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The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1.

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.

Pubmed ID: 22037600

Authors

  • Iwasaki H
  • Takeuchi O
  • Teraguchi S
  • Matsushita K
  • Uehata T
  • Kuniyoshi K
  • Satoh T
  • Saitoh T
  • Matsushita M
  • Standley DM
  • Akira S

Journal

Nature immunology

Publication Data

December 17, 2011

Associated Grants

None

Mesh Terms

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