The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress.

GALLO LUCIANA I.; LAGADARI MARIANA; PIWIEN-PILIPUK GRACIELA ; GALIGNIANA MARIO D.

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2011 vol. 26 p. 30152 - 30160

0021-9258

Confocal microscopy images revealed that the tetratricopeptide repeat motif (TPR)domain immunophilin FKBP51 shows colocalization with the specific mitochondrialmarker MitoTracker. Signal specificity was tested with different antibodies andby FKBP51 knockdown. This unexpected subcellular localization of FKBP51 wasconfirmed by colocalization studies with other mitochondrial proteins,biochemical fractionation, and electron microscopy imaging. Interestingly, FKBP51forms complexes in mitochondria with the glucocorticoid receptor and theHsp90/Hsp70-based chaperone heterocomplex. Although Hsp90 inhibitors favor FKBP51translocation from mitochondria to the nucleus in a reversible manner, TPRdomain-deficient mutants of FKBP51 are constitutively nuclear and fully excluded from mitochondria, suggesting that a functional TPR domain is required for itsmitochondrial localization. FKBP51 overexpression protects cells againstoxidative stress, whereas FKBP51 knockdown makes them more sensitive to injury.In summary, this is the first demonstration that FKBP51 is a major mitochondrial factor that undergoes nuclear-mitochondrial shuttling, an observation that may berelated to antiapoptotic mechanisms triggered during the stress response.