Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis

Abstract

The mitochondrial localization of the membrane proteins Bcl-2 and Bcl-x(L) is essential for their anti-apoptotic function. Here we show that mitochondrial FK506-binding protein 38 (FKBP38), unlike FKBP12, binds to and inhibits calcineurin in the absence of the immunosuppressant FK506, suggesting that FKBP38 is an inherent inhibitor of this phosphatase. FKBP38 is associated with Bcl-2 and Bcl-x(L) in immunoprecipitation assays and colocalizes with these proteins in mitochondria; in addition, the expression of FKBP38 mutant proteins induces a marked redistribution of Bcl-2 and Bcl-x(L). Overexpression of FKBP38 blocks apoptosis, whereas functional inhibition of this protein by a dominant-negative mutant or by RNA interference promotes apoptosis. Thus, FKBP38 might function to inhibit apoptosis by anchoring Bcl-2 and Bcl-x(L) to mitochondria.

An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

“…Furthermore, it was shown that such targeting requires the C-terminal hydrophobic tail of Bcl-2 (Motz et al, 2002). In contrast, Shirane and Nakayama (2003) reported that the mitochondrial FK506-binding protein 38 (FKBP38) interacts with Bcl-2 and plays an important role in targeting Bcl-2 to the mitochondrial membrane. An FKBP38 interacting domain was recently mapped to the unstructured loop of Bcl-2 (Kang et al, 2005).…”

“…It remains to be determined whether requirement of two domains for mitochondrial targeting is a common property for those membrane proteins without a specific mitochondrial targeting signal in their membrane targeting/anchoring domain. Intriguingly, FKBP38 can also interact with Bcl-X L and facilitates its mitochondrial targeting (Shirane and Nakayama, 2003). It would be interesting to determine whether the FKBP38 binding domain resides in the C-terminal mitochondrial targeting sequence of Bcl-X L , because this region of protein alone was shown to be sufficient to confer on Bcl-X L a mitochondrial localization (Kaufmann et al, 2003).…”

“…It was further proposed that lack of specific mitochondrial targeting ability of the C-terminal hydrophobic tail of both Mcl-1 and Bcl-2 is mainly due to lack of sufficient basicity in this region of protein sequences (Kaufmann et al, 2003). Alternatively, FKBP38 was shown to facilitate the mitochondrial import of Bcl-2 (Shirane and Nakayama, 2003) and likely did so via binding to the N-terminal unstructured loop of Bcl-2 (Kang et al, 2005). These results suggest that, like with Mcl-1, mitochondrial targeting of Bcl-2 requires the collaboration of two protein domains, one in the N terminus and the other in the C-terminal end.…”

Hsp90—From signal transduction to cell transformation

“…Table 1 lists proteins for which we have used strains of E. coli that over-express Hsp90 (Plus90α™; Plus90β™; Expression Technologies Inc., San Diego, CA) to prevent aggregation during expression [45][46][47][48][49][50][51][52]. This illustrates the structural and functional disparity among the in vitro clientele of Hsp90.…”

Mechanism of action of Drosophila Reaper in mammalian cells: Reaper globally inhibits protein synthesis and induces apoptosis independent of mitochondrial permeability

“…Bcl-2 overexpression reliably blocks mitochondrial permeabilisation by antagonising the function of BH3 domain-only Bcl-2 family members. 31 Thereby, it inhibits apoptosis induction by multiple stimuli, including UV irradiation of HeLa cells, 32 which was used as a positive control. HeLa cells were transduced with Bcl-2-or vector-encoding retrovirus.…”