

In Public Health, Environmental and Occupational Health

1. Guido Kroemer
2. V. Deretic
3. Beth Levine
4. G. Hotamışlıgil

Citations in the corpus

• Autophagy in inflammation, infection, and immunometabolism (2021, background): “A mixed-function model emerges with autophagy and type I IFN as two parallel cGAS-STING-TBK1 outputs, that contribute to antiviral actions (Gui et al., 2019; Yamashiro et al., 2020).”
• Ferroptosis in infection, inflammation, and immunity (2021, background): “STING1 stimulates the formation of autophagosomes (Gui et al., 2019) and thus promotes ferroptotic cell death under zalcitabine-induced mitochondrial DNA damage or nuclear CTSB-related genomic DNA damage (Hämälistö et al., 2020; Li et al., 2021).”
• Role of neuroinflammation in neurodegeneration development (2023, background): “At the same time, cGAS-STING signaling induces autophagy which is important for the clearance of intracellular DNA and virus.(398) Considering the critical role of autophagy in neurodegeneration,(399) further studies are needed to figure out the role of cGAS-STING mediated autophagy in neurodegenera”