STING-Mediated Autophagy Is Protective against H(2)O(2)-Induced Cell Death

Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the H(2)O(2)-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING(−/−) MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in H(2)O(2)-treated WT cells as compared to STING(−/−) cells. STING(−/−) cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following H(2)O(2) treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against H(2)O(2)-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.