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J. Biol. Chem., Vol. 278, Issue 48, 48204-48209, November 28, 2003
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Cellular Vacuolation and Mitochondrial Cytochrome c Release Are Independent Outcomes of Helicobacter pylori Vacuolating Cytotoxin Activity That Are Each Dependent on Membrane Channel Formation*
¶
From the
Department of Biology and Biochemistry, University of Houston, 369 Science & Research Building II, Houston, Texas 77204-5001 and Departments of Medicine and Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Administration Medical Center, Nashville, Tennessee 37232-2605
Helicobacter pylori vacuolating toxin (VacA) is a secreted toxin that is reported to produce multiple effects on mammalian cells. In this study, we explored the relationship between VacA-induced cellular vacuolation and VacA-induced cytochrome c release from mitochondria. Within intoxicated cells, vacuolation precedes cytochrome c release and occurs at lower VacA concentrations, indicating that cellular vacuolation is not a downstream consequence of cytochrome c release. Conversely, bafilomycin A1 blocks VacA-induced vacuolation but not VacA-induced cytochrome c release, which indicates that cytochrome c release is not a downstream consequence of cellular vacuolation. Acid activation of purified VacA is required for entry of VacA into cells, and correspondingly, acid activation of the toxin is required for both vacuolation and cytochrome c release, which suggests that VacA must enter cells to produce these two effects. Single amino acid substitutions (P9A and G14A) that ablate vacuolating activity and membrane channel-forming activity render VacA unable to induce cytochrome c release. Channel blockers known to inhibit cellular vacuolation and VacA membrane channel activity also inhibit cytochrome c release. These data indicate that cellular vacuolation and mitochondrial cytochrome c release are two independent outcomes of VacA intoxication and that both effects are dependent on the formation of anion-selective membrane channels.
Received for publication, April 21, 2003 , and in revised form, September 8, 2003.
* This work was supported by the National Institutes of Health Grants RO1 AI45928 (to S. R. B.) and RO1 AI39657 (to T. L. C.), the Robert A. Welch Foundation (Grant E-1311), the American Heart Association (Grant 98BG472), and the Medical Research Service of the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed. Tel.: 713-743-8392; Fax: 713-743-8351; E-mail: sblanke{at}uh.edu.
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