Related Experiment Video

Updated: Dec 26, 2025

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

561

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

Maroof Hasan1, Vijay K Gonugunta1, Nicole Dobbs1

  • 1Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.

Proceedings of the National Academy of Sciences of the United States of America
|January 11, 2017
PubMed

Insights

Mice lacking Three-prime repair exonuclease 1 (Trex1) exhibit inflammation and metabolic issues due to the cGAS-STING pathway. TANK-binding kinase 1 (TBK1) activation by this pathway suppresses mTORC1, causing cellular metabolism defects.

Area of Science:

  • Immunology
  • Metabolism
  • Molecular Biology

Background:

  • Trex1 knockout (Trex1-/-) mice develop systemic inflammation via chronic cGAS-STING-TBK1-IRF3 pathway activation.
  • Trex1 deficiency is linked to reduced mammalian target of rapamycin complex 1 (mTORC1) activity, but the mechanism remains undefined.

Purpose of the Study:

  • To investigate the metabolic consequences of Trex1 deficiency.
  • To elucidate the mechanistic link between innate immune activation and metabolic dysregulation in Trex1-/- mice.

Main Methods:

  • Detailed metabolic analysis in Trex1-/- mice and cells.
  • Genetic manipulation (Sting, Irf3, Leptin deficiency) to separate inflammatory and metabolic phenotypes.
  • Identification of key regulatory pathways involved in Trex1 deficiency.

Main Results:

  • Trex1-/- mice display systemic metabolic defects, including impaired mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism.
  • STING deficiency ameliorated both inflammatory and metabolic phenotypes, while IRF3 deficiency primarily resolved inflammation.
  • TBK1 was identified as a crucial regulator suppressing mTORC1 activity in Trex1-/- cells, leading to metabolic abnormalities.

Conclusions:

  • Chronic innate immune activation through TBK1 in Trex1 deficiency suppresses mTORC1 activity.
  • This suppression results in significant cellular and systemic metabolic dysregulation.
Keywords:
TBK1TREX1innate immunitymTORC1metabolism

More Related Videos

Immunometabolic Circuits in Infection for Advancing Host Directed Therapies11:12

Immunometabolic Circuits in Infection for Advancing Host Directed Therapies

Published on: September 13, 2024

766
Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method08:04

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method

Published on: October 23, 2018

19.6K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.5K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.1K
Pulmonary Tuberculosis I01:29

Pulmonary Tuberculosis I

Tuberculosis, often called TB, is a contagious illness primarily caused by Mycobacterium tuberculosis. It mainly affects the lung parenchyma but can also impact other body parts.
Causative Organism
The primary infectious agent causing tuberculosis is Mycobacterium tuberculosis, a slow-growing, acid-fast, aerobic rod that exhibits sensitivity to heat and ultraviolet light. Instances of Mycobacterium bovis and Mycobacterium avium contributing to the development of TB infection are rare.
Mode of...
755
NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The...
9.7K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
11.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.0K