Targeting and alteration of tight junctions by bacteria and their virulence factors such as Clostridium perfringens enterotoxin

  • Miriam Eichner
  • Jonas Protze
  • Anna Piontek
  • Gerd Krause
  • Jörg PiontekEmail author
Invited Review


The integrity of tight junctions, which regulate paracellular permeability, is challenged by many bacterial pathogens. This is caused by inflammatory responses triggered by pathogens and direct interaction of bacteria or their toxins with host epithelial cells. In some cases, tight junction proteins represent receptors for cell surface proteins or toxins of the pathogen, such as Clostridium perfringens enterotoxin (CPE). CPE causes diarrhea and cramps—the symptoms of a common foodborne illness, caused by C. perfringens type A. It uses a subgroup of the claudin family of tight junction proteins as receptors and forms pores in the membrane of intestinal epithelial cells. Ca2+ influx through these pores finally triggers cell damage. In this review, we summarize tight junction targeting and alteration by a multitude of different microorganisms such as C. perfringens, Escherichia coli, Helicobacter pylori, Salmonella typhimurium, Shigella flexneri, Vibrio cholerae, Yersinia enterocolitica, protozoan parasites, and their proteins. A focus is drawn towards CPE, the interaction with its receptors, cellular, and pathophysiological consequences for the intestinal epithelium. In addition, we portend to the use of CPE-based claudin modulators for drug delivery as well as diagnosis and therapy of cancer.


Clostridium perfringens enterotoxin Bacterial receptors Intestinal barrier Claudin targeting Pore-forming toxin 



The authors gratefully acknowledge support by Sonnenfeld-Stiftung, Berlin; Wilhelm Sander-Stiftung, Munich; and Deutsche Forschungsgemeinschaft PI837/4-1 and KR1273/8-1.


  1. 1.
    Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S (2003) Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300:1430–1434. doi: 10.1126/science.1081919 PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Autheman D, Wyder M, Popoff M, D’Herde K, Christen S, Posthaus H (2013) Clostridium perfringens beta-toxin induces necrostatin-inhibitable, calpain-dependent necrosis in primary porcine endothelial cells. PLoS One 8:e64644. doi: 10.1371/journal.pone.0064644 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Awad MM, Bryant AE, Stevens DL, Rood JI (1995) Virulence studies on chromosomal alpha-toxin and theta-toxin mutants constructed by allelic exchange provide genetic evidence for the essential role of alpha-toxin in Clostridium perfringens-mediated gas gangrene. Mol Microbiol 15:191–202. doi: 10.1111/j.1365-2958.1995.tb02234.x PubMedCrossRefGoogle Scholar
  4. 4.
    Backert S, Clyne M, Tegtmeyer N (2011) Molecular mechanisms of gastric epithelial cell adhesion and injection of CagA by Helicobacter pylori. Cell Commun Signal 9:28. doi: 10.1186/1478-811X-9-28 PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ben-David U, Nudel N, Benvenisty N (2013) Immunologic and chemical targeting of the tight-junction protein claudin-6 eliminates tumorigenic human pluripotent stem cells. Nat Commun 4:1992. doi: 10.1038/ncomms2992 PubMedCrossRefGoogle Scholar
  6. 6.
    Bertelsen LS, Paesold G, Marcus SL, Finlay BB, Eckmann L, Barrett KE (2004) Modulation of chloride secretory responses and barrier function of intestinal epithelial cells by the Salmonella effector protein SigD. Am J Physiol Cell Physiol 287:C939–C948. doi: 10.1152/ajpcell.00413.2003 PubMedCrossRefGoogle Scholar
  7. 7.
    Bos J, Smithee L, McClane B, Distefano RF, Uzal F, Songer JG, Mallonee S, Crutcher JM (2005) Fatal necrotizing colitis following a foodborne outbreak of enterotoxigenic Clostridium perfringens type A infection. Clin Infect Dis 40:E78–E83. doi: 10.1086/429829 PubMedCrossRefGoogle Scholar
  8. 8.
    Boyle EC, Brown NF, Finlay BB (2006) Salmonella enterica serovar typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function. Cell Microbiol 8:1946–1957. doi: 10.1111/j.1462-5822.2006.00762.x PubMedCrossRefGoogle Scholar
  9. 9.
    Briggs DC, Naylor CE, Smedley JG III, Lukoyanova N, Robertson S, Moss DS, McClane BA, Basak AK (2011) Structure of the food-poisoning Clostridium perfringens enterotoxin reveals similarity to the aerolysin-like pore-forming toxins. J Mol Biol 413(1):138–149. doi: 10.1016/j.jmb.2011.07.066 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bücker R, Krug SM, Rosenthal R, Günzel D, Fromm A, Zeitz M, Chakraborty T, Fromm M, Epple HJ, Schulzke JD (2011) Aerolysin from Aeromonas hydrophila perturbs tight junction integrity and cell lesion repair in intestinal epithelial HT-29/B6 cells. J Infect Dis 204:1283–1292. doi: 10.1093/infdis/jir504 PubMedCrossRefGoogle Scholar
  11. 11.
