IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Mitochondrial localization and antiapoptotic properties of FKBP51 and cyclophilin A
Autor/es:
LAGADARI M; DANERI-BECERRA C; GALLO L I; ERLEJMAN AG; PIWIEN-PILIPUK G; GALIGNIANA MD
Lugar:
Halle
Reunión:
Congreso; International Symposium on Cyclophilins and other Foldases: Cell Signaling Catalysts & Drug Targets; 2013
Resumen:
Microscopy studies revealed cytoplasmic images of FKBP51 that were compatible with mitochondrial (mt) localization. To test this unpredicted property, several cell types were analyzed. All of them showed colocalization of FKBP51 with the specific mitochondrial marker MitoTracker and with mitochondrial factors such as Tom20, Cyt c, and COX IV. Such unexpected subcellular localization for this immunophilin was confirmed by biochemical fractionation, electron microscopy, and siRNA analysis. Interestingly, mt-FKBP51 forms complexes with mt-GR, mt-Hsp90 and mt-Hsp70. Upon several stimuli (ROS, UV light, TNFalpha, LPS, heat-shock, staurosporin, etc.), mt-FKBP51 rapidly moved to the nucleus (t0.5=15 min) by a mechanism that requires the depolarization of mitochondrial membrane and parallels Cyt c release. When the stimulus was suppressed, FKBP51 rapidly cycled-back to mitochondria. In the nucleus, FKBP51 concentrated in nucleoli in an HSF1-dependent manner. Importantly, the overexpression of FKBP51 increased cell viability against several injuries, whereas its knock-down favored apoptosis (demonstrated by several classical methods). Both tumor cell lines and human cancer tissues showed higher expression of FKBP51 and greater concentration in nucleoli than their normal counterparts. Interestingly, immunoprecipitation assays demonstrated that the antiapoptotic factor Bcl-2 interacts with FKBP51. In order to test whether other immunophilins also show such unforeseen mitochondrial localization, most of the above-described studies were also evaluated for cyclophilin A (CYPA), and similar results were obtained. However CyPA moved towards the nucleus at a slower rate (t0.5=3-4 h) than FKBP51. Nuclear translocation of both immunophilins was independent of their peptidyprolyl isomerase activities, and cycling-back to cytoplasm was CRM-1-independent. In summary, we report the mitochondrial localization of FKBP51 and CYPA, and postulate that their nuclear-mitochondrial trafficking relates directly with their antiapoptotic effects. It is likely that both proteins may share a similar antiapoptotic mechanism that shows a rapid, acute response dependent on FKBP51, and a slower complementary response dependent on CyPA.