TPR-Domain immunophilin FKBP51 is a major mitochondrial protein that protects cells against oxidative stress

GALLO LI, LAGADARI M, PIWIEN-PILIPUK G, GALIGNIANA MD

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Año: 2011 vol. 286 p. 30152 - 30160

0021-9258

Confocal microscopy images revealed that the TPR-domain immunophilin FKBP51 shows colocalization with the specific mitochondrial marker MitoTracker. Signal specificity was tested with different antibodies and by FKBP51 knock-down. This unexpected subcellular localization of FKBP51 was confirmed by colocalization studies with other mitochondrial proteins, biochemical fractionation, and electron microscopy imaging. Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex. While Hsp90 inhibitors favor FKBP51 translocation from mitochondria to the nucleus in a reversible manner, TPR-domain deficient mutants of FKBP51 are constitutively nuclear and fully excluded from mitochondria, suggesting that a functional TPR domain is required for its mitochondrial localization. FKBP51 overexpression protects cells against oxidative stress, whereas FKBP51 knock-down makes them more sensitive to the injury. In summary, this is the first demonstration that FKBP51 is a major mitochondrial factor that undergoes nucleo-mitochondrial shuttling, an observation that may be related to antiapoptotic mechanisms triggered during the stress response.