    Bücker R, Schulz E, Günzel D, Bojarski C, Lee IF, John LJ, Wiegand S, Janssen T, Wieler LH, Dobrindt U, Beutin L, Ewers C, Fromm M, Siegmund B, Troeger H, Schulzke JD (2014) Alpha-haemolysin of Escherichia coli in IBD: a potentiator of inflammatory activity in the colon. Gut 63:1893–1901. doi: 10.1136/gutjnl-2013-306099 PubMedCrossRefGoogle Scholar
  12. 12.
    Caserta JA, Robertson SL, Saputo J, Shrestha A, McClane BA, Uzal FA (2011) Development and application of a mouse intestinal loop model to study the in vivo action of Clostridium perfringens enterotoxin. Infect Immun 79:3020–3027. doi: 10.1128/IAI.01342-10 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Chakrabarti G, McClane BA (2005) The importance of calcium influx, calpain and calmodulin for the activation of CaCo-2 cell death pathways by Clostridium perfringens enterotoxin. Cell Microbiol 7:129–146. doi: 10.1111/j.1462-5822.2004.00442.x PubMedCrossRefGoogle Scholar
  14. 14.
    Chakrabarti G, Zhou X, McClane BA (2003) Death pathways activated in CaCo-2 cells by Clostridium perfringens enterotoxin. Infect Immun 71:4260–4270. doi: 10.1128/IAI.71.8.4260-4270.2003 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Chen J, Ma M, Uzal FA, McClane BA (2014) Host cell-induced signaling causes Clostridium perfringens to upregulate production of toxins important for intestinal infections. Gut Microbes 5:96–107. doi: 10.4161/gmic.26419 PubMedCrossRefGoogle Scholar
  16. 16.
    Chen J, Theoret JR, Shrestha A, Smedley JG 3rd, McClane BA (2012) Cysteine-scanning mutagenesis supports the importance of Clostridium perfringens enterotoxin amino acids 80 to 106 for membrane insertion and pore formation. Infect Immun 80:4078–4088. doi: 10.1128/IAI.00069-12 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Cocco E, Casagrande F, Bellone S, Richter CE, Bellone M, Todeschini P, Holmberg JC, Fu HH, Montagna MK, Mor G, Schwartz PE, Arin-Silasi D, Azoudi M, Rutherford TJ, Abu-Khalaf M, Pecorelli S, Santin AD (2010) Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer. BMC Cancer 10:349. doi: 10.1186/1471-2407-10-349 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Dean P, Kenny B (2004) Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein. Mol Microbiol 54:665–675. doi: 10.1111/j.1365-2958.2004.04308.x PubMedCrossRefGoogle Scholar
  19. 19.
    Di Pierro M, Lu R, Uzzau S, Wang W, Margaretten K, Pazzani C, Maimone F, Fasano A (2001) Zonula occludens toxin structure-function analysis. Identification of the fragment biologically active on tight junctions and of the zonulin receptor binding domain. J Biol Chem 276:19160–19165. doi: 10.1074/jbc.M009674200 PubMedCrossRefGoogle Scholar
  20. 20.
    Dorca-Arevalo J, Pauillac S, Diaz-Hidalgo L, Martin-Satue M, Popoff MR, Blasi J (2014) Correlation between in vitro cytotoxicity and in vivo lethal activity in mice of epsilon toxin mutants from Clostridium perfringens. PLoS One 9:e102417. doi: 10.1371/journal.pone.0102417 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Ebihara C, Kondoh M, Harada M, Fujii M, Mizuguchi H, Tsunoda S, Horiguchi Y, Yagi K, Watanabe Y (2007) Role of Tyr306 in the C-terminal fragment of Clostridium perfringens enterotoxin for modulation of tight junction. Biochem Pharmacol 73:824–830. doi: 10.1016/j.bcp.2006.11.013 PubMedCrossRefGoogle Scholar
  22. 22.
    Fasano A, Uzzau S, Fiore C, Margaretten K (1997) The enterotoxic effect of zonula occludens toxin on rabbit small intestine involves the paracellular pathway. Gastroenterology 112:839–846. doi: 10.1053/gast.1997.v112.pm9041245 PubMedCrossRefGoogle Scholar
  23. 23.
    Fernandez-Miyakawa ME, Pistone Creydt V, Uzal FA, McClane BA, Ibarra C (2005) Clostridium perfringens enterotoxin damages the human intestine in vitro. Infect Immun 73:8407–8410. doi: 10.1128/IAI.73.12.8407-8410.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Fisher DJ, Fernandez-Miyakawa ME, Sayeed S, Poon R, Adams V, Rood JI, Uzal FA, McClane BA (2006) Dissecting the contributions of Clostridium perfringens type C toxins to lethality in the mouse intravenous injection model. Infect Immun 74:5200–5210. doi: 10.1128/IAI.00534-06 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Fujita K, Katahira J, Horiguchi Y, Sonoda N, Furuse M, Tsukita S (2000) Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Lett 476:258–261. doi: 10.1016/S0014-5793(00)01744-0 PubMedCrossRefGoogle Scholar
  26. 26.
    Fukumatsu M, Ogawa M, Arakawa S, Suzuki M, Nakayama K, Shimizu S, Kim M, Mimuro H, Sasakawa C (2012) Shigella targets epithelial tricellular junctions and uses a noncanonical clathrin-dependent endocytic pathway to spread between cells. Cell Host Microbe 11:325–336. doi: 10.1016/j.chom.2012.03.001 PubMedCrossRefGoogle Scholar
  27. 27.
