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Helicobacter pylori Vacuolating Toxin

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Helicobacter pylori Research

Abstract

The vacuolating cytotoxin (VacA) was one of the first H. pylori virulence factors identified. All H. pylori strains contain a vacA gene, but there is variation among H. pylori strains in the levels of VacA secretion and activity of VacA proteins. Strains containing allelic types of vacA that produce more active forms of the toxin are associated with human gastroduodenal disease. Experiments in animal models suggest that VacA may contribute to H. pylori colonization of the stomach, and the toxin has been linked to gastric epithelial damage. VacA induces a variety of effects in cultured epithelial cells, including alterations in membrane trafficking within the endolysosomal system, mitochondrial dysfunction, and cell death. Most VacA effects on cells are a consequence of intracellular toxin activities. Unlike most intracellular-acting bacterial toxins that enzymatically modify target molecules within eukaryotic cells, VacA causes cellular alterations primarily through the formation of intracellular ion-conducting channels. In this chapter, we review the structure and function of VacA, along with the roles of VacA in the pathogenesis of H. pylori-associated diseases.

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References

  • Adrian M, Cover TL, Dubochet J, Heuser JE (2002) Multiple oligomeric states of the Helicobacter pylori vacuolating toxin demonstrated by cryo-electron microscopy. J Mol Biol 318:121–133

    Article  CAS  PubMed  Google Scholar 

  • Akada JK, Aoki H, Torigoe Y, Kitagawa T, Kurazono H, Hoshida H, Nishikawa J, Terai S, Matsuzaki M, Hirayama T, Nakazawa T, Akada R, Nakamura K (2010) Helicobacter pylori CagA inhibits endocytosis of cytotoxin VacA in host cells. Dis Model Mech 3:605–617

    Article  CAS  PubMed  Google Scholar 

  • Akazawa Y, Isomoto H, Matsushima K, Kanda T, Minami H, Yamaghchi N, Taura N, Shiozawa K, Ohnita K, Takeshima F, Nakano M, Moss J, Hirayama T, Nakao K (2013) Endoplasmic reticulum stress contributes to Helicobacter pylori VacA-induced apoptosis. PLoS One 8:e82322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Algood HM, Torres VJ, Unutmaz D, Cover TL (2007) Resistance of primary murine CD4+ T cells to Helicobacter pylori vacuolating cytotoxin. Infect Immun 75:334–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen LA, Schlesinger LS, Kang B (2000) Virulent strains of Helicobacter pylori demonstrate delayed phagocytosis and stimulate homotypic phagosome fusion in macrophages. J Exp Med 191:115–128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Argent RH, Thomas RJ, Letley DP, Rittig MG, Hardie KR, Atherton JC (2008) Functional association between the Helicobacter pylori virulence factors VacA and CagA. J Med Microbiol 57:145–150

    Article  CAS  PubMed  Google Scholar 

  • Atherton JC, Cao P, Peek RM Jr, Tummuru MK, Blaser MJ, Cover TL (1995) Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 270:17771–17777

    Article  CAS  PubMed  Google Scholar 

  • Atherton JC, Peek RM Jr, Tham KT, Cover TL, Blaser MJ (1997) Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 112:92–99

    Article  CAS  PubMed  Google Scholar 

  • Basso D, Zambon CF, Letley DP, Stranges A, Marchet A, Rhead JL, Schiavon S, Guariso G, Ceroti M, Nitti D, Rugge M, Plebani M, Atherton JC (2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135:91–99

    Article  CAS  PubMed  Google Scholar 

  • Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D’elios MM, Telford JL, Baldari CT (2003) The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 198:1887–1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brest P, Hofman V, Lassalle S, Cesaro A, Ricci V, Selva E, Auberger P, Hofman P (2006) Human polymorphonuclear leukocytes are sensitive in vitro to Helicobacter pylori VacA toxin. Helicobacter 11:544–555

    Article  CAS  PubMed  Google Scholar 

  • Bumann D, Aksu S, Wendland M, Janek K, Zimny-Arndt U, Sabarth N, Meyer TF, Jungblut PR (2002) Proteome analysis of secreted proteins of the gastric pathogen Helicobacter pylori. Infect Immun 70:3396–3403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calore F, Genisset C, Casellato A, Rossato M, Codolo G, Esposti MD, Scorrano L, De Bernard M (2010) Endosome-mitochondria juxtaposition during apoptosis induced by Helicobacter pylori VacA. Cell Death Differ 17:1707–1716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caputo R, Tuccillo C, Manzo BA, Zarrilli R, Tortora G, Blanco Cdel V, Ricci V, Ciardiello F, Romano M (2003) Helicobacter pylori VacA toxin up-regulates vascular endothelial growth factor expression in MKN 28 gastric cells through an epidermal growth factor receptor-, cyclooxygenase-2-dependent mechanism. Clin Cancer Res 9:2015–2021

    CAS  PubMed  Google Scholar 

  • Chambers MG, Pyburn TM, Gonzalez-Rivera C, Collier SE, Eli I, Yip CK, Takizawa Y, Lacy DB, Cover TL, Ohi MD (2013) Structural analysis of the oligomeric states of Helicobacter pylori VacA toxin. J Mol Biol 425:524–535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cover TL, Blaser MJ (1992) Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 267:10570–10575

    CAS  PubMed  Google Scholar 

  • Cover TL, Vaughn SG, Cao P, Blaser MJ (1992) Potentiation of Helicobacter pylori vacuolating toxin activity by nicotine and other weak bases. J Infect Dis 166:1073–1078

