Differential retrotranslocation of mitochondrial Bax and Bak.
The Bcl-2 proteins Bax and Bak can permeabilize the outer mitochondrial membrane and commit cells to apoptosis. Pro-survival Bcl-2 proteins control Bax by constant retrotranslocation into the cytosol of healthy cells. The stabilization of cytosolic Bax raises the question whether the functionally redundant but largely mitochondrial Bak shares this level of regulation. Here we report that Bak is retrotranslocated from the mitochondria by pro-survival Bcl-2 proteins. Bak is present in the cytosol of human cells and tissues, but low shuttling rates cause predominant mitochondrial Bak localization. Interchanging the membrane anchors of Bax and Bak reverses their subcellular localization compared to the wild-type proteins. Strikingly, the reduction of Bax shuttling to the level of Bak retrotranslocation results in full Bax toxicity even in absence of apoptosis induction. Thus, fast Bax retrotranslocation is required to protect cells from commitment to programmed death.
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine SGBM, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Franziska
F
Todt
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Zeynep
Z
Cakir
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine SGBM, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Frank
F
Reichenbach
Section for Cardioimmunology, University of Tübingen, Tübingen, Germany Department of Cardiovascular Medicine, University Hospital University of Tübingen, Tübingen, Germany.
Frederic
F
Emschermann
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Joachim
J
Lauterwasser
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany.
Andrea
A
Kaiser
Cancer Research UK Beatson Institute University of Glasgow, Glasgow, UK.
Gabriel
G
Ichim
Cancer Research UK Beatson Institute University of Glasgow, Glasgow, UK.
Stephen W G
SW
Tait
Division of Neuropathology, Institute of Pathology Basel University Hospitals, Basel, Switzerland.
Stephan
S
Frank
Section for Cardioimmunology, University of Tübingen, Tübingen, Germany Department of Cardiovascular Medicine, University Hospital University of Tübingen, Tübingen, Germany.
Harald F
HF
Langer
Institute for Biochemistry and Molecular Biology University of Freiburg, Freiburg, Germany Spemann Graduate School of Biology and Medicine SGBM, Freiburg, Germany BIOSS, Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany frank.edlich@biochemie.uni-freiburg.de.
Frank
F
Edlich
D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
C494772:BAK1 protein, human; C494826:BAX protein, human; D024101:Mitochondrial Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
Bcl‐2 proteins; apoptosis; membrane association; tail anchor