    Garcia JP, Li J, Shrestha A, Freedman JC, Beingesser J, McClane BA, Uzal FA (2014) Clostridium perfringens type A enterotoxin damages the rabbit colon. Infect Immun 82:2211–2218. doi: 10.1128/IAI.01659-14 PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Gerlach RG, Hensel M (2007) Protein secretion systems and adhesins: the molecular armory of gram-negative pathogens. Int J Med Microbiol 297:401–415. doi: 10.1016/j.ijmm.2007.03.017 PubMedCrossRefGoogle Scholar
  29. 29.
    Goldstein J, Morris WE, Loidl CF, Tironi-Farinati C, McClane BA, Uzal FA, Fernandez-Miyakawa ME (2009) Clostridium perfringens epsilon toxin increases the small intestinal permeability in mice and rats. PLoS One 4:e7065. doi: 10.1371/journal.pone.0007065 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gui L, Subramony C, Fratkin J, Hughson MD (2002) Fatal enteritis necroticans (pigbel) in a diabetic adult. Mod Pathol 15:66–70. doi: 10.1038/modpathol.3880491 PubMedCrossRefGoogle Scholar
  31. 31.
    Guttman JA, Samji FN, Li Y, Vogl AW, Finlay BB (2006) Evidence that tight junctions are disrupted due to intimate bacterial contact and not inflammation during attaching and effacing pathogen infection in vivo. Infect Immun 74:6075–6084. doi: 10.1128/IAI.00721-06 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hanajima-Ozawa M, Matsuzawa T, Fukui A, Kamitani S, Ohnishi H, Abe A, Horiguchi Y, Miyake M (2007) Enteropathogenic Escherichia coli, Shigella flexneri, and Listeria monocytogenes recruit a junctional protein, zonula occludens-1, to actin tails and pedestals. Infect Immun 75:565–573. doi: 10.1128/IAI.01479-06 PubMedCrossRefGoogle Scholar
  33. 33.
    Hanna PC, Mietzner TA, Schoolnik GK, McClane BA (1991) Localization of the receptor-binding region of Clostridium perfringens enterotoxin utilizing cloned toxin fragments and synthetic peptides. The 30 C-terminal amino acids define a functional binding region. J Biol Chem 266:11037–11043PubMedGoogle Scholar
  34. 34.
    Harada M, Kondoh M, Ebihara C, Takahashi A, Komiya E, Fujii M, Mizuguchi H, Tsunoda S, Horiguchi Y, Yagi K, Watanabe Y (2007) Role of tyrosine residues in modulation of claudin-4 by the C-terminal fragment of Clostridium perfringens enterotoxin. Biochem Pharmacol 73:206–214. doi: 10.1016/j.bcp.2006.10.002 PubMedCrossRefGoogle Scholar
  35. 35.
    Hardy SP, Denmead M, Parekh N, Granum PE (1999) Cationic currents induced by Clostridium perfringens type A enterotoxin in human intestinal CaCo-2 cells. J Med Microbiol 48:235–243. doi: 10.1099/00222615-48-3-235 PubMedCrossRefGoogle Scholar
  36. 36.
    Hatheway CL (1990) Toxigenic clostridia. Clin Microbiol Rev 3:66–98PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Hemmasi S, Czulkies BA, Schorch B, Veit A, Aktories K, Papatheodorou P (2015) Interaction of the Clostridium difficile binary toxin CDT and its host cell receptor, lipolysis-stimulated lipoprotein receptor (LSR). J Biol Chem 290:14031–14044. doi: 10.1074/jbc.M115.650523 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Hering NA, Fromm A, Kikhney J, Lee IF, Moter A, Schulzke JD, Bücker R (2016) Yersinia enterocolitica affects intestinal barrier function in the colon. J Infect Dis 213:1157–1162. doi: 10.1093/infdis/jiv571 PubMedCrossRefGoogle Scholar
  39. 39.
    Hering NA, Richter JF, Krug SM, Günzel D, Fromm A, Bohn E, Rosenthal R, Bücker R, Fromm M, Troeger H, Schulzke JD (2011) Yersinia enterocolitica induces epithelial barrier dysfunction through regional tight junction changes in colonic HT-29/B6 cell monolayers. Lab Investig 91:310–324. doi: 10.1038/labinvest.2010.180 PubMedCrossRefGoogle Scholar
  40. 40.
    Hodges K, Gill R (2010) Infectious diarrhea: cellular and molecular mechanisms. Gut Microbes 1:4–21. doi: 10.4161/gmic.1.1.11036 PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Horiguchi Y, Uemura T, Kozaki S, Sakaguchi G (1986) Effects of Ca2+ and other cations on the action of Clostridium perfringens enterotoxin. Biochim Biophys Acta 889:65–71. doi: 10.1016/0167-4889(86)90009-1 PubMedCrossRefGoogle Scholar
  42. 42.
    Iacovache I, De Carlo S, Cirauqui N, Dal Peraro M, van der Goot FG, Zuber B (2016) Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process. Nat Commun 7:12062. doi: 10.1038/ncomms12062 PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S (2005) Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171:939–945. doi: 10.1083/jcb.200510043 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    John LJ, Fromm M, Schulzke JD (2011) Epithelial barriers in intestinal inflammation. Antioxid Redox Signal 15:1255–1270. doi: 10.1089/ars.2011.3892 PubMedCrossRefGoogle Scholar
  45. 45.