    Article  CAS  PubMed  Google Scholar 

  • Cover TL, Tummuru MKR, Cao P, Thompson SA, Blaser MJ (1994) Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem 269:10566–10573

    CAS  PubMed  Google Scholar 

  • Cover TL, Hanson PI, Heuser JE (1997) Acid-induced dissociation of VacA, the Helicobacter pylori vacuolating cytotoxin, reveals its pattern of assembly. J Cell Biol 138:759–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cover TL, Krishna US, Israel DA, Peek RM Jr (2003) Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res 63:951–957

    CAS  PubMed  Google Scholar 

  • Czajkowsky DM, Iwamoto H, Cover TL, Shao Z (1999) The vacuolating toxin from Helicobacter pylori forms hexameric pores in lipid bilayers at low pH. Proc Natl Acad Sci U S A 96:2001–2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dailidiene D, Dailide G, Ogura K, Zhang M, Mukhopadhyay AK, Eaton KA, Cattoli G, Kusters JG, Berg DE (2004) Helicobacter acinonychis: genetic and rodent infection studies of a Helicobacter pylori-like gastric pathogen of cheetahs and other big cats. J Bacteriol 186:356–365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Bernard M, Papini E, De Filippis V, Gottardi E, Telford J, Manetti R, Fontana A, Rappuoli R, Montecucco C (1995) Low pH activates the vacuolating toxin of Helicobacter pylori, which becomes acid and pepsin resistant. J Biol Chem 270:23937–23940

    Article  PubMed  Google Scholar 

  • De Bernard M, Arico B, Papini E, Rizzuto R, Grandi G, Rappuoli R, Montecucco C (1997) Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Mol Microbiol 26:665–674

    Article  PubMed  Google Scholar 

  • De Bernard M, Burroni D, Papini E, Rappuoli R, Telford J, Montecucco C (1998) Identification of the Helicobacter pylori VacA toxin domain active in the cell cytosol. Infect Immun 66:6014–6016

    PubMed  PubMed Central  Google Scholar 

  • De Bernard M, Moschioni M, Habermann A, Griffiths G, Montecucco C (2002) Cell vacuolization induced by Helicobacter pylori VacA cytotoxin does not depend on late endosomal SNAREs. Cell Microbiol 4:11–18

    Article  PubMed  Google Scholar 

  • De Bernard M, Cappon A, Pancotto L, Ruggiero P, Rivera J, Del Giudice G, Montecucco C (2005) The Helicobacter pylori VacA cytotoxin activates RBL-2H3 cells by inducing cytosolic calcium oscillations. Cell Microbiol 7:191–198

    Article  PubMed  CAS  Google Scholar 

  • Debellis L, Papini E, Caroppo R, Montecucco C, Curci S (2001) Helicobacter pylori cytotoxin VacA increases alkaline secretion in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol 281:G1440–G1448

    CAS  PubMed  Google Scholar 

  • Domanska G, Motz C, Meinecke M, Harsman A, Papatheodorou P, Reljic B, Dian-Lothrop EA, Galmiche A, Kepp O, Becker L, Gunnewig K, Wagner R, Rassow J (2010) Helicobacter pylori VacA toxin/subunit p34: targeting of an anion channel to the inner mitochondrial membrane. PLoS Pathog 6:e1000878

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eaton KA, Cover TL, Tummuru MK, Blaser MJ, Krakowka S (1997) Role of vacuolating cytotoxin in gastritis due to Helicobacter pylori in gnotobiotic piglets. Infect Immun 65:3462–3464

    CAS  PubMed  PubMed Central  Google Scholar 

  • Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, Van Doorn LJ, Carneiro F, Sobrinho-Simoes M (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94:1680–1687

    Article  CAS  PubMed  Google Scholar 

  • Fiocca R, Necchi V, Sommi P, Ricci V, Telford J, Cover TL, Solcia E (1999) Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion pathway and budding of outer membrane vesicles. Uptake of released toxin and vesicles by gastric epithelium. J Pathol 188:220–226

    Article  CAS  PubMed  Google Scholar 

  • Fischer W, Buhrdorf R, Gerland E, Haas R (2001) Outer membrane targeting of passenger proteins by the vacuolating cytotoxin autotransporter of Helicobacter pylori. Infect Immun 69:6769–6775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Foo JH, Culvenor JG, Ferrero RL, Kwok T, Lithgow T, Gabriel K (2010) Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria. J Mol Biol 401:792–798

    Article  CAS  PubMed  Google Scholar 

  • Forsyth MH, Atherton JC, Blaser MJ, Cover TL (1998) Heterogeneity in levels of vacuolating cytotoxin gene (vacA) transcription among Helicobacter pylori strains. Infect Immun 66:3088–3094

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fujikawa A, Shirasaka D, Yamamoto S, Ota H, Yahiro K, Fukada M, Shintani T, Wada A, Aoyama N, Hirayama T, Fukamachi H, Noda M (2003) Mice deficient in protein tyrosine phosphatase receptor type Z are resistant to gastric ulcer induction by VacA of Helicobacter pylori. Nat Genet 33:375–381

