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, Zhijian Chen

Research output: Contribution to journalLetter

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)262-266
Number of pages5
JournalNature
Volume567
Issue number7747
DOIs
StatePublished - Mar 14 2019

Fingerprint

Autophagy
Interferons
GMP synthase (glutamine-hydrolyzing)
Phosphotransferases
Sea Anemones
DNA Viruses
GTP Phosphohydrolases
cyclic guanosine monophosphate-adenosine monophosphate
Cytosol
Cytoplasm
Cytokines
Membranes
DNA
Infection
Proteins

ASJC Scopus subject areas

  • General

Cite this

Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. / Gui, Xiang; Yang, Hui; Li, Tuo; Tan, Xiaojun; Shi, Peiqing; Li, Minghao; Du, Fenghe; Chen, Zhijian.

In: Nature, Vol. 567, No. 7747, 14.03.2019, p. 262-266.

Research output: Contribution to journalLetter

Gui, X, Yang, H, Li, T, Tan, X, Shi, P, Li, M, Du, F & Chen, Z 2019, 'Autophagy induction via STING trafficking is a primordial function of the cGAS pathway', Nature, vol. 567, no. 7747, pp. 262-266. https://doi.org/10.1038/s41586-019-1006-9
Gui, Xiang ; Yang, Hui ; Li, Tuo ; Tan, Xiaojun ; Shi, Peiqing ; Li, Minghao ; Du, Fenghe ; Chen, Zhijian. / Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. In: Nature. 2019 ; Vol. 567, No. 7747. pp. 262-266.
@article{8f89b2337ced45498fd369911c43ea33,
title = "Autophagy induction via STING trafficking is a primordial function of the cGAS pathway",
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.",
author = "Xiang Gui and Hui Yang and Tuo Li and Xiaojun Tan and Peiqing Shi and Minghao Li and Fenghe Du and Zhijian Chen",
year = "2019",
month = "3",
day = "14",
doi = "10.1038/s41586-019-1006-9",
language = "English (US)",
volume = "567",
pages = "262--266",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7747",

}

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

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 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85062871501&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062871501&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1006-9

DO - 10.1038/s41586-019-1006-9

M3 - Letter

C2 - 30842662

AN - SCOPUS:85062871501

VL - 567

SP - 262

EP - 266

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7747

ER -