    Katahira J, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N (1997) Molecular cloning and functional characterization of the receptor for Clostridium perfringens enterotoxin. J Cell Biol 136:1239–1247PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Katahira J, Sugiyama H, Inoue N, Horiguchi Y, Matsuda M, Sugimoto N (1997) Clostridium perfringens enterotoxin utilizes two structurally related membrane proteins as functional receptors in vivo. J Biol Chem 272:26652–26658. doi: 10.1074/jbc.272.42.26652 PubMedCrossRefGoogle Scholar
  47. 47.
    Keyburn AL, Boyce JD, Vaz P, Bannam TL, Ford ME, Parker D, Di Rubbo A, Rood JI, Moore RJ (2008) NetB, a new toxin that is associated with avian necrotic enteritis caused by Clostridium perfringens. PLoS Pathog 4:e26. doi: 10.1371/journal.ppat.0040026 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kimura J, Abe H, Kamitani S, Toshima H, Fukui A, Miyake M, Kamata Y, Sugita-Konishi Y, Yamamoto S, Horiguchi Y (2010) Clostridium perfringens enterotoxin interacts with claudins via electrostatic attraction. J BiolChem 285:401–408. doi: 10.1074/jbc.M109.051417 Google Scholar
  49. 49.
    Kitadokoro K, Nishimura K, Kamitani S, Fukui-Miyazaki A, Toshima H, Abe H, Kamata Y, Sugita-Konishi Y, Yamamoto S, Karatani H, Horiguchi Y (2011) Crystal structure of Clostridium perfringens enterotoxin displays features of beta-pore-forming toxins. J Biol Chem 286:19549–19555. doi: 10.1074/jbc.M111.228478 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kobelt D, Aumann J, Schmidt M, Wittig B, Fichtner I, Behrens D, Lemm M, Freundt G, Schlag PM, Walther W (2014) Preclinical study on combined chemo- and nonviral gene therapy for sensitization of melanoma using a human TNF-alpha expressing MIDGE DNA vector. Mol Oncol 8:609–619. doi: 10.1016/j.molonc.2013.12.019 PubMedCrossRefGoogle Scholar
  51. 51.
    Kohler H, Sakaguchi T, Hurley BP, Kase BA, Reinecker HC, McCormick BA (2007) Salmonella enterica serovar typhimurium regulates intercellular junction proteins and facilitates transepithelial neutrophil and bacterial passage. Am J Physiol Gastrointest Liver Physiol 293:G178–G187. doi: 10.1152/ajpgi.00535.2006 PubMedCrossRefGoogle Scholar
  52. 52.
    Kokai-Kun JF, McClane BA (1997) Deletion analysis of the Clostridium perfringens enterotoxin. Infect Immun 65:1014–1022PubMedPubMedCentralGoogle Scholar
  53. 53.
    Kominsky SL, Tyler B, Sosnowski J, Brady K, Doucet M, Nell D, Smedley JG III, McClane B, Brem H, Sukumar S (2007) Clostridium perfringens enterotoxin as a novel-targeted therapeutic for brain metastasis. Cancer Res 67:7977–7982. doi: 10.1158/0008-5472.CAN-07-1314 PubMedCrossRefGoogle Scholar
  54. 54.
    Kominsky SL, Vali M, Korz D, Gabig TG, Weitzman SA, Argani P, Sukumar S (2004) Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. Am J Pathol 164:1627–1633. doi: 10.1016/S0002-9440(10)63721-2 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Kondoh M, Takahashi A, Fujii M, Yagi K, Watanabe Y (2006) A novel strategy for a drug delivery system using a claudin modulator. Biol Pharm Bull 29:1783–1789. doi: 10.1248/bpb.29.1783 PubMedCrossRefGoogle Scholar
  56. 56.
    Krause G, Protze J, Piontek J (2015) Assembly and function of claudins: structure-function relationships based on homology models and crystal structures. Semin Cell Dev Biol 42:3–12. doi: 10.1016/j.semcdb.2015.04.010 PubMedCrossRefGoogle Scholar
  57. 57.
    Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE (2008) Structure and function of claudins. Biochim Biophys Acta 1778:631–645. doi: 10.1016/j.bbamem.2007.10.018 PubMedCrossRefGoogle Scholar
  58. 58.
    Krueger S, Hundertmark T, Kuester D, Kalinski T, Peitz U, Roessner A (2007) Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract 203:433–444. doi: 10.1016/j.prp.2007.04.003 PubMedCrossRefGoogle Scholar
  59. 59.
    Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, Huber O, Schulzke JD, Fromm M (2009) Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell 20:3713–3724. doi: 10.1091/mbc.E09-01-0080 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Kuehne SA, Collery MM, Kelly ML, Cartman ST, Cockayne A, Minton NP (2014) Importance of toxin a, toxin B, and CDT in virulence of an epidemic Clostridium difficile strain. J Infect Dis 209:83–86. doi: 10.1093/infdis/jit426 PubMedCrossRefGoogle Scholar
  61. 61.
    Loffler A, Labbe R (1986) Characterization of a parasporal inclusion body from sporulating, enterotoxin-positive Clostridium perfringens type A. J Bacteriol 165:542–548PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Los FC, Randis TM, Aroian RV, Ratner AJ (2013) Role of pore-forming toxins in bacterial infectious diseases. Microbiol Molecular Biol Rev 77:173–207. doi: 10.1128/MMBR.00052-12 CrossRefGoogle Scholar
  63. 63.