    Article  CAS  PubMed  Google Scholar 

  • Galmiche A, Rassow J, Doye A, Cagnol S, Chambard JC, Contamin S, De Thillot V, Just I, Ricci V, Solcia E, Van Obberghen E, Boquet P (2000) The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J 19:6361–6370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gangwer KA, Mushrush DJ, Stauff DL, Spiller B, Mcclain MS, Cover TL, Lacy DB (2007) Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc Natl Acad Sci U S A 104:16293–16298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gangwer KA, Shaffer CL, Suerbaum S, Lacy DB, Cover TL, Bordenstein SR (2010) Molecular evolution of the Helicobacter pylori vacuolating toxin gene vacA. J Bacteriol 192:6126–6135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garner JA, Cover TL (1996) Binding and internalization of the Helicobacter pylori vacuolating cytotoxin by epithelial cells. Infect Immun 64:4197–4203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gauthier NC, Ricci V, Gounon P, Doye A, Tauc M, Poujeol P, Boquet P (2004) Glycosylphosphatidylinositol-anchored proteins and actin cytoskeleton modulate chloride transport by channels formed by the Helicobacter pylori vacuolating cytotoxin VacA in HeLa cells. J Biol Chem 279:9481–9489

    Article  CAS  PubMed  Google Scholar 

  • Gauthier NC, Monzo P, Kaddai V, Doye A, Ricci V, Boquet P (2005) Helicobacter pylori VacA cytotoxin: a probe for a clathrin-independent and Cdc42-dependent pinocytic pathway routed to late endosomes. Mol Biol Cell 16:4852–4866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gauthier NC, Ricci V, Landraud L, Boquet P (2006) Helicobacter pylori VacA toxin: a tool to study novel early endosomes. Trends Microbiol 14:292–294

    Article  CAS  PubMed  Google Scholar 

  • Gauthier NC, Monzo P, Gonzalez T, Doye A, Oldani A, Gounon P, Ricci V, Cormont M, Boquet P (2007) Early endosomes associated with dynamic F-actin structures are required for late trafficking of H. pylori VacA toxin. J Cell Biol 177:343–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gebert B, Fischer W, Weiss E, Hoffman R, Haas R (2003) Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 301:1099–1102

    Article  CAS  PubMed  Google Scholar 

  • Genisset C, Puhar A, Calore F, De Bernard M, Dell’antone P, Montecucco C (2007) The concerted action of the Helicobacter pylori cytotoxin VacA and of the v-ATPase proton pump induces swelling of isolated endosomes. Cell Microbiol 9:1481–1490

    Article  CAS  PubMed  Google Scholar 

  • Ghiara P, Rossi M, Marchetti M, Di Tommaso A, Vindigni C, Ciampolini F, Covacci A, Telford JL, De Magistris MT, Pizza M, Rappuoli R, Del Giudice G (1997) Therapeutic intragastric vaccination against Helicobacter pylori in mice eradicates an otherwise chronic infection and confers protection against reinfection. Infect Immun 65:4996–5002

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Rivera C, Gangwer KA, Mcclain MS, Eli IM, Chambers MG, Ohi MD, Lacy DB, Cover TL (2010) Reconstitution of Helicobacter pylori VacA toxin from purified components. Biochemistry 49:5743–5752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Rivera C, Algood HM, Radin JN, Mcclain MS, Cover TL (2012) The intermediate region of Helicobacter pylori VacA is a determinant of toxin potency in a Jurkat T cell assay. Infect Immun 80:2578–2588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guarino A, Bisceglia M, Canani RB, Boccia MC, Mallardo G, Bruzzese E, Massari P, Rappuoli R, Telford J (1998) Enterotoxic effect of the vacuolating toxin produced by Helicobacter pylori in Caco-2 cells. J Infect Dis 178:1373–1378

    Article  CAS  PubMed  Google Scholar 

  • Gupta VR, Patel HK, Kostolansky SS, Ballivian RA, Eichberg J, Blanke SR (2008) Sphingomyelin functions as a novel receptor for Helicobacter pylori VacA. PLoS Pathog 4:e1000073

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gupta VR, Wilson BA, Blanke SR (2010) Sphingomyelin is important for the cellular entry and intracellular localization of Helicobacter pylori VacA. Cell Microbiol 12:1517–1533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hennig EE, Godlewski MM, Butruk E, Ostrowski J (2005) Helicobacter pylori VacA cytotoxin interacts with fibronectin and alters HeLa cell adhesion and cytoskeletal organization in vitro. FEMS Immunol Med Microbiol 44:143–150

    Article  CAS  PubMed  Google Scholar 

  • Hisatsune J, Yamasaki E, Nakayama M, Shirasaka D, Kurazono H, Katagata Y, Inoue H, Han J, Sap J, Yahiro K, Moss J, Hirayama T (2007) Helicobacter pylori VacA enhances PGE2 production through induction of COX-2 expression via a p38 MAP kinase/ATF-2 cascade in AZ-521 cells. Infect Immun 75:4472–4481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hisatsune J, Nakayama M, Isomoto H, Kurazono H, Mukaida N, Mukhopadhyay AK, Azuma T, Yamaoka Y, Sap J, Yamasaki E, Yahiro K, Moss J, Hirayama T (2008) Molecular characterization of Helicobacter pylori VacA induction of IL-8 in U937 cells reveals a prominent role for p38MAPK in activating transcription factor-2, cAMP response element binding protein, and NF-kappaB activation. J Immunol 180:5017–5027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotchin NA, Cover TL, Akhtar N (2000) Cell vacuolation induced by the VacA cytotoxin of Helicobacter pylori is regulated by the Rac1 GTPase. J Biol Chem 275:14009–14012

    Article  CAS  PubMed  Google Scholar 

  • Ilver D, Barone S, Mercati D, Lupetti P, Telford JL (2004) Helicobacter pylori toxin VacA is transferred to host cells via a novel contact-dependent mechanism. Cell Microbiol 6:167–174

