title: Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.
abstract: Three-prime repair exonuclease 1 knockout (Trex1-/-) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1-/-mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1-/-background, and many metabolic defects persist in Trex1-/-Irf3-/-cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1-/-mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1-/-cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Maroof
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Gonugunta
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nicole
authors.initials: N
authors.lastname: Dobbs
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Aktar
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Palchik
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Calvaruso
authors.affiliation: Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.|McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; nan.yan@utsouthwestern.edu.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
authors.forename: Nan
authors.identifier: 0000-0002-0637-3989
authors.initials: N
authors.lastname: Yan
mesh_terms: D000818:Animals; D004734:Energy Metabolism / Q000502:physiology; D005223:Fats / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000502:physiology; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009712:Nucleotides, Cyclic / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology
chemical_list: D005223:Fats; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C498588:Tbk1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases
keywords: TBK1; TREX1; innate immunity; mTORC1; metabolism