Autophagy. 2023 Jul 20.
STING1 (stimulator of interferon response cGAMP interactor 1) plays an essential role in immune responses for virus inhibition via inducing the production of type I interferon, inflammatory factors and macroautophagy/autophagy. In this study, we found that STING1 activation could induce not only canonical autophagy but also non-canonical autophagy (NCA) which is independent of the ULK1 or BECN1 complexes to form MAP1LC3/LC3-positive structures. Whether STING1-induced NCA has similar characters and physiological functions to canonical autophagy is totally unknown. Different from canonical autophagy, NCA could increase single-membrane structures and failed to degrade long-lived proteins, and could be strongly suppressed by interrupting vacuolar-type H+-translocating ATPase (V-ATPase) activity. Importantly, STING1-induced NCA could effectively inhibit DNA virus HSV-1 in cell model. Moreover, STING1[1-340], a STING1 mutant lacking immunity and inflammatory response due to deletion of the tail end of STING1, could degrade virus through NCA alone, suggesting that the antiviral effect of activated STING1 could be separately mediated by inherent immunity, canonical autophagy, and NCA. In addition, the translocation and dimerization of STING1 do not rely on its immunity function and autophagy pathway. Similar to canonical autophagy, LC3-positive structures of NCA induced by STING1 could finally fuse with lysosomes, and the degradation of HSV-1 could be reverted by inhibition of lysosome function, suggesting that the elimination of DNA virus via NCA still requires the lysosome pathway. Collectively, we proved that besides its classical immunity function and canonical autophagy pathway, STING1-induced NCA is also an efficient antiviral pathway for the host cell.
Keywords: HSV-1; STING1; autophagy; inherent immunity; lysosome degradation; noncanonical autophagy