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Ku70 suppresses the apoptotic translocation of Bax to mitochondria

Nature Cell Biology volume 5, pages 320–329 (2003)Cite this article

A Retraction to this article was published on 01 April 2007

A Corrigendum to this article was published on 01 April 2004

Abstract

Bax induces mitochondrial-dependent cell death signals in mammalian cells. However, the mechanism of how Bax is kept inactive has remained unclear. Yeast-based functional screening of Bax inhibitors from mammalian cDNA libraries identified Ku70 as a new Bax suppressor. Bax-mediated apoptosis was suppressed by overexpression of Ku70 in mammalian cells, but enhanced by downregulation of Ku70. We found that Ku70 interacts with Bax, and that the carboxyl terminus of Ku70 and the amino terminus of Bax are required for this interaction. Bax is known to translocate from the cytosol to mitochondria when cells receive apoptotic stimuli. We found that Ku70 blocks the mitochondrial translocation of Bax. These results suggest that in addition to its previously recognized DNA repair activity in the nucleus, Ku70 has a cytoprotective function in the cytosol that controls the localization of Bax.

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Figure 1: Ku70 inhibits Bax-induced cell death.
Figure 2: Ku70 inhibits caspase activation and cytochrome c release.
Figure 3: Lowering Ku70 levels abolishes sensitivity to apoptotic stimuli.
Figure 4: Interaction of Ku70 and Bax.
Figure 5: Ku70 specifically inhibits the Bax-mediated cell death pathway.
Figure 6: Ku70 regulates the localization of Bax.
Figure 7: Ku70 suppresses the translocation of Bax to mitochondria.
Figure 8: Ku70 maintains the inactive state of Bax.

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Acknowledgements

We thank R. Takahashi (Riken Brain Science Research Institute), M. Miura (Riken Brain Research Institute), D. Green (La Jolla Institute for Allergy and Immunology), J. Reed (The Burnham Institute), J. Gorski (Blood Research Institute) and D. Wang for their invaluable suggestions, critical reviewing of the manuscript and encouragement. This work was supported in part by the Blood Center Research Foundation, Northwest Mutual Foundation, Taiho Pharmaceutical Company Ltd. for S.M., and in part by National Institute of Health/National Cancer Institute grant # CA78530 to D.A.B. Supplementary Information accompanies the paper on www.nature.com/naturecellbiology.

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Author notes

  1. Motoshi Sawada and Weiyong Sun: These authors contributed equally to this work.

Authors and Affiliations

  1. Blood Research Institute, The Blood Center of South Eastern Wisconsin, 8727 Watertown Plank Rd, Milwaukee, 53226, WI, USA

    Motoshi Sawada, Weiyong Sun, Paulette Hayes & Shigemi Matsuyama

  2. Department of Biochemistry, Medical College of Wisconsin, 8727 Watertown Plank Rd, Milwaukee, 53226, WI, USA

    Motoshi Sawada, Weiyong Sun, Paulette Hayes & Shigemi Matsuyama

  3. Departments of Radiation Oncology and Pharmacology, Case Western Reserve University and University Hospitals of Cleveland, BRB-326 East, 10900 Euclid Avenue, Cleveland, 44106-4942, OH, USA

    Konstantin Leskov & David A. Boothman

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  1. Motoshi Sawada
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Correspondence to Shigemi Matsuyama.

Supplementary information

Supplementary Figures

Figure S1 a, Flow cytometric propidium iodide (PI) exclusion analysis. (PPT 2857 kb)

Figure S2 a-d, „Entire gels” of co-immunoprecipitation (co-ip) of endogenous Ku70 and Bax.

Figure S3 a-d, The interaction between Ku70 and Bax in primary mouse brain (a and b) and primary mouse fibroblasts (c and d).

Figure S4 a, Ku70-deficiency alone does not induce membrane integration of Bax in mitochondria.

Figure legends (PDF 18 kb)

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Sawada, M., Sun, W., Hayes, P. et al. Ku70 suppresses the apoptotic translocation of Bax to mitochondria. Nat Cell Biol 5, 320–329 (2003). https://doi.org/10.1038/ncb950

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