Apoptosis is essential for an organism's development, homeostasis, and protection from damaged cells.1,2 There is more than one pathway by which apoptosis can occur, and which pathway is chosen depends greatly on the stimulus and the condition of the cell. Signals from death receptors, cytotoxic granule proteins, cytotoxic drugs, and adverse growth conditions are all examples of apoptotic stimuli.2 One of the main apoptosis pathways is characterized by permeablization of the outer mitochondrial membrane (OMM) and the subsequent release of Cytochrome c into the cytosol. This triggers the assembly of the apoptosome, a large caspase-activating protein complex that ultimately leads to cell death.1 Cytochrome c release is regulated both positively and negatively by different members of the Bcl-2 protein family. Localized predominantly to the OMM, Bcl-2, and its close relative Bcl-xL, are thought to act primarily by inhibiting pro-apoptotic proteins and preventing release of Cytochrome c from mitochondria.3,4 Despite their well-known and critical functions, it is not fully understood how these Bcl-2 family members are targeted to the OMM. Shirane and Nakayama have found that a member of the immunophilin family, FK506-binding protein 38 (FKBP38), plays a critical role in these processes.5 They identified a specific interaction between FKBP38 and Bcl-2 through yeast two-hybrid assays and confirmed these initial experiments with co-immunoprecipitation studies using several mammalian cell lines. They found that the suppression of endogenous FKBP38 by RNA interference (RNAi) or transfection of a mutant FKBP38 missing the transmembrane (TM) domain necessary for mitochon-drial insertion (FKBP38DTM), resulted in the translocation of Bcl-2 and Bcl-xL from the OMM to the cytosol. In addition, transfection with a mutant form designed to target FKBP38 to the plasma membrane (FKBP38CAAX) resulted in Bcl-2 and Bcl-xL localization to the cell periphery (Figure 1A). In functional assays, transfection of wild-type FKBP38 protected cells from apoptotic stimuli including Ca2+ elevations and growth factor withdrawal, while RNAi-depleted expression or expression of the mutant FKBP38DTM enhanced susceptibility to apoptosis (Figure 1B).
|Figure 1. A. Wild-type FKBP38 targets Bcl-2 (and Bcl-xL) to the outer mitochondrial membrane (OMM), while mutant FKBP38 targets Bcl-2 to either the cytosol (FKBP38DTM) or the plasma membrane (FKBP38CAAX). B. Wild-type FKBP38 protects cells from apoptotic stimuli, while RNAi-depleted expression of wild-type FKBP38 or expression of the mutant FKBP38DTM enhances susceptibility to apoptosis.|
These results demonstrate that FKBP38 plays an important role in apoptosis through its involvement in the mechanism that targets Bcl-2 and Bcl-xL to the OMM. Future investigations will likely include further elucidation of the function of FKBP38 and its association with Bcl-2 and Bcl-xL, while identifying other potential interacting proteins and novel activities. It has already been suggested that FKBP38 may play a role in the cross-talk between the Bcl-2 and the Calcineurin/NF-AT apoptosis signaling pathways and in cell size regulation through interactions with tuberous sclerosis (TSC) genes.1,6