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Chronic innate immune activation of TBK1 suppresses mTORC1 activity and
dysregulates cellular metabolism
#MMPMID28069950
Hasan M
; Gonugunta VK
; Dobbs N
; Ali A
; Palchik G
; Calvaruso MA
; DeBerardinis RJ
; Yan N
Proc Natl Acad Sci U S A
2017[Jan]; 114
(4
): 746-751
PMID28069950
show ga
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.
|Animals
[MESH]
|Energy Metabolism/physiology
[MESH]
|Fats/metabolism
[MESH]
|Female
[MESH]
|Glycolysis/physiology
[MESH]
|Immunity, Innate/*immunology
[MESH]
|Inflammation/immunology/metabolism
[MESH]
|Interferon Regulatory Factor-3/metabolism
[MESH]
|Male
[MESH]
|Mechanistic Target of Rapamycin Complex 1/*metabolism
[MESH]
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