FKBP51 is located in mitochondria and shows antiapoptotic function

GALLO LI, PIWIEN PILIPUK G, GALIGNIANA MD

SEEON, ALEMANIA

Conferencia; 4th International Conference on the Hsp90 Chaperone Machinery; 2008

FKBP51 is an hsp90-binding immunophilin (IMM) bound to steroid receptors (SRs). Recently, we reported that FKBP51 is replaced by FKBP52 or PP5 in a steroid-dependent manner. Because both IMMs efficiently bind dynein motors and FKBP51 does not, this IMM swapping favors the SR retrotransport. Nonetheless, several functional properties of FKBP51 have not been elucidated to date. In this work, we first analyzed FKBP51 subcellular distribution. Confocal microscopy imaging of several cell types showed colocalization of FKBP51 with Tom20, cyt c, COX IV and MitoTracker stain, suggesting that most of the FKBP51 pool is located in mitochondria (mt-51). This surprising finding was confirmed by biochemical fractionation, electron microscopy imaging and the loss of signal with specific iRNA. Interestingly, we found that mt-51 exists alone and complexed with mt-GR, mt-hsp90 and mt-hsp70. Upon several stimuli (ROS, UV light, TNFalpha, LPS, cAMP, etc.), mt-51 rapidly moved to the nucleus along with mt-hsp70. The IMM release from mitochondria is dependent on the membrane depolarization and shares identical kinetics as cyt c release. Overexpression of FKBP51 increased cell viability against several injuries, whereas its knock-down favored programmed cell death as demonstrated by studies on nuclear condensation, DNA fragmentation, caspase activation, cyt c release, annexin V immunostaining, etc. Immunoprecipitation assays demonstrated that the antiapoptotic factor Bcl-2 interacts with FKBP51 in the same complex, suggesting a role of the IMM in Bcl-2 function. Interestingly, most analyzed tumor cells showed high expression of FKBP51 located in nuclei. In summary, here we report for the first time that FKBP51 is localized in mitochondria and undergoes a rapid nuclear-mitochondrial shuttling during the onset of several stimuli. Importantly, this novel subcellular localization of FKBP51 is related to an antiapoptotic action.