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

Zhao Lei, Meihong Deng, Zhongjie Yi, Qian Sun, Richard A. Shapiro, Hongbo Xu, Tunliang Li, Patricia A. Loughran, John E. Griepentrog, Hai Huang, Melanie J. Scott, Feizhou Huang, Timothy R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)G655-G667
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume314
Issue number6
DOIs
StatePublished - Jun 2018
Externally publishedYes

Keywords

  • Anoxia
  • Apoptosis
  • Cytosolic DNA sensing
  • DAMPs
  • Hypoxia

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