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A more recent version of this article appeared on April 1, 2004
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Submitted on August 22, 2003
Revised on December 13, 2003
Accepted on January 5, 2004
1 Departments of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37212
2 Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131
3 Departments of Surgery, Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232; Veteran Affairs Medical Center, Nashville, TN 37212
4 Departments of Microbiology and Immunology and Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232; Veteran Affairs Medical Center, Nashville, TN 37212
* Corresponding author. E-mail address: timothy.L.cover{at}vanderbilt.edu.
Helicobacter pylori VacA is a secreted protein toxin that may contribute to the pathogenesis of peptic ulcer disease and gastric adenocarcinoma. When added to cultured mammalian cells in the presence of weak bases (e.g., ammonium chloride), VacA induces the formation of large cytoplasmic vacuoles. Here we report a previously unrecognized capacity of VacA to induce clustering and perinuclear redistribution of late endocytic compartments. In contrast to VacA-induced cell vacuolation, VacA-induced clustering and redistribution of late endocytic compartments is not dependent on the presence of weak bases and is not inhibited by bafilomycin A1. VacA mutant toxins defective in the capacity to form anion-selective membrane channels fail to cause clustering and redistribution. VacA-induced clusters of late endocytic compartments undergo transformation into vacuoles following the addition of ammonium chloride. VacA-induced clustering and redistribution of late endocytic compartments occur in cells expressing wild-type or constitutively active Rab7, but not in cells expressing dominant-negative mutant Rab7. In VacA-treated cells containing clustered late endocytic compartments, overexpression of dominant-negative Rab7 causes reversion to a nonclustered distribution. Redistribution of late endocytic compartments to the perinuclear region requires a functional microtubule cytoskeleton, whereas clustering of these compartments and vacuole formation do not. These data provide evidence that clustering of late endocytic compartments is a critical mechanistic step in the process of VacA-induced cell vacuolation. We speculate that VacA-induced alterations in late endocytic membrane traffic contribute to the capacity of H. pylori to persistently colonize the human gastric mucosa.
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