The G-protein-coupled receptor kinase 5 inhibits NFκB transcriptional activity by inducing nuclear accumulation of IκBα

G-protein-coupled receptor (GPCR) kinases, GPCR, are known as serine/threonine kinases that regulate GPCR signaling, but recent findings propose functions for these kinases besides receptor desensitization. Indeed, GRK5 can translocate to the nucleus by means of a nuclear localization sequence, suggesting that this kinase regulates transcription events in the nucleus. To evaluate the effect of GRK5-I kappa b alpha interaction on NF kappa B signaling, we induced the overexpression and the knockdown of GRK5 in cell cultures. GRK5 overexpression causes nuclear accumulation of I kappa B alpha, leading to the inhibition of NF kappa B transcriptional activity. Opposite results are achieved by GRK5 knockdown through siRNA. A physical interaction between GRK5 and I kappa B alpha, rather than phosphorylative events, appears as the underlying mechanism. We identify the regulator of gene protein signaling homology domain of GRK5 (RH) and the IN-terminal domain Of I kappa B alpha as the regions involved in such interaction. To confirm the biological relevance of this mechanism of regulation for NF kappa B, we evaluated the effects of GRK5-RH on NF kappa B-dependent phenotypes. In particular, GRK5-RH overexpression impairs apoptosis protection and cytokine production in vitro and inflammation and tissue regeneration in vivo. Our results reveal an unexpected role for GRK5 in the regulation of NF kappa B transcription activity. Placing these findings in perspective, this mechanism may represent a therapeutic target for all those conditions involving excessive NF kappa B activity.