WIP1 phosphatase is a negative regulator of NF-[kappa]B signalling

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...

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Veröffentlicht in:Nature cell biology 2009-05, Vol.11 (5), p.659
Hauptverfasser: Chew, Joanne, Biswas, Subhra, Shreeram, Sathyavageeswaran, Humaidi, Mahathir, Wong, Ee Tsin, Dhillion, Manprit Kaur, Teo, Hsiangling, Hazra, Amit, Fang, Cheok Chit, López-collazo, Eduardo, Bulavin, Dmitry V, Tergaonkar, Vinay
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Sprache:eng
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Zusammenfassung: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.
ISSN:1465-7392
1476-4679
DOI:10.1038/ncb1873