Immunophilin FKBP38, an inherent inhibitor of calcineurin, targets Bcl-2 to mitochondria and inhibits apoptosis

Various apoptotic stimuli induce mitochondrial dysfunction. Bcl-2 and Bcl-xL antagonize apoptosis by blocking the release of caspase activators such as cytochrome c from mitochondria. We demonstrated that FKBP38, a member of the immunophilin family, interacts and targets these anti-apoptotic proteins Bcl-2 and Bcl-xL, thereby assisting them in their pro-survival role. FKBP38 is specifically localized on mitochondria, at which FKBP38 is colocalized with Bcl-2 and Bcl-xL. Expression of exogenous FKBP38 promotes mitochondrial targeting of Bcl-2 and Bcl-xL, while dominant-negative FKBP38 or siRNA of FKBP38 disturbs their localization. On the other hand, unlike FKBP12, FKBP38 inhibits serine/threonine phosphatase calcineurin in an FK506-independent manner. Overexpression of FKBP38 inhibits apoptosis, while expression of dominant-negative FKBP38 or depletion of endogenous FKBP38 increases the sensitivity for apoptosis. Thus, FKBP38 has unique features among members of the immunophilin family.