Chronic STING-dependent activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism in mice

Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and cellular metabolism.