    Ma T, Verkman AS (1999) Aquaporin water channels in gastrointestinal physiology. J Physiol 517(Pt 2):317–326. doi: 10.1111/j.1469-7793.1999.0317t.x PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Mahendran V, Liu F, Riordan SM, Grimm MC, Tanaka MM, Zhang L (2016) Examination of the effects of Campylobacter concisus zonula occludens toxin on intestinal epithelial cells and macrophages. Gut Pathog 8:18. doi: 10.1186/s13099-016-0101-9 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Mancheno JM, Tateno H, Sher D, Goldstein IJ (2010) Laetiporus sulphureus lectin and aerolysin protein family. Adv Exp Med Biol 677:67–80PubMedCrossRefGoogle Scholar
  66. 66.
    Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, Akashi M, Nishi E, Furuse M (2011) LSR defines cell corners for tricellular tight junction formation in epithelial cells. J Cell Sci 124:548–555. doi: 10.1242/jcs.072058 PubMedCrossRefGoogle Scholar
  67. 67.
    Matsuda M, Ozutsumi K, Sugimoto N, Iwahashi H (1986) Primary action of Clostridium perfringens type A enterotoxin on HeLa and Vero cells in the absence of extracellular calcium: rapid and characteristic changes in membrane permeability. Biochem Biophys Res Commun 141(2):704–710PubMedCrossRefGoogle Scholar
  68. 68.
    Matsuda M, Sugimoto N (1979) Calcium-independent and dependent steps in action of Clostridium perfringens enterotoxin on Hela and Vero cells. Biochem and Biophys Res Commun 91:629–636. doi: 10.1016/0006-291X(79)91568-7 CrossRefGoogle Scholar
  69. 69.
    Matsuda T, Okada Y, Inagi E, Tanabe Y, Shimizu Y, Nagashima K, Sakurai J, Nagahama M, Tanaka S (2007) Enteritis necroticans ‘pigbel’ in a Japanese diabetic adult. Pathol Int 57:622–626. doi: 10.1111/j.1440-1827.2007.02149.x PubMedCrossRefGoogle Scholar
  70. 70.
    Matsuzawa T, Kuwae A, Abe A (2005) Enteropathogenic Escherichia coli type III effectors EspG and EspG2 alter epithelial paracellular permeability. Infect Immun 73:6283–6289. doi: 10.1128/IAI.73.10.6283-6289.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    McDonel JL (1980) Clostridium perfringens toxins (type A, B, C, D, E). Pharmacol Ther 10:617–655. doi: 10.1016/0163-7258(80)90031-5 PubMedCrossRefGoogle Scholar
  72. 72.
    McDonel JL, Demers GW (1982) In vivo effects of enterotoxin from Clostridium perfringens type A in the rabbit colon: binding vs. biologic activity. J Infect Dis 145:490–494. doi: 10.1093/infdis/145.4.490 PubMedCrossRefGoogle Scholar
  73. 73.
    McDonel JL (1986) Toxins of Clostridium perfringens types a, B, C, D and E. In: Dorner F, Drews H (eds) Pharmacology of bacterial toxins. Pergamon Press, Oxford, pp. 477–517Google Scholar
  74. 74.
    Michl P, Buchholz M, Rolke M, Kunsch S, Lohr M, McClane B, Tsukita S, Leder G, Adler G, Gress TM (2001) Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology 121:678–684. doi: 10.1053/gast.2001.27124 PubMedCrossRefGoogle Scholar
  75. 75.
    Mogk S, Meiwes A, Shtopel S, Schraermeyer U, Lazarus M, Kubata B, Wolburg H, Duszenko M (2014) Cyclical appearance of African trypanosomes in the cerebrospinal fluid: new insights in how trypanosomes enter the CNS. PLoS One 9:e91372. doi: 10.1371/journal.pone.0091372 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Monturiol-Gross L, Flores-Diaz M, Campos-Rodriguez D, Mora R, Rodriguez-Vega M, Marks DL, Alape-Giron A (2014) Internalization of Clostridium perfringens alpha-toxin leads to ERK activation and is involved on its cytotoxic effect. Cell Microbiol 16:535–547. doi: 10.1111/cmi.12237 PubMedCrossRefGoogle Scholar
  77. 77.
    Morin PJ (2007) Claudin proteins in ovarian cancer. Dis Markers 23:453–457. doi: 10.1155/2007/674058 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Morita K, Furuse M, Fujimoto K, Tsukita S (1999) Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A 96:511–516PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Mosley M, Knight J, Neesse A, Michl P, Iezzi M, Kersemans V, Cornelissen B (2015) Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer. J Nucl Med 56:745–751. doi: 10.2967/jnumed.114.152496 PubMedCrossRefGoogle Scholar
  80. 80.
    Muza-Moons MM, Schneeberger EE, Hecht GA (2004) Enteropathogenic Escherichia coli infection leads to appearance of aberrant tight junctions strands in the lateral membrane of intestinal epithelial cells. Cell Microbiol 6:783–793. doi: 10.1111/j.1462-5822.2004.00404.x PubMedCrossRefGoogle Scholar
  81. 81.
