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

Maroof Hasan, Vijay K. Gonugunta, Nicole Dobbs, Aktar Ali, Guillermo Palchik, Maria A. Calvaruso, Ralph J. DeBerardinis, Nan Yan

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)746-751
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number4
DOIs
StatePublished - Jan 24 2017

Fingerprint

GMP synthase (glutamine-hydrolyzing)
Inflammation
Interferon Regulatory Factor-3
Phenotype
Lipogenesis
Glycolysis
Bites and Stings
Leptin
Knockout Mice
Interferons
Energy Metabolism
Respiration
Phosphotransferases
Fats
mechanistic target of rapamycin complex 1
Genes
three prime repair exonuclease 1
cyclic guanosine monophosphate-adenosine monophosphate

Keywords

  • Innate immunity
  • Metabolism
  • mTORC1
  • TBK1
  • TREX1

ASJC Scopus subject areas

  • General

Cite this

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism. / Hasan, Maroof; Gonugunta, Vijay K.; Dobbs, Nicole; Ali, Aktar; Palchik, Guillermo; Calvaruso, Maria A.; DeBerardinis, Ralph J.; Yan, Nan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 4, 24.01.2017, p. 746-751.

Research output: Contribution to journalArticle

Hasan, Maroof ; Gonugunta, Vijay K. ; Dobbs, Nicole ; Ali, Aktar ; Palchik, Guillermo ; Calvaruso, Maria A. ; DeBerardinis, Ralph J. ; Yan, Nan. / Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 4. pp. 746-751.
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