The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha.

Authors:
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Alfonso Campanile
Alfonso Campanile
Ospedale Maggiore Policlinico
Giovanna Giuseppina Altobelli
Giovanna Giuseppina Altobelli
School of Medicine and Surgery
Indianapolis | United States
Vincenzo Cimini
Vincenzo Cimini
Medical School
Boston | United States
Gennaro Galasso
Gennaro Galasso
Federico II University
Italy

Proc Natl Acad Sci U S A 2008 Nov 13;105(46):17818-23. Epub 2008 Nov 13.

Dipartimento di Medicina Clinica, Scienze Cardiovascolari, ed Immunologiche, Università Federico II, 80134 Naples, Italy.

G-protein-coupled receptor (GPCR) kinases, GRKs, 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-IkappaB alpha interaction on NFkappaB signaling, we induced the overexpression and the knockdown of GRK5 in cell cultures. GRK5 overexpression causes nuclear accumulation of IkappaB alpha, leading to the inhibition of NFkappaB transcriptional activity. Opposite results are achieved by GRK5 knockdown through siRNA. A physical interaction between GRK5 and IkappaB 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 N-terminal domain of IkappaB alpha as the regions involved in such interaction. To confirm the biological relevance of this mechanism of regulation for NFkappaB, we evaluated the effects of GRK5-RH on NFkappaB-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 NFkappaB transcription activity. Placing these findings in perspective, this mechanism may represent a therapeutic target for all those conditions involving excessive NFkappaB activity.

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http://dx.doi.org/10.1073/pnas.0804446105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2584738PMC

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November 2008
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