Abstract
Helicobacter pylori VacA is a channel-forming toxin unrelated to other known bacterial toxins. Most H. pylori strains contain a vacA gene, but there is marked variation among strains in VacA toxin activity. This variation is attributable to strain-specific variations in VacA amino acid sequences, as well as variations in the levels of VacA transcription and secretion. In this review, we discuss epidemiologic studies showing an association between specific vacA allelic types and gastric cancer, as well as studies that have used animal models to investigate VacA activities relevant to gastric cancer. We also discuss the mechanisms by which VacA-induced cellular alterations may contribute to the pathogenesis of gastric cancer.
Highlights
Description of VacAH. pylori VacA derives its name from the protein’s ability to induce vacuolation in intoxicated cells
Many human epidemiologic studies have detected an association between H. pylori strains containing certain types of vacA alleles and an increased risk of gastric cancer or premalignant gastric lesions
One interpretation is that the human epidemiologic results reflect the association between certain vacA allelic variants and other strain-specific genetic elements that contribute to gastric cancer pathogenesis, and VacA has no direct role in the pathogenesis of gastric cancer
Summary
H. pylori VacA derives its name from the protein’s ability to induce vacuolation in intoxicated cells. Fragments [18,23,24,25], but there is no evidence that this cleavage is required for the toxin’s activities [26] Both the p33 and p55 domains are important for toxin binding to cells and internalization of the toxin into mammalian cells [27,28]. Experiments analyzing VacA fragments expressed in transfected mammalian cells revealed that the minimum-length fragment required to induce vacuolation includes the entire p33 domain plus the amino-terminal ~110 amino acids of the p55 domain [29,30,31]. It has been proposed that the formation of VacA anion channels in endosomal membranes, coupled with vacuolar ATPase activity, leads to the osmotic swelling of endosomal compartments and the formation of vacuoles visible by light microscopy [40,61,62]. VacA-induced cell death may be a consequence of the reduced expression of pro-survival factors [73]
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