Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):746-751. doi: 10.1073/pnas.1611113114. Epub 2017 Jan 9.

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

Author information

1
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390.
7
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; nan.yan@utsouthwestern.edu.
8
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

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.

KEYWORDS:

TBK1; TREX1; innate immunity; mTORC1; metabolism

PMID:
28069950
PMCID:
PMC5278463
DOI:
10.1073/pnas.1611113114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center