INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
MITOCHONDRIAL LOCALIZATION AND ANTIAPOPTOTIC PROPERTIES OF FKBP51 AND CYCLOPHILIN A
Autor/es:
LAGADARI M, DANERI C, GALLO L, ERLEJMAN AG, PIWIEN-PILIPUK G, GALIGNIANA MD
Lugar:
Halle-Saale
Reunión:
Conferencia; 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.