title: S-palmitoylation represents a novel mechanism regulating the mitochondrial targeting of BAX and initiation of apoptosis.
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.
authors: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zülpicher Strasse 47, Cologne 50674, Germany.
authors: M
authors: M
authors: Fröhlich
authors: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zülpicher Strasse 47, Cologne 50674, Germany.
authors: B
authors: B
authors: Dejanovic
authors: Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine, Cologne University, Goldenfels Strasse 19-21, Cologne 50935, Germany.
authors: H
authors: H
authors: Kashkar
authors: Institute of Biochemistry, Department of Chemistry and Center for Molecular Medicine, Cologne University, Zülpicher Strasse 47, Cologne 50674, Germany.
authors: G
authors: G
authors: Schwarz
authors: 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.
authors: S
authors: S
authors: Nussberger
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine; D057809:HEK293 Cells; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D054878:Lipoylation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D000217:Acyltransferases; D003545:Cysteine