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- Title
WIP1 phosphatase is a negative regulator of NF-κB signalling.
- Authors
Chew, Joanne; Biswas, Subhra; Shreeram, Sathyavageeswaran; Humaidi, Mahathir; Ee Tsin Wong; Dhillion, Manprit Kaur; Hsiangling Teo; Hazra, Amit; Cheok Chit Fang; López-Collazo, Eduardo; Bulavin, Dmitry V.; Tergaonkar, Vinay
- Abstract
Post-translational modifications of NF-κB through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-κB, 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-κB signalling. WIP1-mediated regulation of NF-κB occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-κB activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-κB function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-κB. 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-κB 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-κB signalling in vivo.
- Subjects
PHOSPHATASES; PHOSPHORYLATION; PROTEIN kinases; CHROMATIN; NF-kappa B; CYTOLOGY; BIOLOGICAL research
- Publication
Nature Cell Biology, 2009, Vol 11, Issue 5, p659
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb1873