Identification of interleukin-1 receptor-associated kinase 1 as a critical component that induces post-transcriptional activation of IκB-ζ

FEBS J. 2012 Jan;279(2):211-22. doi: 10.1111/j.1742-4658.2011.08416.x. Epub 2011 Nov 30.

Abstract

IκB-ζ, an essential inflammatory regulator, is specifically induced by Toll-like receptor ligands or interleukin (IL)-1β by post-transcriptional activation mediated via a 165-nucleotide element in IκB-ζ mRNA. Here, we analyzed the Toll-like receptor-IL-1 receptor signaling components involved in the post-transcriptional regulation of IκB-ζ with mutated estrogen receptor [ER(T2)] fusion proteins. Upon 4-hydroxytamoxifen treatment, the ER(T2) fusion proteins with IL-1 receptor-associated kinase (IRAK)1 and IRAK4 elicited specific activation of a reporter gene for the post-transcriptional regulation of IκB-ζ. The tumor necrosis factor receptor-associated factor (TRAF)6-ER(T2) protein activated nuclear factor-κB, but not post-transcriptional regulation, indicating that activation of IRAK1/4, but not of TRAF6, is sufficient to activate the 165-nucleotide element-mediated post-transcriptional mechanism. Interestingly, the post-transcriptional mechanism was not activated in TRAF6-deficient cells, indicating an essential role for TRAF6. Thus, the signaling pathway leading to nuclear factor-κB activation and the post-transcriptional activation bifurcates at IRAK1, suggesting a new pathway activated by IRAK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Estrogen Receptor Modulators / pharmacology
  • Estrogen Receptor beta / agonists
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Gene Silencing
  • Genes, Reporter / drug effects
  • HEK293 Cells
  • Humans
  • I-kappa B Proteins
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutant Proteins / antagonists & inhibitors
  • Mutant Proteins / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • RNA Processing, Post-Transcriptional*
  • RNA, Messenger / metabolism*
  • Recombinant Fusion Proteins / agonists
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • Estrogen Receptor Modulators
  • Estrogen Receptor beta
  • I-kappa B Proteins
  • Mutant Proteins
  • NF-kappa B
  • NFKBIZ protein, human
  • Nuclear Proteins
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 6
  • IRAK1 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases