Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Significance Patients with chronic autoimmune and autoinflammatory diseases often also present metabolic phenotypes. The molecular connection between inflammation and metabolism is incompletely understood. We describe a mouse model, three-prime repair exonuclease 1 knockout, that presents both chronic systemic inflammation and metabolic dysregulation. We genetically separated the inflammation and metabolic phenotypes and biochemically identified TANK-binding kinase 1 (TBK1) as a key regulator of mammalian target of rapamycin complex 1, a master regulator of metabolism. Chronically activated TBK1 and interferon signaling are associated with many autoimmune diseases, including systemic lupus erythematosus. Our study provides a mechanism by which the innate immune signaling pathways regulate cellular metabolism.