    Nagahama M, Hayashi S, Morimitsu S, Sakurai J (2003) Biological activities and pore formation of Clostridium perfringens beta toxin in HL 60 cells. J Biol Chem 278:36934–36941. doi: 10.1074/jbc.M306562200 PubMedCrossRefGoogle Scholar
  82. 82.
    Nagahama M, Sakurai J (1991) Distribution of labeled Clostridium perfringens epsilon toxin in mice. Toxicon 29:211–217PubMedCrossRefGoogle Scholar
  83. 83.
    Nava P, Vidal JE (2016) The CpAL system regulates changes of the trans-epithelial resistance of human enterocytes during Clostridium perfringens type C infection. Anaerobe 39:143–149. doi: 10.1016/j.anaerobe.2016.04.002 PubMedCrossRefGoogle Scholar
  84. 84.
    Neesse A, Hahnenkamp A, Griesmann H, Buchholz M, Hahn SA, Maghnouj A, Fendrich V, Ring J, Sipos B, Tuveson DA, Bremer C, Gress TM, Michl P (2013) Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 62:1034–1043. doi: 10.1136/gutjnl-2012-302577 PubMedCrossRefGoogle Scholar
  85. 85.
    Nusrat A, von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA (2001) Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect Immun 69:1329–1336. doi: 10.1128/IAI.69.3.1329-1336.2001 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Oda M, Terao Y, Sakurai J, Nagahama M (2015) Membrane-binding mechanism of Clostridium perfringens alpha-toxin. Toxins (Basel) 7:5268–5275. doi: 10.3390/toxins7124880 CrossRefGoogle Scholar
  87. 87.
    Olsen SJ, MacKinnon LC, Goulding JS, Bean NH, Slutsker L (2000) Surveillance for foodborne-disease outbreaks—United States, 1993–1997. MMWR CDC Surveill Summ 49:1–62PubMedGoogle Scholar
  88. 88.
    Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G, Brummelkamp TR, Aktories K (2011) Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A 108:16422–16427. doi: 10.1073/pnas.1109772108 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Peralta-Ramirez J, Hernandez JM, Manning-Cela R, Luna-Munoz J, Garcia-Tovar C, Nougayrede JP, Oswald E, Navarro-Garcia F (2008) EspF interacts with nucleation-promoting factors to recruit junctional proteins into pedestals for pedestal maturation and disruption of paracellular permeability. Infect Immun 76:3854–3868. doi: 10.1128/IAI.00072-08 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Petit L, Gibert M, Gourch A, Bens M, Vandewalle A, Popoff MR (2003) Clostridium perfringens epsilon toxin rapidly decreases membrane barrier permeability of polarized MDCK cells. Cell Microbiol 5:155–164. doi: 10.1046/j.1462-5822.2003.00262.x PubMedCrossRefGoogle Scholar
  91. 91.
    Petrillo TM, Beck-Sague CM, Songer JG, Abramowsky C, Fortenberry JD, Meacham L, Dean AG, Lee H, Bueschel DM, Nesheim SR (2000) Enteritis necroticans (pigbel) in a diabetic child. N Engl J Med 342:1250–1253. doi: 10.1056/NEJM200004273421704 PubMedCrossRefGoogle Scholar
  92. 92.
    Protze J, Eichner M, Piontek A, Dinter S, Rossa J, Blecharz KG, Vajkoczy P, Piontek J, Krause G (2015) Directed structural modification of Clostridium perfringens enterotoxin to enhance binding to claudin-5. Cell Mol Life Sci 72:1417–1432. doi: 10.1007/s00018-014-1761-6 PubMedCrossRefGoogle Scholar
  93. 93.
    Rajabian T, Gavicherla B, Heisig M, Muller-Altrock S, Goebel W, Gray-Owen SD, Ireton K (2009) The bacterial virulence factor InlC perturbs apical cell junctions and promotes cell-to-cell spread of Listeria. Nat Cell Biol 11:1212–1218. doi: 10.1038/ncb1964 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Richard JF, Mainguy G, Gibert M, Marvaud JC, Stiles BG, Popoff MR (2002) Transcytosis of iota-toxin across polarized CaCo-2 cells. Mol Microbiol 43:907–917. doi: 10.1046/j.1365-2958.2002.02806.x PubMedCrossRefGoogle Scholar
  95. 95.
    Robertson SL, Smedley JG III, Singh U, Chakrabarti G, Van Itallie CM, Anderson JM, McClane BA (2007) Compositional and stoichiometric analysis of Clostridium perfringens enterotoxin complexes in Caco-2 cells and claudin 4 fibroblast transfectants. Cell Microbiol 9:2734–2755. doi: 10.1111/j.1462-5822.2007.00994.x PubMedCrossRefGoogle Scholar
  96. 96.
    Robertson SL, Smedley JG, McClane BA (2010) Identification of a claudin-4 residue important for mediating the host cell binding and action of Clostridium perfringens enterotoxin. Inf ect Immun 78:505–517. doi: 10.1128/IAI.00778-09 CrossRefGoogle Scholar
  97. 97.
    Romanov V, Whyard TC, Waltzer WC, Gabig TG (2014) A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. Cancer Lett 351:260–264. doi: 10.1016/j.canlet.2014.06.009 PubMedCrossRefGoogle Scholar
  98. 98.
