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

Z Lei, M Deng, Z Yi, Q Sun… - American Journal …, 2018 - journals.physiology.org
Z Lei, M Deng, Z Yi, Q Sun, RA Shapiro, H Xu, T Li, PA Loughran, JE Griepentrog, H Huang…
American Journal of Physiology-Gastrointestinal and Liver …, 2018journals.physiology.org
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 …
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.
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