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Cell Death Dis. 2014 Feb 13;5:e1057. doi: 10.1038/cddis.2014.17.

S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis.

Author information

1
Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zülpicher Strasse 47, Cologne 50674, Germany.
2
Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine, Cologne University, Goldenfels Strasse 19-21, Cologne 50935, Germany.
3
1] Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zülpicher Strasse 47, Cologne 50674, Germany [2] Biophysics Department, Institute of Biology, University of Stuttgart, Pfaffenwaldring 57, Stuttgart 70550, Germany.

Abstract

The intrinsic pathway of apoptotic cell death is mainly mediated by the BCL-2-associated X (BAX) protein through permeabilization of the mitochondrial outer membrane (MOM) and the concomitant release of cytochrome c into the cytosol. In healthy, non-apoptotic cells, BAX is predominantly localized in the cytosol and exhibits a dynamic shuttle cycle between the cytosol and the mitochondria. Thus, the initial association with mitochondria represents a critical regulatory step enabling BAX to insert into MOMs, promoting the release of cytochrome c and ultimately resulting in apoptosis. However, the molecular mode of how BAX associates with MOMs and whether a cellular regulatory mechanism governs this process is poorly understood. Here we show that in both primary tissues and cultured cells, the association with MOMs and the proapoptotic action of BAX is controlled by its S-palmitoylation at Cys-126. A lack of BAX palmitoylation reduced BAX mitochondrial translocation, BAX oligomerization, caspase activity and apoptosis. Furthermore, ectopic expression of specific palmitoyl transferases in cultured healthy cells increases BAX S-palmitoylation and accelerates apoptosis, whereas malignant tumor cells show reduced BAX S-palmitoylation consistent with their reduced BAX-mediated proapoptotic activity. Our findings suggest that S-palmitoylation of BAX at Cys126 is a key regulatory process of BAX-mediated apoptosis.

PMID:
24525733
PMCID:
PMC3944235
DOI:
10.1038/cddis.2014.17
[Indexed for MEDLINE]
Free PMC Article

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