Thr-435 phosphorylation regulates RelA (p65) NF-κB subunit transactivation
Résumé
Phosphorylation of the RelA (p65) NF-κB subunit has been previously shown to modulate its ability to induce or repress transcription. Here we have investigated the consequences of Thr-435 phosphorylation within the C-terminal transactivation domain of RelA. We confirm that Thr-435 is phosphorylated in cells and is induced by TNFα treatment. Mutational analysis of this site revealed gene specific effects on transcription, with a T435D phosphomimetic mutant significantly enhancing Cxcl2 mRNA levels in reconstituted Rela-/- mouse embryonic fibroblasts. Chromatin immunoprecipitation analysis revealed that this mutation results in enhanced levels of histone acetylation, associated with decreased recruitment of the histone deacetylase HDAC1. Moreover, mutation of this site disrupted RelA interaction with HDAC1 in vitro. Thr-435 phosphorylation of promoter bound RelA was also detected at NF-κB target genes following TNFα treatment in wild type MEFs. Phosphorylation at this site therefore provides an additional mechanism through which the specificity of NF-κB transcriptional activity can be modulated in cells.
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