    Saadat I, Higashi H, Obuse C, Umeda M, Murata-Kamiya N, Saito Y, Lu H, Ohnishi N, Azuma T, Suzuki A, Ohno S, Hatakeyama M (2007) Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 447:330–333. doi: 10.1038/nature05765 PubMedCrossRefGoogle Scholar
  99. 99.
    Saeki R, Kondoh M, Kakutani H, Matsuhisa K, Takahashi A, Suzuki H, Kakamu Y, Watari A, Yagi K (2010) A claudin-targeting molecule as an inhibitor of tumor metastasis. J Pharmacol Exp Ther 334:576–582. doi: 10.1124/jpet.110.168070 PubMedCrossRefGoogle Scholar
  100. 100.
    Saitoh Y, Suzuki H, Tani K, Nishikawa K, Irie K, Ogura Y, Tamura A, Tsukita S, Fujiyoshi Y (2015) Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science 347:775–778. doi: 10.1126/science.1261833 PubMedCrossRefGoogle Scholar
  101. 101.
    Sakaguchi T, Kohler H, Gu X, McCormick BA, Reinecker HC (2002) Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells. Cell Microbiol 4:367–381. doi: 10.1046/j.1462-5822.2002.00197.x PubMedCrossRefGoogle Scholar
  102. 102.
    Sakurai J, Nagahama M, Oda M, Tsuge H, Kobayashi K (2009) Clostridium perfringens iota-toxin: structure and function. Toxins (Basel) 1:208–228. doi: 10.3390/toxins1020208 CrossRefGoogle Scholar
  103. 103.
    Santin AD, Bellone S, Siegel ER, McKenney JK, Thomas M, Roman JJ, Burnett A, Tognon G, Bandiera E, Pecorelli S (2007) Overexpression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in uterine carcinosarcomas. Clin Cancer Res 13:3339–3346PubMedCrossRefGoogle Scholar
  104. 104.
    Santin AD, Cane S, Bellone S, Palmieri M, Siegel ER, Thomas M, Roman JJ, Burnett A, Cannon MJ, Pecorelli S (2005) Treatment of chemotherapy-resistant human ovarian cancer xenografts in C.B-17/SCID mice by intraperitoneal administration of Clostridium perfringens enterotoxin. Cancer Res 65:4334–4342. doi: 10.1158/0008-5472.CAN-04-3472 PubMedCrossRefGoogle Scholar
  105. 105.
    Sarker MR, Carman RJ, McClane BA (1999) Inactivation of the gene (cpe) encoding Clostridium perfringens enterotoxin eliminates the ability of two cpe-positive C. perfringens type A human gastrointestinal disease isolates to affect rabbit ileal loops. Mol Microbiol 33:946–958. doi: 10.1046/j.1365-2958.1999.01534.x PubMedCrossRefGoogle Scholar
  106. 106.
    Sayeed S, Fernandez-Miyakawa ME, Fisher DJ, Adams V, Poon R, Rood JI, Uzal FA, McClane BA (2005) Epsilon-toxin is required for most Clostridium perfringens type D vegetative culture supernatants to cause lethality in the mouse intravenous injection model. Infect Immun 73:7413–7421. doi: 10.1128/IAI.73.11.7413-7421.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sayeed S, Uzal FA, Fisher DJ, Saputo J, Vidal JE, Chen Y, Gupta P, Rood JI, McClane BA (2008) Beta toxin is essential for the intestinal virulence of Clostridium perfringens type C disease isolate CN3685 in a rabbit ileal loop model. Mol Microbiol 67:15–30. doi: 10.1111/j.1365-2958.2007.06007.x PubMedCrossRefGoogle Scholar
  108. 108.
    Schmidt E, Kelly SM, van der Walle CF (2007) Tight junction modulation and biochemical characterisation of the zonula occludens toxin C-and N-termini. FEBS Lett 581:2974–2980. doi: 10.1016/j.febslet.2007.05.051 PubMedCrossRefGoogle Scholar
  109. 109.
    Schmitz H, Barmeyer C, Gitter AH, Wullstein F, Bentzel CJ, Fromm M, Riecken EO, Schulzke JD (2000) Epithelial barrier and transport function of the colon in ulcerative colitis. Ann N Y Acad Sci 915:312–326. doi: 10.1111/j.1749-6632.2000.tb05259.x PubMedCrossRefGoogle Scholar
  110. 110.
    Sherman S, Klein E, McClane BA (1994) Clostridium perfringens type A enterotoxin induces tissue damage and fluid accumulation in rabbit ileum. J Diarrhoeal Dis Res 12:200–207PubMedGoogle Scholar
  111. 111.
    Shinoda T, Shinya N, Ito K, Ohsawa N, Terada T, Hirata K, Kawano Y, Yamamoto M, Kimura-Someya T, Yokoyama S, Shirouzu M (2016) Structural basis for disruption of claudin assembly in tight junctions by an enterotoxin. Sci Rep 6:33632. doi: 10.1038/srep33632 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Shrestha A, McClane BA (2013) Human claudin-8 and -14 are receptors capable of conveying the cytotoxic effects of Clostridium perfringens enterotoxin. MBio 4(1):e00594–e00512. doi: 10.1128/mBio.00594-12 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Sidik SM, Huet D, Ganesan SM, Huynh MH, Wang T, Nasamu AS, Thiru P, Saeij JP, Carruthers VB, Niles JC, Lourido S (2016) A genome-wide CRISPR screen in toxoplasma identifies essential apicomplexan genes. Cell 166(1423–1435):e1412. doi: 10.1016/j.cell.2016.08.019 Google Scholar
  114. 114.
