cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING

Am J Physiol Gastrointest Liver Physiol. 2018 Jun 1;314(6):G655-G667. doi: 10.1152/ajpgi.00326.2017. Epub 2018 Feb 15.


Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS-/-), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS-/- mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS-/- mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS-/- hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.

Keywords: DAMPs; anoxia; apoptosis; cytosolic DNA sensing; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Autophagy / physiology*
  • DNA Nucleotidyltransferases / physiology
  • Interferon Inducers / metabolism
  • Interferon Type I* / genetics
  • Interferon Type I* / metabolism
  • Liver* / blood supply
  • Liver* / metabolism
  • Liver* / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nucleotides, Cyclic / metabolism*
  • Nucleotidyltransferases / metabolism*
  • Protective Agents / metabolism
  • Reperfusion Injury* / metabolism
  • Reperfusion Injury* / prevention & control
  • Signal Transduction


  • Interferon Inducers
  • Interferon Type I
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Protective Agents
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA Nucleotidyltransferases
  • Nucleotidyltransferases
  • cGAS protein, mouse