Kinase independent inhibition of NFκB transcriptional activity by GRK5 through IκBα stabilization.

Abstract

Members of the G protein receptor kinase (GRK) family that regulates receptor desensitization and members of the nuclear transcription factors family NF[kappa]B have been recently and convincingly demonstrated to interact, although the effects on transcription and gene expression have not yet been described. Using overexpression, knockdown (small interfering RNA) and mutagenesis experiments, we demonstrate that GRK5 couples to and stabilizes the NF[kappa]B inhibitor I[kappa]B[alpha], and inhibits NF[kappa]B activity. Studies with minigenes suggest that the N-terminal Regulation of G protein Signaling (RGS) homology (RH) domain confers GRK5 such ability. GRK5-RH domain overexpression affects NF[kappa]B dependent phenotypes, such as apoptosis protection, cytokine production and inflammation and tissue regeneration. Our results reveal a novel, unexpected role of GRK5 in NF[kappa]B transcription activity regulation that represents a possible target for diagnostic and therapeutics