FKBP proteins as new targets of pholyphenol-mediated NF-kB inhibition

MARÍA F. CAMISAY; SONIA A. DE LEO; MARC COX; MARIO D. GALIGNIANA; ALEJANDRA G. ERLEJMAN

Buenos Aires

Congreso; VI International Conference on Polyphenols and Health; 2013

Oxygen Club of California

NF-kB (RelA/p50) activation depends on its nuclear translocation. Because FK506-binding proteins (FKBPs) FKBP51 and FKBP52 regulate the subcellular localization of steroid receptors, we studied whether these factors also affect the nuclear translocation of RelA/p50. FKBP51 forms complexes with RelA/p50 delaying its nuclear translocation. Cell stimulation with phorbol-ester (PMA) promotes FKBP51 exchange with FKBP52, favoring RelA/p50 nuclear accumulation. While NF-kB transcriptional response was significantly abrogated by FKBP51 in a concentration-dependent manner, FKBP52 showed a positive effect in a competitive fashion. PPIase-activity is not required for FKBP51 inhibitory action, but punctual mutations in essential amino-acids of the PPIase domain of FKBP52 (FKBP52F67Y and FKBP52F130Y) abolished NF-kB activity, an effect reverted by overexpression of wtFKBP52. Epigallocatechin-gallate (EGCG) is a polyphenol previously described as PPIase inhibitor. Accordingly, cells pre-incubated with EGCG (25uM-1h) blocked FKBP52 stimulatory action. Non-transfected cells under the same condition did not show significant NF-kB activation. We postulate that FKBP52 is a novel stimulator factor of NF-kB, whose effect depends on its intrinsic PPIase-activity. These observations raise the possibility that NFkB function may be regulated by the expression balance of both FKBPs, and suggest that FKBP52 could be a critical biological target for the pharmacological mechanism of action of polyphenols.