INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
FKBP proteins as new targets of pholyphenol-mediated NF-kB inhibition
Autor/es:
CAMISAY MF, DE LEO SA, COX M, GALIGNIANA MD, ERLEJMAN AG
Reunión:
Congreso; VI International Conference on Polyphenols and Health; 2013
Resumen:
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 (25mM-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