The IκB Kinase Complex Regulates the Stability of Cytokine-Encoding mRNA Induced by TLR-IL-1R by Controlling Degradation of regnase-1

Nat Immunol. 2011 Oct 30;12(12):1167-75. doi: 10.1038/ni.2137.

Abstract

Toll-like receptor (TLR) signaling activates the inhibitor of transcription factor NF-κB (IκB) kinase (IKK) complex, which governs NF-κB-mediated transcription during inflammation. The RNase regnase-1 serves a critical role in preventing autoimmunity by controlling the stability of mRNAs that encode cytokines. Here we show that the IKK complex controlled the stability of mRNA for interleukin 6 (IL-6) by phosphorylating regnase-1 in response to stimulation via the IL-1 receptor (IL-1R) or TLR. Phosphorylated regnase-1 underwent ubiquitination and degradation. Regnase-1 was reexpressed in IL-1R- or TLR-activated cells after a period of lower expression. Regnase-1 mRNA was negatively regulated by regnase-1 itself via a stem-loop region present in the regnase-1 3' untranslated region. Our data demonstrate that the IKK complex phosphorylates not only IκBα, thereby activating transcription, but also regnase-1, thereby releasing a 'brake' on IL-6 mRNA expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cell Line, Tumor
  • Cytokines / genetics*
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • I-kappa B Kinase / metabolism*
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Interleukin-6 / genetics
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Protein Binding
  • RNA Stability*
  • RNA, Messenger / metabolism*
  • Receptors, Interleukin-1 / metabolism*
  • Ribonucleases / metabolism*
  • Toll-Like Receptors / metabolism*

Substances

  • Cytokines
  • Interleukin-6
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Toll-Like Receptors
  • Interleukin-1 Receptor-Associated Kinases
  • I-kappa B Kinase
  • Ribonucleases
  • regnase-1, human
  • regnase-1, mouse