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

Nature. 2019 Mar;567(7747):262-266. doi: 10.1038/s41586-019-1006-9. Epub 2019 Mar 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagosomes / metabolism
  • Autophagy*
  • 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
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Class III Phosphatidylinositol 3-Kinases / metabolism
  • Cytosol / virology
  • DNA Viruses / genetics
  • DNA Viruses / metabolism
  • DNA, Viral / metabolism
  • Endoplasmic Reticulum / metabolism
  • Evolution, Molecular
  • Golgi Apparatus / metabolism
  • HEK293 Cells
  • Humans
  • Interferons / biosynthesis
  • Interferons / immunology
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Monomeric GTP-Binding Proteins / metabolism
  • Nucleotides, Cyclic / immunology
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / metabolism*
  • Phosphate-Binding Proteins
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism
  • Sea Anemones
  • Signal Transduction*
  • Vesicular Transport Proteins / metabolism

Substances

  • Autophagy-Related Protein 5
  • BECN1 protein, human
  • Beclin-1
  • Carrier Proteins
  • DNA, Viral
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Phosphate-Binding Proteins
  • SEC24C protein, human
  • STING protein, human
  • Vesicular Transport Proteins
  • WIPI-2 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Interferons
  • Class III Phosphatidylinositol 3-Kinases
  • Autophagy-Related Protein-1 Homolog
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Ulk1 protein, mouse
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • SAR1A protein, human
  • Monomeric GTP-Binding Proteins