Related Experiment Video

Updated: Feb 28, 2026

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
11:44

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3

Published on: January 24, 2016

12.6K

Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses

Shengduo Liu1, Shasha Chen1, Xinran Li1

  • 1Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.

Cell Host & Microbe
|June 16, 2017
PubMed

Insights

Src family kinases (SFKs) inhibit TBK1, a key antiviral protein, through tyrosine phosphorylation. Inhibiting SFKs boosts innate antiviral immunity and protects against viral infections.

Area of Science:

  • Immunology
  • Molecular Biology
  • Virology

Background:

  • Cytosolic nucleic acid sensing triggers interferon production for antiviral defense.
  • Protein ubiquitination and Ser/Thr phosphorylation regulate these antiviral cascades.
  • TBK1 is a critical kinase in antiviral pathways, but its regulation is not fully understood.

Purpose of the Study:

  • To investigate the regulatory mechanisms of TBK1 in innate antiviral immunity.
  • To identify kinases that modulate TBK1 activity.
  • To explore the therapeutic potential of targeting these regulatory pathways.

Main Methods:

  • Investigated TBK1 phosphorylation using biochemical assays.
  • Utilized knockout cell lines (Lck/Hck/Fgr triple knockout) and ectopic expression systems.
  • Administered small-molecule SFK inhibitors in cellular and animal models (zebrafish, mice).
  • Analyzed viral infection-induced gene expression and protein activation (IRF3).

Main Results:

  • Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, inhibiting its dimerization and activation.
  • Antiviral responses were significantly enhanced in SFK-deficient cells.
  • Ectopic SFK expression impaired antiviral defense in cells and zebrafish.
  • SFK inhibitors bolstered antiviral responses and provided protection against viral infections in zebrafish and mice.
  • Viral infection upregulated SFKs via IRF3, establishing a negative feedback loop.

Conclusions:

  • TBK1 activity is negatively regulated by tyrosine phosphorylation mediated by SFKs.
  • SFKs are functionally integrated into innate antiviral immunity, acting as negative regulators.
  • Targeting SFKs with small-molecule inhibitors represents a potential therapeutic strategy to enhance antiviral immunity.
Keywords:
IRF3Src family kinaseTBK1antiviral responsecytosolic nucleic acid sensinginnate immunitykinase inhibitorprotein modificationtyrosine phosphorylationzebrafish

More Related Videos

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production08:32

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production

Published on: March 2, 2014

11.0K
Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells09:15

Tyramide Signal Amplification for the Immunofluorescent Staining of ZBP1-Dependent Phosphorylation of RIPK3 and MLKL After HSV-1 Infection in Human Cells

Published on: October 20, 2022

2.9K

Related Concept Videos

Receptor Tyrosine Kinases01:26

Receptor Tyrosine Kinases

Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
19.9K
Immune Response Against Viral Pathogens01:29

Immune Response Against Viral Pathogens

The immune system's response to viral infections is a complex and coordinated process involving natural killer (NK) cells, T cell-mediated responses, and antibody-mediated responses.
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
2.2K
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.7K
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR...
2.9K
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...
13.4K
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...
10.1K