Ku70 suppresses the apoptotic translocation of bax to mitochondria

Motoshi Sawada; Weiyong Sun; Paulette Hayes; Konstantin Leskov; David A. Boothman; Shigemi Matsuyama

doi:10.1038/ncb950

Ku70 suppresses the apoptotic translocation of bax to mitochondria

Motoshi Sawada, Weiyong Sun, Paulette Hayes, Konstantin Leskov, David A. Boothman, Shigemi Matsuyama

Research output: Contribution to journal › Article › peer-review

319 Scopus citations

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.

Original language	English (US)
Pages (from-to)	320-329
Number of pages	10
Journal	Nature cell biology
Volume	5
Issue number	4
DOIs	https://doi.org/10.1038/ncb950
State	Published - Apr 1 2003

ASJC Scopus subject areas

Cell Biology

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title = "Ku70 suppresses the apoptotic translocation of bax to mitochondria",

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.",

author = "Motoshi Sawada and Weiyong Sun and Paulette Hayes and Konstantin Leskov and Boothman, {David A.} and Shigemi Matsuyama",

note = "Funding Information: ACKNOWLEDGMENTS 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.",

year = "2003",

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doi = "10.1038/ncb950",

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T1 - Ku70 suppresses the apoptotic translocation of bax to mitochondria

AU - Sawada, Motoshi

AU - Sun, Weiyong

AU - Hayes, Paulette

AU - Leskov, Konstantin

AU - Boothman, David A.

AU - Matsuyama, Shigemi

N1 - Funding Information: ACKNOWLEDGMENTS 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.

PY - 2003/4/1

Y1 - 2003/4/1

N2 - 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.

AB - 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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Ku70 suppresses the apoptotic translocation of bax to mitochondria

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