    Article  CAS  PubMed  Google Scholar 

  • Ito Y, Azuma T, Ito S, Suto H, Miyaji H, Yamazaki Y, Kohli Y, Kuriyama M (1998) Full-length sequence analysis of the vacA gene from cytotoxic and noncytotoxic Helicobacter pylori. J Infect Dis 178:1391–1398

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto H, Czajkowsky DM, Cover TL, Szabo G, Shao Z (1999) VacA from Helicobacter pylori: a hexameric chloride channel. FEBS Lett 450:101–104

    Article  CAS  PubMed  Google Scholar 

  • Jain P, Luo ZQ, Blanke SR (2011) Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death. Proc Natl Acad Sci U S A 108:16032–16037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kersulyte D, Rossi M, Berg DE (2013) Sequence divergence and conservation in genomes of Helicobacter cetorum strains from a dolphin and a whale. PLoS One 8:e83177

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim JM, Kim JS, Lee JY, Kim YJ, Youn HJ, Kim IY, Chee YJ, Oh YK, Kim N, Jung HC, Song IS (2007) Vacuolating cytotoxin in Helicobacter pylori water-soluble proteins upregulates chemokine expression in human eosinophils via Ca2+ influx, mitochondrial reactive oxygen intermediates, and NF-kappaB activation. Infect Immun 75:3373–3381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JM, Kim JS, Lee JY, Sim YS, Kim YJ, Oh YK, Yoon HJ, Kang JS, Youn J, Kim N, Jung HC, Kim S (2010) Dual effects of Helicobacter pylori vacuolating cytotoxin on human eosinophil apoptosis in early and late periods of stimulation. Eur J Immunol 40:1651–1662

    Article  CAS  PubMed  Google Scholar 

  • Kim JM, Kim JS, Yoo DY, Ko SH, Kim N, Kim H, Kim YJ (2011) Stimulation of dendritic cells with Helicobacter pylori vacuolating cytotoxin negatively regulates their maturation via the restoration of E2F1. Clin Exp Immunol 166:34–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kimura M, Goto S, Wada A, Yahiro K, Niidome T, Hatakeyama T, Aoyagi H, Hirayama T, Kondo T (1999) Vacuolating cytotoxin purified from Helicobacter pylori causes mitochondrial damage in human gastric cells. Microb Pathog 26:45–52

    Article  CAS  PubMed  Google Scholar 

  • Kimura M, Goto S, Ihara Y, Wada A, Yahiro K, Niidome T, Aoyagi H, Hirayama T, Kondo T (2001) Impairment of glutathione metabolism in human gastric epithelial cells treated with vacuolating cytotoxin from Helicobacter pylori. Microb Pathog 31:29–36

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi H, Kamiya S, Suzuki T, Kohda K, Muramatsu S, Kurumada T, Ohta U, Miyazawa M, Kimura N, Mutoh N, Shirai T, Takagi A, Harasawa S, Tani N, Miwa T (1996) The effect of Helicobacter pylori on gastric acid secretion by isolated parietal cells from a guinea pig. Association with production of vacuolating toxin by H. pylori. Scand J Gastroenterol 31:428–433

    Article  CAS  PubMed  Google Scholar 

  • Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J (2001) Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun 69:5080–5087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Letley DP, Rhead JL, Twells RJ, Dove B, Atherton JC (2003) Determinants of non-toxicity in the gastric pathogen Helicobacter pylori. J Biol Chem 278:26734–26741

    Article  CAS  PubMed  Google Scholar 

  • Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR (1988) Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol 26:93–99

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Wandinger-Ness A, Goldenring JR, Cover TL (2004) Clustering and redistribution of late endocytic compartments in response to Helicobacter pylori vacuolating toxin. Mol Biol Cell 15:1946–1959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lupetti P, Heuser JE, Manetti R, Massari P, Lanzavecchia S, Bellon PL, Dallai R, Rappuoli R, Telford JL (1996) Oligomeric and subunit structure of the Helicobacter pylori vacuolating cytotoxin. J Cell Biol 133:801–807

    Article  CAS  PubMed  Google Scholar 

  • Marchetti M, Rossi M, Giannelli V, Giuliani MM, Pizza M, Censini S, Covacci A, Massari P, Pagliaccia C, Manetti R, Telford JL, Douce G, Dougan G, Rappuoli R, Ghiara P (1998) Protection against Helicobacter pylori infection in mice by intragastric vaccination with H. pylori antigens is achieved using a non-toxic mutant of E. coli heat-labile enterotoxin (LT) as adjuvant. Vaccine 16:33–37

    Article  CAS  PubMed  Google Scholar 

  • Massari P, Manetti R, Burroni D, Nuti S, Norais N, Rappuoli R, Telford JL (1998) Binding of the Helicobacter pylori vacuolating cytotoxin to target cells. Infect Immun 66:3981–3984

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mcclain MS, Schraw W, Ricci V, Boquet P, Cover TL (2000) Acid-activation of Helicobacter pylori vacuolating cytotoxin (VacA) results in toxin internalization by eukaryotic cells. Mol Microbiol 37:433–442

