Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity

被引:115
作者
Willhite, DC [1 ]
Blanke, SR [1 ]
机构
[1] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA
关键词
D O I
10.1046/j.1462-5822.2003.00347.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Helicobacter pylori vacuolating cytotoxin (VacA) intoxicates mammalian cells resulting in reduction of mitochondrial transmembrane potential (DeltaPsi(m) reduction) and cytochrome c release, two events consistent with the modulation of mitochondrial membrane permeability. We now demonstrate that the entry of VacA into cells and the capacity of VacA to form anion-selective channels are both essential for DeltaPsi(m) reduction and cytochrome c release. Subsequent to cell entry, a substantial fraction of VacA localizes to the mitochondria. Neither DeltaPsi(m) reduction nor cytochrome c release within VacA-intoxicated cells requires cellular caspase activity. Moreover, VacA cellular activity is not sensitive to cyclosporin A, suggesting that VacA does not induce the mitochondrial permeability transition as a mechanism for DeltaPsi(m) reduction and cytochrome c release. Time-course and dose-response studies indicate that DeltaPsi(m) reduction occurs substantially before and at lower concentrations of VacA than cytochrome c release. Collectively, these results support a model that VacA enters mammalian cells, localizes to the mitochondria, and modulates mitochondrial membrane permeability by a mechanism dependent on toxin channel activity ultimately resulting in cytochrome c release. This model represents a novel mechanism for regulation of a mitochondrial-dependent apoptosis pathway by a bacterial toxin.
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页码:143 / 154
页数:12
相关论文
共 67 条
[31]  
Mannick EE, 1996, CANCER RES, V56, P3238
[32]   DEVELOPMENT OF A MOUSE MODEL OF HELICOBACTER-PYLORI INFECTION THAT MIMICS HUMAN-DISEASE [J].
MARCHETTI, M ;
ARICO, B ;
BURRONI, D ;
FIGURA, N ;
RAPPUOLI, R ;
GHIARA, P .
SCIENCE, 1995, 267 (5204) :1655-1658
[33]  
MARSHALL BJ, 1984, LANCET, V1, P1311
[34]   ATTEMPT TO FULFILL KOCH POSTULATES FOR PYLORIC CAMPYLOBACTER [J].
MARSHALL, BJ ;
ARMSTRONG, JA ;
MCGECHIE, DB ;
GLANCY, RJ .
MEDICAL JOURNAL OF AUSTRALIA, 1985, 142 (08) :436-439
[35]   Acid activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells [J].
McClain, MS ;
Schraw, W ;
Ricci, V ;
Boquet, P ;
Cover, TL .
MOLECULAR MICROBIOLOGY, 2000, 37 (02) :433-442
[36]   Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin [J].
Mcclain, MS ;
Iwamoto, H ;
Cao, P ;
Vinion-Dubiel, AD ;
Li, Y ;
Szabo, G ;
Shao, ZF ;
Cover, TL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (14) :12101-12108
[37]   A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation [J].
McClain, MS ;
Cao, P ;
Iwamoto, H ;
Vinion-Dubiel, AD ;
Szabo, G ;
Shao, ZF ;
Cover, TL .
JOURNAL OF BACTERIOLOGY, 2001, 183 (22) :6499-6508
[38]   Induction of gastric epithelial apoptosis by Helicobacter pylori [J].
Moss, SF ;
Calam, J ;
Agarwal, B ;
Wang, S ;
Holt, PR .
GUT, 1996, 38 (04) :498-501
[39]   Helicobacter pylori induces apoptosis of rat gastric parietal cells [J].
Neu, B ;
Randlkofer, P ;
Neuhofer, M ;
Voland, P ;
Mayerhofer, A ;
Gerhard, M ;
Schepp, W ;
Prinz, C .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2002, 283 (02) :G309-G318
[40]   IDENTIFICATION AND INHIBITION OF THE ICE/CED-3 PROTEASE NECESSARY FOR MAMMALIAN APOPTOSIS [J].
NICHOLSON, DW ;
ALI, A ;
THORNBERRY, NA ;
VAILLANCOURT, JP ;
DING, CK ;
GALLANT, M ;
GAREAU, Y ;
GRIFFIN, PR ;
LABELLE, M ;
LAZEBNIK, YA ;
MUNDAY, NA ;
RAJU, SM ;
SMULSON, ME ;
YAMIN, TT ;
YU, VL ;
MILLER, DK .
NATURE, 1995, 376 (6535) :37-43