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A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
11:27

A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α

Published on: November 2, 2018

Interleukin-1 receptor-associated kinase (IRAK) -1-mediated NF-kappaB activation requires cytosolic and nuclear

Gang Liu1, Young-Jun Park, Edward Abraham

  • 1Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|February 16, 2008
PubMed

Insights

Interleukin-1 receptor-associated kinase (IRAK)-1 has a novel nuclear role in activating NF-kappaB-dependent gene expression. This nuclear IRAK-1 function complements its known cytoplasmic actions in the Toll-like receptor/interleukin-1 receptor pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Interleukin-1 receptor-associated kinase (IRAK)-1 is crucial for Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling.
  • IRAK-1 mediates NF-kappaB activation through IKK activation, IkappaB degradation, and NF-kappaB nuclear translocation.

Purpose of the Study:

  • To investigate a novel nuclear function of IRAK-1 in NF-kappaB-dependent gene expression.
  • To elucidate the mechanisms by which nuclear IRAK-1 influences transcriptional activity.

Main Methods:

  • Stimulation of cells with IL-1 and LPS.
  • CRM-1-dependent nuclear export blockade.
  • Analysis of NF-kappaB transcriptional activity.
  • Chromatin immunoprecipitation assays.
  • In vitro and in vivo histone phosphorylation assays.

Main Results:

  • Nuclear localization of IRAK-1 increases upon cellular stimulation or blockade of nuclear export.
  • Induced IRAK-1 enhances NF-kappaB transcriptional activity, preceding IkappaB-alpha degradation.
  • IRAK-1 binds to the IkappaB-alpha promoter and enhances p65 subunit binding.
  • IRAK-1 phosphorylates histone H3 in vitro and is required for IL-1-induced histone H3 phosphorylation in vivo.

Conclusions:

  • IRAK-1 exerts both cytoplasmic and nuclear functions in activating NF-kappaB-dependent transcription.
  • Nuclear IRAK-1 directly participates in regulating NF-kappaB target gene expression.
  • These findings reveal a dual role for IRAK-1 in innate immune signaling pathways.

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