title: Endosome-mitochondria juxtaposition during apoptosis induced by H. pylori VacA.
abstract: The vacuolating cytotoxin (VacA) is an important virulence factor of Helicobacter pylori with pleiotropic effects on mammalian cells, including the ability to trigger mitochondria-dependent apoptosis. However, the mechanism by which VacA exerts its apoptotic function is unclear. Using a genetic approach, in this study we show that killing by VacA requires the proapoptotic Bcl-2 family members BAX and BAK at the mitochondrial level, but not adequate endoplasmic reticulum Ca²(+) levels, similarly controlled by BAX and BAK. A combination of subcellular fractionation and imaging shows that wild-type VacA, but not mutants in its channel-forming region, induces the accumulation of BAX on endosomes and endosome-mitochondria juxtaposition that precedes the retrieval of active BAX on mitochondria. It is noteworthy that in Bax- and Bak-deficient cells, VacA is unable to cause endosome-mitochondria juxtaposition and is not retrieved in mitochondria. Thus, VacA causes BAX/BAK-dependent juxtaposition of endosomes and mitochondria early in the process of cell death, revealing a new function for these proapoptotic proteins in the regulation of relative position of organelles.
authors.affiliation: Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Calore
authors.forename: C
authors.initials: C
authors.lastname: Genisset
authors.forename: A
authors.initials: A
authors.lastname: Casellato
authors.forename: M
authors.initials: M
authors.lastname: Rossato
authors.forename: G
authors.initials: G
authors.lastname: Codolo
authors.forename: M D
authors.initials: MD
authors.lastname: Esposti
authors.forename: L
authors.initials: L
authors.lastname: Scorrano
authors.forename: M
authors.initials: M
authors.lastname: de Bernard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D019254:Genes, bcl-2; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; C074689:VacA protein, Helicobacter pylori; D037521:Virulence Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D002118:Calcium