    Article  CAS  PubMed  Google Scholar 

  • Mcclain MS, Cao P, Iwamoto H, Vinion-Dubiel AD, Szabo G, Shao Z, Cover TL (2001) A 12-amino-acid segment, present in type s2 but not type s1 Helicobacter pylori VacA proteins, abolishes cytotoxin activity and alters membrane channel formation. J Bacteriol 183:6499–6508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mcclain MS, Iwamoto H, Cao P, Vinion-Dubiel AD, Li Y, Szabo G, Shao Z, Cover TL (2003) Essential role of a GXXXG motif for membrane channel formation by Helicobacter pylori vacuolating toxin. J Biol Chem 278:12101–12108

    Article  CAS  PubMed  Google Scholar 

  • Menaker RJ, Ceponis PJ, Jones NL (2004) Helicobacter pylori induces apoptosis of macrophages in association with alterations in the mitochondrial pathway. Infect Immun 72:2889–2898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molinari M, Galli C, Norais N, Telford JL, Rappuoli R, Luzio JP, Montecucco C (1997) Vacuoles induced by Helicobacter pylori toxin contain both late endosomal and lysosomal markers. J Biol Chem 272:25339–25344

    Article  CAS  PubMed  Google Scholar 

  • Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C (1998) Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med 187:135–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moll G, Papini E, Colonna R, Burroni D, Telford J, Rappuoli R, Montecucco C (1995) Lipid interaction of the 37-kDa and 58-kDa fragments of the Helicobacter pylori cytotoxin. Eur J Biochem 234:947–952

    Article  CAS  PubMed  Google Scholar 

  • Montecucco C, Rappuoli R (2001) Living dangerously: how Helicobacter pylori survives in the human stomach. Nat Rev Mol Cell Biol 2:457–466

    Article  CAS  PubMed  Google Scholar 

  • Nakayama M, Kimura M, Wada A, Yahiro K, Ogushi KI, Niidome T, Fujikawa A, Shirasaka D, Aoyama N, Kurazono H, Noda M, Moss J, Hirayama T (2004) Helicobacter pylori VacA activates the p38/ATF-2-mediated signal pathway in AZ-521 cells. J Biol Chem 279:7024–7028

    Article  CAS  PubMed  Google Scholar 

  • Nakayama M, Hisatsune J, Yamasaki E, Isomoto H, Kurazono H, Hatakeyama M, Azuma T, Yamaoka Y, Yahiro K, Moss J, Hirayama T (2009) Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem 284:1612–1619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nguyen VQ, Caprioli RM, Cover TL (2001) Carboxy-terminal proteolytic processing of Helicobacter pylori vacuolating toxin. Infect Immun 69:543–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oertli M, Noben M, Engler DB, Semper RP, Reuter S, Maxeiner J, Gerhard M, Taube C, Muller A (2013) Helicobacter pylori gamma-glutamyl transpeptidase and vacuolating cytotoxin promote gastric persistence and immune tolerance. Proc Natl Acad Sci U S A 110:3047–3052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogura K, Maeda S, Nakao M, Watanabe T, Tada M, Kyutoku T, Yoshida H, Shiratori Y, Omata M (2000) Virulence factors of Helicobacter pylori responsible for gastric diseases in mongolian gerbil. J Exp Med 192:1601–1610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oldani A, Cormont M, Hofman V, Chiozzi V, Oregioni O, Canonici A, Sciullo A, Sommi P, Fabbri A, Ricci V, Boquet P (2009) Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog 5:e1000603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Oswald-Richter K, Torres VJ, Sundrud MS, Vancompernolle SE, Cover TL, Unutmaz D (2006) Helicobacter pylori VacA toxin inhibits human immunodeficiency virus infection of primary human T cells. J Virol 80:11767–11775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Padilla PI, Wada A, Yahiro K, Kimura M, Niidome T, Aoyagi H, Kumatori A, Anami M, Hayashi T, Fujisawa J, Saito H, Moss J, Hirayama T (2000) Morphologic differentiation of HL-60 cells is associated with appearance of RPTPbeta and induction of Helicobacter pylori VacA sensitivity. J Biol Chem 275:15200–15206

    Article  CAS  PubMed  Google Scholar 

  • Pagliaccia C, De Bernard M, Lupetti P, Ji X, Burroni D, Cover TL, Papini E, Rappuoli R, Telford JL, Reyrat JM (1998) The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity. Proc Natl Acad Sci U S A 95:10212–10217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pagliaccia C, Wang XM, Tardy F, Telford JL, Ruysschaert JM, Cabiaux V (2000) Structure and interaction of VacA of Helicobacter pylori with a lipid membrane. Eur J Biochem 267:104–109

    Article  CAS  PubMed  Google Scholar 

  • Pai R, Cover TL, Tarnawski AS (1999) Helicobacter pylori vacuolating cytotoxin (VacA) disorganizes the cytoskeletal architecture of gastric epithelial cells. Biochem Biophys Res Commun 262:245–250

    Article  CAS  PubMed  Google Scholar 

  • Papini E, De Bernard M, Milia E, Bugnoli M, Zerial M, Rappuoli R, Montecucco C (1994) Cellular vacuoles induced by Helicobacter pylori originate from late endosomal compartments. Proc Natl Acad Sci U S A 91:9720–9724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papini E, Satin B, Bucci C, De Bernard M, Telford JL, Manetti R, Rappuoli R, Zerial M, Montecucco C (1997) The small GTP binding protein rab7 is essential for cellular vacuolation induced by Helicobacter pylori cytotoxin. EMBO J 16:15–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papini E, Satin B, Norais N, De Bernard M, Telford JL, Rappuoli R, Montecucco C (1998) Selective increase of the permeability of polarized epithelial cell monolayers by Helicobacter pylori vacuolating toxin. J Clin Invest 102:813–820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Patel HK, Willhite DC, Patel RM, Ye D, Williams CL, Torres EM, Marty KB, Macdonald RA, Blanke SR (2002) Plasma membrane cholesterol modulates cellular vacuolation induced by the Helicobacter pylori vacuolating cytotoxin. Infect Immun 70:4112–4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radin JN, Gonzalez-Rivera C, Ivie SE, Mcclain MS, Cover TL (2011) Helicobacter pylori VacA induces programmed necrosis in gastric epithelial cells. Infect Immun 79:2535–2543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Radin JN, Gaddy JA, Gonzalez-Rivera C, Loh JT, Algood HM, Cover TL (2013) Flagellar localization of a Helicobacter pylori autotransporter protein. MBio 4:e00613-12

