WIP1 phosphatase is a negative regulator of NF-kappaB signalling

Nat Cell Biol. 2009 May;11(5):659-66. doi: 10.1038/ncb1873. Epub 2009 Apr 19.


Post-translational modifications of NF-kappaB through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-kappaB, but little is known about the phosphatases that dephosphorylate it. By using a genome-scale siRNA screen, we identified the WIP1 phosphatase as a negative regulator of NF-kappaB signalling. WIP1-mediated regulation of NF-kappaB occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-kappaB activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-kappaB function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-kappaB. Phosphorylation of Ser 536 is known to be essential for the transactivation function of p65, as it is required for recruitment of the transcriptional co-activator p300. WIP1-mediated regulation of p65 regulated binding of NF-kappaB to p300 and hence chromatin remodelling. Consistent with our results, mice lacking WIP1 showed enhanced inflammation. These results provide the first genetic proof that a phosphatase directly regulates NF-kappaB signalling in vivo.

MeSH terms

  • Animal Structures / drug effects
  • Animal Structures / metabolism
  • Animals
  • Cell Line, Tumor
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • HeLa Cells
  • Humans
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mice, Mutant Strains
  • Models, Biological
  • NF-kappa B / metabolism*
  • Phosphoprotein Phosphatases / physiology*
  • Phosphorylation / drug effects
  • Protein Phosphatase 2C
  • RNA, Small Interfering / genetics
  • Sepsis / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Spleen / cytology
  • Spleen / drug effects
  • Spleen / metabolism
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology
  • p300-CBP Transcription Factors / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Interleukin-1
  • Lipopolysaccharides
  • NF-kappa B
  • RNA, Small Interfering
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • p300-CBP Transcription Factors
  • p38 Mitogen-Activated Protein Kinases
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Ppm1d protein, mouse
  • Protein Phosphatase 2C