WIP1 phosphatase is a negative regulator of NF-kappaB signalling

Joanne Chew; Subhra Biswas; Sathyavageeswaran Shreeram; Mahathir Humaidi; Ee Tsin Wong; Manprit Kaur Dhillion; Hsiangling Teo; Amit Hazra; Cheok Chit Fang; Eduardo López-Collazo; Dmitry V Bulavin; Vinay Tergaonkar

doi:10.1038/ncb1873

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.

Authors

Joanne Chew¹, Subhra Biswas, Sathyavageeswaran Shreeram, Mahathir Humaidi, Ee Tsin Wong, Manprit Kaur Dhillion, Hsiangling Teo, Amit Hazra, Cheok Chit Fang, Eduardo López-Collazo, Dmitry V Bulavin, Vinay Tergaonkar

Affiliation

¹ Laboratory of NF- kappaB signalling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673.

PMID: 19377466
DOI: 10.1038/ncb1873

Abstract

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

Substances

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