    Article  PubMed  PubMed Central  Google Scholar 

  • Radin JN, Gonzalez-Rivera C, Frick-Cheng AE, Sheng J, Gaddy JA, Rubin DH, Algood HM, Mcclain MS, Cover TL (2014) Role of connexin 43 in Helicobacter pylori VacA-induced cell death. Infect Immun 82:423–432

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Raju D, Hussey S, Ang M, Terebiznik MR, Sibony M, Galindo-Mata E, Gupta V, Blanke SR, Delgado A, Romero-Gallo J, Ramjeet MS, Mascarenhas H, Peek RM, Correa P, Streutker C, Hold G, Kunstmann E, Yoshimori T, Silverberg MS, Girardin SE, Philpott DJ, El Omar E, Jones NL (2012) Vacuolating cytotoxin and variants in Atg16L1 that disrupt autophagy promote Helicobacter pylori infection in humans. Gastroenterology 142:1160–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reyrat JM, Lanzavecchia S, Lupetti P, De Bernard M, Pagliaccia C, Pelicic V, Charrel M, Ulivieri C, Norais N, Ji X, Cabiaux V, Papini E, Rappuoli R, Telford JL (1999) 3D imaging of the 58 kDa cell binding subunit of the Helicobacter pylori cytotoxin. J Mol Biol 290:459–470

    Article  CAS  PubMed  Google Scholar 

  • Rhead JL, Letley DP, Mohammadi M, Hussein N, Mohagheghi MA, Eshagh Hosseini M, Atherton JC (2007) A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 133:926–936

    Article  CAS  PubMed  Google Scholar 

  • Ricci V, Sommi P, Fiocca R, Romano M, Solcia E, Ventura U (1997) Helicobacter pylori vacuolating toxin accumulates within the endosomal- vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia. J Pathol 183:453–459

    Article  CAS  PubMed  Google Scholar 

  • Ricci V, Galmiche A, Doye A, Necchi V, Solcia E, Boquet P (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 11:3897–3909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salama NR, Otto G, Tompkins L, Falkow S (2001) Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69:730–736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satin B, Norais N, Telford J, Rappuoli R, Murgia M, Montecucco C, Papini E (1997) Effect of Helicobacter pylori vacuolating toxin on maturation and extracellular release of procathepsin D and on epidermal growth factor degradation. J Biol Chem 272:25022–25028

    Article  CAS  PubMed  Google Scholar 

  • Schmitt W, Haas R (1994) Genetic analysis of the Helicobacter pylori vacuolating cytotoxin: structural similarities with the IgA protease type of exported protein. Mol Microbiol 12:307–319

    Article  CAS  PubMed  Google Scholar 

  • Schraw W, Li Y, Mcclain MS, Van Der Goot FG, Cover TL (2002) Association of Helicobacter pylori vacuolating toxin (VacA) with lipid rafts. J Biol Chem 277:34642–34650

    Article  CAS  PubMed  Google Scholar 

  • Sewald X, Gebert-Vogal B, Prassl S, Barwig I, Weiss E, Fabbri M, Osicka R, Schiemann M, Busch DH, Semmrich M, Holzmann B, Sebo P, Haas R (2008) CD18 is the T-lymphocyte receptor of the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe 3:20–29

    Article  CAS  PubMed  Google Scholar 

  • Sewald X, Jimenez-Soto L, Haas R (2011) PKC-dependent endocytosis of the Helicobacter pylori vacuolating cytotoxin in primary T lymphocytes. Cell Microbiol 13:482–496

    Article  CAS  PubMed  Google Scholar 

  • Skibinski DA, Genisset C, Barone S, Telford JL (2006) The cell-specific phenotype of the polymorphic vacA midregion is independent of the appearance of the cell surface receptor protein tyrosine phosphatase beta. Infect Immun 74:49–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smoot DT, Resau JH, Earlington MH, Simpson M, Cover TL (1996) Effects of Helicobacter pylori vacuolating cytotoxin on primary cultures of human gastric epithelial cells. Gut 39:795–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sundrud MS, Torres VJ, Unutmaz D, Cover TL (2004) Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci U S A 101:7727–7732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Supajatura V, Ushio H, Wada A, Yahiro K, Okumura K, Ogawa H, Hirayama T, Ra C (2002) Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines. J Immunol 168:2603–2607

    Article  CAS  PubMed  Google Scholar 

  • Suzuki J, Ohnishi H, Shibata H, Wada A, Hirayama T, Iiri T, Ueda N, Kanamaru C, Tsuchida T, Mashima H, Yasuda H, Fujita T (2001) Dynamin is involved in human epithelial cell vacuolation caused by the Helicobacter pylori-produced cytotoxin VacA. J Clin Invest 107:1329

