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

Nature Cell Biology volume 5, pages 28–37 (2003)Cite this article

Abstract

The mitochondrial localization of the membrane proteins Bcl-2 and Bcl-xL 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-xL 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-xL. 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-xL to mitochondria.

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Figure 1: Association of FKBP38 with Bcl-2 and Bcl-xL.
Figure 2: FKBP38 interacts with calcineurin in the absence of FK506.
Figure 3: Inhibition of calcineurin activity by FKBP38.
Figure 4: Colocalization of FKBP38 with Bcl-2 and Bcl-xL in mitochondria.
Figure 5: Mitochondrial targeting of Bcl-2 and Bcl-xL by FKBP38.
Figure 6: Anti-apoptotic action of FKBP38.
Figure 7: Functional suppression of FKBP38 by siRNA.

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Acknowledgements

We thank Y. Tsujimoto for the Bcl-2 cDNA; S. Fields for the pBTM116 vector; T. Kitamura for the pMX-puro vector; G. Crabtree for the calcineurin cDNAs; N. Motoyama for the Bcl-xL cDNA; F. Shibasaki for the GFP–NF-AT4 expression vector (pcDNA3–CAG–GFP–Myc–NF-AT4-N); H. Yokoi for the Cyp40 cDNA; K. Mihara for GFP–Tom20 and Omp25 cDNA; Fujisawa Pharmaceuticals for FK506; Y. Gotoh, N. Takahashi, D. Kohda and A. Yamanaka for discussion; R. Yasukohchi, N. Nishimura and K. Mori for technical assistance; and M. Kimura and C. Sugita for help in preparing the manuscript.

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  1. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Fukuoka, Japan

    Michiko Shirane & Keiichi I. Nakayama

  2. CREST, Japan Science and Technology Corporation (JST), Kawaguchi, 332-0012, Saitama, Japan

    Michiko Shirane & Keiichi I. Nakayama

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Correspondence to Keiichi I. Nakayama.

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Figure S1. Vimentin is secreted via the classical ER/Golgi pathway. (PDF 183 kb)

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Shirane, M., Nakayama, K. Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol 5, 28–37 (2003). https://doi.org/10.1038/ncb894

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