WIP1 phosphatase is a negative regulator of NF-κB signalling

Post-translational modifications of NF-kappa B through phosphorylations enhance its transactivation potential. Much is known about the kinases that phosphorylate NF-kappa B, 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-kappa B signalling. WIP1-mediated regulation of NF-kappa B occurs in both a p38-dependent and independent manner. Overexpression of WIP1 resulted in decreased NF-kappa B activation in a dose-dependent manner, whereas WIP1 knockdown resulted in increased NF-kappa B function. We show that WIP1 is a direct phosphatase of Ser 536 of the p65 subunit of NF-kappa B. 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-kappa B 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-kappa B signalling in vivo.