    CAS  Google Scholar 

  • Suzuki J, Ohnishi H, Wada A, Hirayama T, Ohno H, Ueda N, Yasuda H, Iiri T, Wada Y, Futai M, Mashima H (2003) Involvement of syntaxin 7 in human gastric epithelial cell vacuolation induced by the Helicobacter pylori-produced cytotoxin VacA. J Biol Chem 278:25585–25590

    Article  CAS  PubMed  Google Scholar 

  • Szabo I, Brutsche S, Tombola F, Moschioni M, Satin B, Telford JL, Rappuoli R, Montecucco C, Papini E, Zoratti M (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 18:5517–5527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tabel G, Hoa NT, Tarnawski A, Chen J, Domek M, Ma TY (2003) Helicobacter pylori infection inhibits healing of the wounded duodenal epithelium in vitro. J Lab Clin Med 142:421–430

    Article  CAS  PubMed  Google Scholar 

  • Tan S, Noto JM, Romero-Gallo J, Peek RM Jr, Amieva MR (2011) Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog 7:e1002050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tegtmeyer N, Zabler D, Schmidt D, Hartig R, Brandt S, Backert S (2009) Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol 11:488–505

    Article  CAS  PubMed  Google Scholar 

  • Telford JL, Ghiara P, Dell’orco M, Comanducci M, Burroni D, Bugnoli M, Tecce MF, Censini S, Covacci A, Xiang Z et al (1994) Gene structure of the Helicobacter pylori cytotoxin and evidence of its key role in gastric disease. J Exp Med 179:1653–1658

    Article  CAS  PubMed  Google Scholar 

  • Terebiznik MR, Vazquez CL, Torbicki K, Banks D, Wang T, Hong W, Blanke SR, Colombo MI, Jones NL (2006) Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. Infect Immun 74:6599–6614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Terebiznik MR, Raju D, Vazquez CL, Torbricki K, Kulkarni R, Blanke SR, Yoshimori T, Colombo MI, Jones NL (2009) Effect of Helicobacter pylori’s vacuolating cytotoxin on the autophagy pathway in gastric epithelial cells. Autophagy 5:370–379

    Article  CAS  PubMed  Google Scholar 

  • Tombola F, Carlesso C, Szabo I, De Bernard M, Reyrat JM, Telford JL, Rappuoli R, Montecucco C, Papini E, Zoratti M (1999a) Helicobacter pylori vacuolating toxin forms anion-selective channels in planar lipid bilayers: possible implications for the mechanism of cellular vacuolation. Biophys J 76:1401–1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tombola F, Oregna F, Brutsche S, Szabo I, Del Giudice G, Rappuoli R, Montecucco C, Papini E, Zoratti M (1999b) Inhibition of the vacuolating and anion channel activities of the VacA toxin of Helicobacter pylori. FEBS Lett 460:221–225

    Article  CAS  PubMed  Google Scholar 

  • Tombola F, Morbiato L, Del Giudice G, Rappuoli R, Zoratti M, Papini E (2001) The Helicobacter pylori VacA toxin is a urea permease that promotes urea diffusion across epithelia. J Clin Invest 108:929–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Torres VJ, Ivie SE, Mcclain MS, Cover TL (2005) Functional properties of the p33 and p55 domains of the Helicobacter pylori vacuolating cytotoxin. J Biol Chem 280:21107–21114

    Article  CAS  PubMed  Google Scholar 

  • Torres VJ, Vancompernolle SE, Sundrud MS, Unutmaz D, Cover TL (2007) Helicobacter pylori vacuolating cytotoxin inhibits activation-induced proliferation of human T and B lymphocyte subsets. J Immunol 179:5433–5440

    Article  CAS  PubMed  Google Scholar 

  • Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, Nagano O, Matsuzaki J, Hibi T (2012) Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 12:764–777

    Article  CAS  PubMed  Google Scholar 

  • Tuo B, Song P, Wen G, Sewald X, Gebert-Vogl B, Haas R, Manns M, Seidler U (2009) Helicobacter pylori vacuolating cytotoxin inhibits duodenal bicarbonate secretion by a histamine-dependent mechanism in mice. J Infect Dis 199:505–512

    Article  PubMed  Google Scholar 

  • Van Doorn LJ, Figueiredo C, Sanna R, Plaisier A, Schneeberger P, De Boer W, Quint W (1998) Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pylori. Gastroenterology 115:58–66

    Article  PubMed  Google Scholar 

  • Vinion-Dubiel AD, Mcclain MS, Czajkowsky DM, Iwamoto H, Ye D, Cao P, Schraw W, Szabo G, Blanke SR, Shao Z, Cover TL (1999) A dominant negative mutant of Helicobacter pylori vacuolating toxin (VacA) inhibits VacA-induced cell vacuolation. J Biol Chem 274:37736–37742

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Wattiez R, Paggliacia C, Telford JL, Ruysschaert J, Cabiaux V (2000) Membrane topology of VacA cytotoxin from H. pylori. FEBS Lett 481:96–100

    Article  CAS  PubMed  Google Scholar 

  • Wang W-C, Wang H-J, Kuo C-H (2001) Two distinctive cell binding patterns by vacuolating toxin fused with glutathione S-transferase: one high-affinity m1-specific binding and the other lower-affinity binding for variant m forms. Biochemistry 40:11887–11896

