Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.

Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC and RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.Abbreviation: ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; GABARAP: GABA type A receptor-associated protein; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB.