The dual-specificity phosphatase DUSP14 negatively regulates tumor necrosis factor- and interleukin-1-induced nuclear factor-κB activation by dephosphorylating the protein kinase TAK1

J Biol Chem. 2013 Jan 11;288(2):819-25. doi: 10.1074/jbc.M112.412643. Epub 2012 Dec 10.

Abstract

The transcription factor NF-κB is critically involved in the inflammatory response triggered by the proinflammatory cytokines TNF and IL-1. Various studies have demonstrated that activation of TAK1 (TGF-β-activated kinase 1) is an essential step in TNF- and IL-1-induced NF-κB activation pathways. In this study, we identified a member of the dual-specificity phosphatase family, DUSP14, as a negative regulator of TNF- and IL-1-triggered NF-κB activation by expression screens. We found that DUSP14 interacted with TAK1 and that this interaction was enhanced by TNF or IL-1 stimulation. Overexpression of DUSP14 dephosphorylated TAK1 at Thr-187, a residue in the activation loop critically involved in TAK1 activation. Knockdown of DUSP14 increased basal as well as TNF- and IL-1-induced TAK1 phosphorylation at Thr-187. Overexpression of DUSP14, but not its phosphatase-deficient mutant, inhibited TNF- and IL-1-induced as well as TAK1-mediated NF-κB activation, whereas knockdown of DUSP14 had opposite effects. These findings suggest that DUSP14 negatively regulates TNF- or IL-1-induced NF-κB activation by dephosphorylating TAK1 at Thr-187. Our study reveals a new post-translational regulatory mechanism of NF-κB activation triggered by the proinflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / physiology*
  • Gene Knockdown Techniques
  • Humans
  • Interleukin-1 / physiology*
  • MAP Kinase Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Mitogen-Activated Protein Kinase Phosphatases / physiology*
  • NF-kappa B / metabolism*
  • Phosphorylation
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Interleukin-1
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP14 protein, human
  • Dual-Specificity Phosphatases