INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
Regulation of NF-ƒÛB Transcriptional Activity by High Molecular Weight Immunophilins
Autor/es:
ERLEJMAN AG, MOLINARI AM, MAZAIRA GI, GALIGNIANA MD
Lugar:
Les Diablerets
Reunión:
Congreso; 5th International Conference on the Hsp90 Chaperone Machine; 2010
Institución organizadora:
Hsp90 Organization
Resumen:
In previous studies, we demonstrated that the balance between the hsp90-binding immunophilins FKBP51 and FKBP52 are related to the subcellular localization and the biological action of various nuclear factors such as steroid receptors and p53. In this sense, both immunophilins have always shown antagonistic activity. Therefore, in this work we asked whether other nuclear factor such as NF-kB is also affected in similar fashion. In cells stimulated with the phorbol-ester PMA, the transcriptional activity of NF-kB was inhibited in an FKBP51-dependent manner. Immunophilins possess two key domains, the TPR domain, through which they associate to hsp90, and the PPIase domain, responsible for the peptidylprolyl-isomerase activity. Neither the inhibition of the isomerase activity by the drug FK506 nor the overexpression of a TPR domain mutant unable to interact with hsp90 modified the inhibitory effect of FKBP51. However, the overexpression of the wild-type TPR domain reverted the effect of FKBP51, suggesting that it is essential for the inhibitory action of this immunophilin on NF-kB function. FKBP52, a highly homologous partner of FKBP51, showed a potent stimulatory effect on NF-kB activity. Importantly, FKBP51 co-immunoprecipitated with RelA/p65 subunit of NF-kB in an hsp90-independent manner, and its overexpression delayed RelA/p65 nuclear translocation. On the other hand, FKBP52 replaced FKBP51 in the complex when the cells were stimulated with PMA, and the inhibitory action of the latter was reverted by overexpression of the former. It is postulated that the FKBP52 to FKBP51 ratio favors the biological response of NF-kB in a TPR-domain dependent manner.