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Identified virulence factors of Helicobacter: Toxin


VacA (vacuolating cytotoxin A)  

Related genes: vacA;
Keywords: Toxin; Pore-forming toxin; A-B type;
Characteristics:
VacA expression is determined by variation in the signal sequence (s1a, s1b, s1c, s2) and mid-region (m1, m2) of the vacA gene. s1-type signaling-sequence allele produce functional VacA toxin, whereas s2-type produce VacA with little cytotoxic activity. And s1/m1 strains are more toxic than s1/m2 strains.
Structure features:
Proteolytic cleavage of the VacA protoxin (140 kDa) at its N and C termini yields a 33-aa signal sequence, a mature 90-kDa secreted protein, and a C-terminal fragment that remains localized in the bacterial cell.
The secreted protein is structured in two distinct parts. First, amino-terminal 37-kDa region, rich in β-pleated sheets. This region begins with a 32-residue hydrophobic segment with a propensity to insert into membranes, and ends with a protease-sensitive segment. Second, the following 58-kDa part is predicted to consist of two domains, separated by a flexible segment of variable length: the first domain is highly conserved, whereas the second one is genetically considerably diverse.
Figures:
Current model of the cellular activities of VacA cytotoxin (Reproduced from: Montecucco C, Rappuoli R, 2001. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol. 2(6):457-466.)


Mechanism:
The secreted VacA toxin oligomerized into rosettes. It binds to the apical portion of epithelial cells and inserts into the plasma membrane, forming a hexameric anion-selective channel of low conductance. These channels are release bicarbonate and organic anions from the cell cytosol to support bacterial growth. The toxin channels are slowly endocytosed and eventually reach late endosomal compartment, increasing their permeability to anions with enhancements of the electrogenic vacuolar ATPase (vATPase) proton pump. In the presence of weak bases, including the ammonia generated by the Helicobacter pylori urease, osmotically active acidotropic ions will accumulate in the endosomes. This leads to water influx and vesicle swelling, and essential step in vacuole formation. By an as-yet-unidentified mechanism, the VacA toxin alters tight junctions and increases the paracellular route of permeability providing iron, nickel and other nutrients, this TER (trans-epithelial resistance) effect of VacA could be mediated through specific interaction with the recently identified cytosolic protein VIP54..
VacA is the first bacterial virulence factor that exploits the important plasma membrane sphingolipid, sphingomyelin (SM), as a cellular receptor.
References:
Montecucco et al., 2001. Helicobacter pylori VacA Vacuolating Cytotoxin and HP-Nap Neutrophil Activating Protein. In Achtman M, Suerbaum S (ed.), Helicobacter pylor: Molecular and Cellular Biology. Norfolk Horizon Scientific Press. Wymondham. pp. 245-262.
Cover TL, Blaser MJ, 1992. Purification and characterization of the vacuolating toxin from Helicobacter pylori. J. Biol. Chem. 267(15):10570-10575.
Telford JL, et al., 1994. Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J. Exp. Med. 179(5):1653-1658.
Lupetti P, et al., 1996. Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J. Cell Biol. 133(4):801-807.
Papini E, et al., 1997. The small GTP binding protein rab7 is essential for cellular vacuolation induced by Helicobacter pylori cytotoxin. EMBO J. 16(1):15-24.
Cover TL, et al., 1997. Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J. Cell Biol. 138(4):759-769.
Lanzavecchia S, et al., 1998. Three-dimensional reconstruction of metal replicas of the Helicobacter pylori vacuolating cytotoxin. J. Struct. Biol. 121(1):9-18.
Pagliaccia C, et al., 1998. The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc. Natl. Acad. Sci. USA. 95(17):10212-10217.
Tombola F, et al., 1999. Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: possible implications for the mechanism of cellular vacuolation. Biophys. J. 76(3):1401-1409.
Iwamoto H, et al., 1999. VacA from Helicobacter pylori: a hexameric chloride channel. FEBS Lett. 450:101-104.
Reyrat JM, et al., 1999. 3D imaging of the 58 kDa cell binding subunit of the Helicobacter pylori cytotoxin. J. Mol. Biol. 290(2):459-470.
Szabo I, et al., 1999. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. EMBO J. 18(20):5517-5527.
Szabo I, et al., 1999. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. EMBO J. 18(20):5517-5527.
De Bernard M, et al., 2000. The VacA toxin of Helicobacter pylori identifies a new intermediate filament-interacting protein. EMBO J. 19(1):48-56.
Hotchin NA, et al., 2000. Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase. J. Biol. Chem. 275(19):14009-14012.
Letley DP, Atherton JC, 2000. Natural diversity in the N terminus of the mature vacuolating cytotoxin of Helicobacter pylori determines cytotoxin activity. J. Bacteriol. 182(11):3278-3280.
Ricci V, et al., 2000. High cell sensitivity to Helicobacter pylori VacA toxin depends on a GPI-anchored protein and is not blocked by inhibition of the clathrin-mediated pathway of endocytosis. Mol. Biol. Cell 11(11):3897-3909.
McClain MS, et al., 2001. Amino-terminal hydrophobic region of Helicobacter pylori vacuolating cytotoxin (VacA) mediates transmembrane protein dimerization. Infect. Immun. 69(2):1181-1184.
Montecucco C, Rappuoli R, 2001. Living dangerously: how Helicobacter pylori survives in the human stomach. Nat. Rev. Mol. Cell Biol. 2(6):457-466.
Schraw W, et al., 2002. Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J. Biol. Chem. 277(37):34642-34650.
McClain MS, et al., 2003. Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J. Biol. Chem. 278(14):12101-12108.
Montecucco C, de Bernard M, 2003. Molecular and cellular mechanisms of action of the vacuolating cytotoxin (VacA) and neutrophil-activating protein (HP-NAP) virulence factors of Helicobacter pylori. Microbes Infect. 5(8):715-721.
Kim S, et al., 2004. Membrane channel structure of Helicobacter pylori vacuolating toxin: role of multiple GXXXG motifs in cylindrical channels. Proc. Natl. Acad. Sci. USA. 101(16):5988-5991.
Gupta VR, et al., 2008. Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. PLoS Pathog. 4(5):e1000073.








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