Journal
CELL DEATH AND DIFFERENTIATION
Volume 17, Issue 11, Pages 1707-1716Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2010.42
Keywords
Helicobacter pylori; VacA; apoptosis; mitochondria; BAX
Categories
Funding
- Italian Ministry of University
- University of Padova [CPDA074121/07]
- Fondazione Berlucchi
- Associazione Italiana per la Ricerca sul Cancro grant regionale
- European Community
- Telethon Italy
- Compagnia di San Paolo Italy
- AIRC Italy
- Electron Microscopy, Genova, Italy [GTF07002]
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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. Cell Death and Differentiation (2010) 17, 1707-1716; doi:10.1038/cdd.2010.42; published online 30 April 2010
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