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Chapter 9 : Vacuolating Cytotoxin

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Abstract:

In 1992, the protein mediating the effect was purified and named the vacuolating cytotoxin. Interest in VacA has been intense, partly because of its potential as a novel tool for exploring aspects of eukaryotic cell biology, but mainly because of its putative role in the pathogenesis of -associated diseases, in particular peptic ulceration and distal gastric adenocarcinoma. Insertional mutagenesis of abrogates the capacity of to induce vacuolation in epithelial cells, and ablates several other -induced toxic effects. Translocation of IgAl protease across the bacterial cytoplasmic membrane is accomplished via a Sec-mediated process and is accompanied by cleavage of an amino-terminal signal peptide. When VacA is exposed to acidic or alkaline pH, VacA oligomers dissociate into monomeric components of about 90 kDa, each measuring about 6 by 14 nm. mutant strains, constructed with inframe deletions in the portion of encoding the amino-terminal region of the toxin, express truncated VacA proteins that are secreted but fail to oligomerize and lack detectable cytotoxic activity. VacA causes epithelial cell vacuolation in vitro, but this does not lead rapidly to cell death. produces a toxin that has damaging effects on epithelial cells, and colonization is a strong risk factor for the development of peptic ulceration.

Citation: Atherton J, Cover T, Papini E, Telford J. 2001. Vacuolating Cytotoxin, p 97-110. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch9

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Figures

Image of Figure 1
Figure 1

Schematic of the vacuolating cytotoxin gene, , and protein, VacA (not to scale). vacA alleles vary between strains and this variation is most marked in the second part of the signal region and the ∼800-bp mid region. Alleles can be classified according to signal and mid-region type. The translated polypeptide is a protoxin that is amino- and carboxy-terminally processed during secretion. The mature processed toxin slowly dissociates into ∼37- and ∼58-kDa fragments during storage.

Citation: Atherton J, Cover T, Papini E, Telford J. 2001. Vacuolating Cytotoxin, p 97-110. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch9
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Image of Figure 2
Figure 2

Image of the top surface of a soluble VacA oligomer, which has a diameter of approximately 30 nm. This is a three-dimensional reconstruction from electron micrographs of quick-freeze deep-etch metal replicas of VacA. (Reprinted from reference with permission.)

Citation: Atherton J, Cover T, Papini E, Telford J. 2001. Vacuolating Cytotoxin, p 97-110. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch9
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Image of Figure 3
Figure 3

(A) Atomic force microscopy image of VacA two-dimensional crystals on a supported lipid bilayer. (B) Processed image of VacA two-dimensional crystals. The line diagram in the top right corner illustrates the orientation of a single oligomer within the crystal. Individual oligomers within the crystal have an overall diameter of about 28 nm. (Reprinted from reference with permission.)

Citation: Atherton J, Cover T, Papini E, Telford J. 2001. Vacuolating Cytotoxin, p 97-110. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch9
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Image of Figure 4
Figure 4

Cartoon illustrating a possible model for interaction of VacA with the epithelial cell. The inactive, soluble oligomer, made up of p37 and p58 fragments, can be disrupted by acidic or alkaline treatment to release active monomeric VacA. Both the oligomeric and the monomeric toxin are thought to undergo nonspecific binding (NB) to the plasma membrane (PM), which probably does not result in endocytosis. Only activated toxin is thought to undergo specific binding (SB), which may allow toxin internalization. The recently identified RPTP-β appears to be one specific VacA receptor (R). Hydrophobic VacA monomers can insert into the plasma membrane, where they associate to form a pore. The structure of this membrane-associated oligomeric VacA may be different from that of the soluble inactive oligomer. The membrane-associated toxin is an anion (X−) selective channel, which allows changes in ionic flux at the level of the plasma membrane. (E): Membrane-associated VacA is internalized, presumably by receptor-mediated endocytosis, transported, and accumulated in endolysosomes. The toxin receptors are depicted still associated with the toxin, but it is not clear whether the pore-receptor complex becomes dissociated. In one possible model, anion conduction by endocytosed VacA channels stimulates electrogenic proton pumping activity of the V-ATPase. In the presence of ammonia (or other weak bases) this may lead to ammonium ion accumulation in the endolysosomal compartment. The increased concentration of the osmotically active ammonium ions is believed to lead to water influx, swelling of endolysosomes, and vacuole formation.

Citation: Atherton J, Cover T, Papini E, Telford J. 2001. Vacuolating Cytotoxin, p 97-110. In Mobley H, Mendz G, Hazell S (ed), . ASM Press, Washington, DC. doi: 10.1128/9781555818005.ch9
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