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Related Concept Videos

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.
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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...
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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 are of three kinds RI, RII, and RIII. The RI...
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Related Experiment Video

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Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization
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Published on: October 6, 2019

IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway.

Mumtaz Yaseen Balkhi1, Katherine A Fitzgerald, Paula M Pitha

  • 1Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD 21218, USA.

Cellular Signalling
|September 30, 2009
PubMed
Summary

Interferon regulatory factors (IRFs) are key in antiviral responses. This study identifies IKK alpha and alkaline phosphatase as novel negative regulators of IRF-5 activity in the MyD88 pathway.

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Last Updated: Jun 20, 2026

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Published on: October 6, 2019

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

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Published on: January 24, 2016

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Interferon regulatory factors (IRFs), including IRF-3, IRF-5, and IRF-7, are crucial for innate antiviral immunity.
  • IRF-3 and IRF-7 activation involves phosphorylation by TBK-1 and IKK epsilon.
  • The specific kinase responsible for IRF-5 phosphorylation within the MyD88 signaling pathway remained unidentified.

Purpose of the Study:

  • To identify the kinase that phosphorylates IRF-5 in the MyD88 signaling pathway.
  • To elucidate the molecular mechanisms by which IRF-5 activity is regulated.
  • To understand the role of these regulatory mechanisms in controlling inflammatory responses.

Main Methods:

  • Investigated the role of IKK alpha in IRF-5 phosphorylation and dimerization.
  • Assessed the impact of IKK alpha-mediated phosphorylation on transcriptional activation of type 1 interferon and inflammatory cytokines.
  • Examined the effect of IKK alpha on K63 ubiquitination of IRF-5.
  • Identified interactions between IRF-5 and alkaline phosphatase.

Main Results:

  • IKK alpha phosphorylates IRF-5, inducing dimer formation, which is typically indicative of activation.
  • However, IKK alpha-induced IRF-5 phosphorylation inhibits transcriptional activation of type 1 interferon and inflammatory cytokine promoters.
  • Phosphorylation by IKK alpha inhibits essential K63 ubiquitination of IRF-5.
  • IRF-5 interacts with alkaline phosphatase, leading to its de-phosphorylation.
  • MyD88-activated IRF-5 induces alkaline phosphatase expression, suggesting an autoregulatory loop.

Conclusions:

  • IKK alpha acts as a negative regulator of IRF-5 activity within the MyD88 pathway.
  • Alkaline phosphatase also functions as a negative regulator by de-phosphorylating IRF-5.
  • These findings reveal a novel autoregulatory mechanism controlling IRF-5 activity and inflammatory responses.