Helicobacter pylori Vacuolating Cytotoxin Induces Activation of the Proapoptotic Proteins Bax and Bak, Leading to Cytochrome c Release and Cell Death, Independent of Vacuolation

Yamasaki, Eiki; Wada, Akihiro; Kumatori, Atsushi; Nakagawa, Ichirô; Funao, Junko; Nakayama, Masaaki; Hisatsune, Junzo; Kimura, Miyuki; Moss, Joel; Hirayama, Toshiya

doi:10.1074/jbc.m509404200

Cited by 145 publications

(171 citation statements)

References 49 publications

(30 reference statements)

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“…Activated Bax undergoes homo-oligomerization and may participate in the formation of a large mitochondrial transition pore complex that facilitates cytochrome c release [36]. Recently, a paper demonstrated that Bax was activated and localized to mitochondria in gastric epithelial cells exposed to H. pylori VacA [22]. Consistent with this observation, our results demonstrated the translocation of Bax protein to mitochondria in VacA-exposed eosinophils.…”

Section: Discussionsupporting

confidence: 88%

“…The purified protein was activated immediately before use on cells; 250 mM HCl was added to the purified VacA until a pH of 2.0 was reached [43]. NH 4 Cl (5 mM) was also added to the medium to enhance the VacA activity [22].…”

Section: Purification Of H Pylori Vacamentioning

confidence: 99%

“…A Bax-specific siRNA was constructed as described by Yamasaki et al [22]. siRNA against c-IAP2 (Birc3) was purchased from Gibco-Invitrogen (Stealth Select RNAi TM siRNA, HSS100562, Carlsbad, CA, USA) [50].…”

Section: Transfectionmentioning

confidence: 99%

“…Therefore, apoptosis may regulate pathogenesis of several infectious diseases [18][19][20][21]. Considering that H. pylori VacA induces apoptosis in gastric epithelial cells via a mitochondria-dependent pathway [22], VacA may influence the apoptotic processes of eosinophils.…”

Section: Introductionmentioning

confidence: 99%

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Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation

Kim

Lee

et al. 2010

Eur J Immunol

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Although Helicobacter pylori infections of the gastric mucosa are characterized by the infiltration of inflammatory cells such as eosinophils, the responses of eosinophils to H. pylori vacuolating cytotoxin (VacA) have not been fully elucidated. This study investigates the role of VacA in the apoptosis of human eosinophils. We treated human eosinophils with purified H. pylori VacA and observed that induction of apoptosis is a relatively late event. Expression of cellular inhibitor of apoptosis protein (c-IAP)-2 was upregulated during the early period of VacA stimulation, and transfection with c-IAP2 siRNA augmented apoptotic cell death. VacA caused the translocation of cytoplasmic Bax to the mitochondria and increased cytochrome c release from mitochondria in eosinophils. Transfection of an EoL-1 eosinophil cell line with Bax siRNA decreased the release of cytochrome c and DNA fragmentation. Furthermore, apoptosis facilitated by Bax and cytochrome c was primarily regulated by p38 MAPK in VacA-treated eosinophils. These results suggest that the exposure of human eosinophils to H. pylori VacA induces the early upregulation of c-IAP2 and a relatively late apoptotic response, with the apoptosis progressing through a sequential pathway that includes p38 MAPK activation, Bax translocation, and cytochrome c release.

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Section: Discussionsupporting

confidence: 88%

Section: Purification Of H Pylori Vacamentioning

confidence: 99%

Section: Transfectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation

Kim

Lee

et al. 2010

Eur J Immunol

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“…Subsequent to binding plasma membrane sphingomyelin (12,13), and potentially additional protein components (14,15), VacA is internalized and induces mitochondrial dysfunction and mitochondrial outer membrane permeabilization (MOMP) (16). Intracellular VacA localizes to mitochondria (16,17), and isolated mitochondria rapidly import purified VacA beyond the outer membrane (17,18), resulting in dissipation of the mitochondrial transmembrane potential (ΔΨ m ) (19). VacA-dependent MOMP occurs after ΔΨ m dissipation (16) and requires activation of the eukaryotic proapoptotic effector Bcl-2-associated X protein (Bax) (19).…”

mentioning

confidence: 99%

Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death

Jain

Luo

Blanke³

2011

Proc. Natl. Acad. Sci. U.S.A.

148

119

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A number of pathogenic bacteria target mitochondria to modulate the host's apoptotic machinery. Studies here revealed that infection with the human gastric pathogen Helicobacter pylori disrupts the morphological dynamics of mitochondria as a mechanism to induce host cell death. The vacuolating cytotoxin A (VacA) is both essential and sufficient for inducing mitochondrial network fragmentation through the mitochondrial recruitment and activation of dynamin-related protein 1 (Drp1), which is a critical regulator of mitochondrial fission within cells. Inhibition of Drp1-induced mitochondrial fission within VacA-intoxicated cells inhibited the activation of the proapoptotic Bcl-2-associated X (Bax) protein, permeabilization of the mitochondrial outer membrane, and cell death. Our data reveal a heretofore unrecognized strategy by which a pathogenic microbe engages the host's apoptotic machinery.cytochrome c | mitochondrial dynamics | gastric cancer | gastric ulcer | toxin

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Helicobacter PyloriInfection Control by Autophagy

Greenfield

Dang

Jones

2014

Autophagy, Infection, and the Immune Response

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Helicobacter pylori Vacuolating Cytotoxin Induces Activation of the Proapoptotic Proteins Bax and Bak, Leading to Cytochrome c Release and Cell Death, Independent of Vacuolation

Cited by 145 publications

References 49 publications

Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation

Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation

Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death

Helicobacter PyloriInfection Control by Autophagy

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