Differential retrotranslocation of mitochondrial Bax and Bak

• Published in: The EMBO journal Vol. 34; no. 1; pp. 67 - 80
• Main Authors: Todt, Franziska, Cakir, Zeynep, Reichenbach, Frank, Emschermann, Frederic, Lauterwasser, Joachim, Kaiser, Andrea, Ichim, Gabriel, Tait, Stephen WG, Frank, Stephan, Langer, Harald F, Edlich, Frank
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 02-01-2015; Nature Publishing Group UK; BlackWell Publishing Ltd
• Subjects: Apoptosis; Apoptosis - physiology; bcl-2 Homologous Antagonist-Killer Protein - genetics; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2 proteins; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Cell Line; Cytosol - metabolism; EMBO07; Humans; membrane association; Membranes; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Protein Transport - physiology; Proteins; tail anchor; apoptosis; Bcl‐2 proteins; tail anchor; membrane association
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201488806

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.
Synopsis
Pro‐apoptotic proteins Bax and Bak kill cells by permeabilizing the outer mitochondrial membrane. Mitochondrial localization and thus apoptosis induction by both proteins is controlled by their retrotranslocation dynamics governed by the hydrophobicity of the C‐terminal membrane anchor.
The pro‐apoptotic Bcl‐2 protein Bak is retrotranslocated from the mitochondria into the cytosol dependent on pro‐survival Bcl‐2 proteins.
Bax and Bak retrotranslocate at different rates by the same retrotranslocation process.
Rapid Bax shuttling protects cells from apoptosis in the presence or absence of apoptotic stimuli.
The hydrophobicity of the membrane anchor determines shuttling and localization of Bax and Bak.
Graphical Abstract
Pro‐apoptotic proteins Bax and Bak kill cells by permeabilizing the outer mitochondrial membrane. Mitochondrial localization and thus apoptosis induction by both proteins is controlled by their retrotranslocation dynamics governed by the hydrophobicity of the C‐terminal membrane anchor.