    Article  CAS  PubMed  Google Scholar 

  • Wang HT, Li ZH, Yuan JP, Zhao W, Shi XD, Tong SQ, Guo XK (2005) Effect of Helicobacter pylori VacA on gene expression of gastric cancer cells. World J Gastroenterol 11:109–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang F, Xia P, Wu F, Wang D, Wang W, Ward T, Liu Y, Aikhionbare F, Guo Z, Powell M, Liu B, Bi F, Shaw A, Zhu Z, Elmoselhi A, Fan D, Cover TL, Ding X, Yao X (2008) Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells. J Biol Chem 283:26714–26725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weiss G, Forster S, Irving A, Tate M, Ferrero RL, Hertzog P, Frokiaer H, Kaparakis-Liaskos M (2013) Helicobacter pylori VacA suppresses Lactobacillus acidophilus-induced interferon beta signaling in macrophages via alterations in the endocytic pathway. MBio 4:e00609–e00612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willhite DC, Blanke SR (2004) Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell Microbiol 6:143–154

    Article  CAS  PubMed  Google Scholar 

  • Willhite DC, Ye D, Blanke SR (2002) Fluorescence resonance energy transfer microscopy of the Helicobacter pylori vacuolating cytotoxin within mammalian cells. Infect Immun 70:3824–3832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Willhite DC, Cover TL, Blanke SR (2003) Cellular vacuolation and mitochondrial cytochrome c release are independent outcomes of Helicobacter pylori vacuolating cytotoxin activity that are each dependent on membrane channel formation. J Biol Chem 278:48204–48209

    Article  CAS  PubMed  Google Scholar 

  • Winter JA, Letley DP, Cook KW, Rhead JL, Zaitoun AM, Ingram RJM, Amilon KR, Croxall NJ, Kaye PV, Robinson K, Atherton JC (2014) A role for the vacuolating cytotoxin, VacA, in colonization and Helicobacter pylori – induced metaplasia in the stomach. J Infect Dis 210:954–963

    Article  PubMed  PubMed Central  Google Scholar 

  • Wirth HP, Beins MH, Yang M, Tham KT, Blaser MJ (1998) Experimental infection of Mongolian gerbils with wild-type and mutant Helicobacter pylori strains. Infect Immun 66:4856–4866

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yahiro K, Niidome T, Kimura M, Hatakeyama T, Aoyagi H, Kurazono H, Imagawa K, Wada A, Moss J, Hirayama T (1999) Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyrosine phosphatase beta. J Biol Chem 274:36693–36699

    Article  CAS  PubMed  Google Scholar 

  • Yahiro K, Wada A, Nakayama M, Kimura T, Ogushi K, Niidome T, Aoyagi H, Yoshino K, Yonezawa K, Moss J, Hirayama T (2003) Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. J Biol Chem 278:19183–19189

    Article  CAS  PubMed  Google Scholar 

  • Yahiro K, Wada A, Yamasaki E, Nakayama M, Nishi Y, Hisatsune J, Morinaga N, Sap J, Noda M, Moss J, Hirayama T (2004) Essential domain of receptor tyrosine phosphatase beta (RPTPbeta) for interaction with Helicobacter pylori vacuolating cytotoxin. J Biol Chem 279:51013–51021

    Article  CAS  PubMed  Google Scholar 

  • Yahiro K, Satoh M, Nakano M, Hisatsune J, Isomoto H, Sap J, Suzuki H, Nomura F, Noda M, Moss J, Hirayama T (2012) Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. J Biol Chem 287:31104–31115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J, Nakayama M, Hisatsune J, Kimura M, Moss J, Hirayama T (2006) Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax and Bak, leading to cytochrome c release and cell death, independent of vacuolation. J Biol Chem 281:11250–11259

    Article  CAS  PubMed  Google Scholar 

  • Ye D, Blanke SR (2000) Mutational analysis of the Helicobacter pylori vacuolating toxin amino terminus: identification of amino acids essential for cellular vacuolation. Infect Immun 68:4354–4357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye D, Willhite DC, Blanke SR (1999) Identification of the minimal intracellular vacuolating domain of the Helicobacter pylori vacuolating toxin. J Biol Chem 274:9277–9282

    Article  CAS  PubMed  Google Scholar 

  • Yokoyama K, Higashi H, Ishikawa S, Fujii Y, Kondo S, Kato H, Azuma T, Wada A, Hirayama T, Aburatani H, Hatakeyama M (2005) Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci U S A 102:9661–9666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng PY, Jones NL (2003) Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol 5:25–40

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine and Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA

    Timothy L. Cover

  2. Department of Pathobiology, School of Veterinary Medicine, University of Illinois, Urbana, IL, USA

    Robin L. Holland

  3. Department of Microbiology, Department of Pathobiology, Institute for Genomic Biology, School of Molecular and Cellular Biology, University of Illinois, Urbana, IL, USA

    Steven R. Blanke

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  1. Timothy L. Cover
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  2. Robin L. Holland
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  3. Steven R. Blanke
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Correspondence to Timothy L. Cover or Steven R. Blanke .

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Editors and Affiliations

  1. Division of Microbiology;Dept of Biology, Friedrich Alexander Univ;Erlangen-Nuremb, Erlangen, Bayern, Germany

    Steffen Backert

  2. Dept of Medicine-Gastroenteology, Baylor College of Medicine, Houston, USA

    Yoshio Yamaoka

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Cover, T.L., Holland, R.L., Blanke, S.R. (2016). Helicobacter pylori Vacuolating Toxin. In: Backert, S., Yamaoka, Y. (eds) Helicobacter pylori Research. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55936-8_5

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