    Simonovic I, Rosenberg J, Koutsouris A, Hecht G (2000) Enteropathogenic Escherichia coli dephosphorylates and dissociates occludin from intestinal epithelial tight junctions. Cell Microbiol 2:305–315. doi: 10.1046/j.1462-5822.2000.00055.x PubMedCrossRefGoogle Scholar
  115. 115.
    Singh U, Mitic LL, Wieckowski EU, Anderson JM, McClane BA (2001) Comparative biochemical and immunocytochemical studies reveal differences in the effects of Clostridium perfringens enterotoxin on polarized CaCo-2 cells versus Vero cells. J Biol Chem 276:33402–33412. doi: 10.1074/jbc.M104200200 PubMedCrossRefGoogle Scholar
  116. 116.
    Singh U, Van Itallie CM, Mitic LL, Anderson JM, McClane BA (2000) CaCo-2 cells treated with Clostridium perfringens enterotoxin form multiple large complex species, one of which contains the tight junction protein occludin. J Biol Chem 275:18407–18417. doi: 10.1074/jbc.M001530200 PubMedCrossRefGoogle Scholar
  117. 117.
    Smedley JG, Saputo J, Parker JC, Fernandez-Miyakawa ME, Robertson SL, McClane BA, Uzal FA (2008) Noncytotoxic Clostridium perfringens enterotoxin (CPE) variants localize CPE intestinal binding and demonstrate a relationship between CPE-induced cytotoxicity and enterotoxicity. Infect Immun 76:3793–3800. doi: 10.1128/IAI.00460-08 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Smedley JG, Uzal FA, McClane BA (2007) Identification of a prepore large-complex stage in the mechanism of action of Clostridium perfringens enterotoxin. Infect Immun 75:2381–2390. doi: 10.1128/IAI.01737-06 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Sonoda N, Furuse M, Sasaki H, Yonemura S, Katahira J, Horiguchi Y, Tsukita S (1999) Clostridium perfringens Enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 147:195–204PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Suzuki H, Nishizawa T, Tani K, Yamazaki Y, Tamura A, Ishitani R, Dohmae N, Tsukita S, Nureki O, Fujiyoshi Y (2014) Crystal structure of a claudin provides insight into the architecture of tight junctions. Science 344:304–307. doi: 10.1126/science.1248571 PubMedCrossRefGoogle Scholar
  121. 121.
    Szczesny P, Iacovache I, Muszewska A, Ginalski K, van der Goot FG, Grynberg M (2011) Extending the aerolysin family: from bacteria to vertebrates. PLoS One 6:e20349. doi: 10.1371/journal.pone.0020349 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Takagishi T, Oda M, Kabura M, Kurosawa M, Tominaga K, Urano S, Ueda Y, Kobayashi K, Kobayashi T, Sakurai J, Terao Y, Nagahama M (2015) Clostridium perfringens alpha-toxin induces Gm1a clustering and Trka phosphorylation in the host cell membrane. PLoS One 10:e0120497. doi: 10.1371/journal.pone.0120497 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Takahashi A, Komiya E, Kakutani H, Yoshida T, Fujii M, Horiguchi Y, Mizuquchi H, Tsutsumi Y, Tsunoda SI, Koizumi N, Isoda K, Yagi K, Watanabe Y, Kondoh M (2008) Domain mapping of a claudin-4 modulator, the C-terminal region of C-terminal fragment of Clostridium perfringens enterotoxin, by site-directed mutagenesis. Biochem Pharmacol 75:1639–1648PubMedCrossRefGoogle Scholar
  124. 124.
    Takahashi A, Kondoh M, Suzuki H, Yagi K (2011) Claudin as a target for drug development. Curr Med Chem 18:1861–1865. doi: 10.1016/j.bcp.2007.12.016 PubMedCrossRefGoogle Scholar
  125. 125.
    Takahashi A, Saito Y, Kondoh M, Matsushita K, Krug SM, Suzuki H, Tsujino H, Li X, Aoyama H, Matsuhisa K, Uno T, Fromm M, Hamakubo T, Yagi K (2012) Creation and biochemical analysis of a broad-specific claudin binder. Biomaterials 33:3464–3474. doi: 10.1016/j.biomaterials.2012.01.017 PubMedCrossRefGoogle Scholar
  126. 126.
    Thanabalasuriar A, Kim J, Gruenheid S (2013) The inhibition of COPII trafficking is important for intestinal epithelial tight junction disruption during enteropathogenic Escherichia coli and Citrobacter rodentium infection. Microbes Infect 15:738–744. doi: 10.1016/j.micinf.2013.05.001 PubMedCrossRefGoogle Scholar
  127. 127.
    Thiagarajah JR, Donowitz M, Verkman AS (2015) Secretory diarrhoea: mechanisms and emerging therapies. Nat Rev Gastroenterol Hepatol 12:446–457. doi: 10.1038/nrgastro.2015.111 PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Thiagarajah JR, Verkman AS (2013) Chloride channel-targeted therapy for secretory diarrheas. Curr Opin Pharmacol 13:888–894. doi: 10.1016/j.coph.2013.08.005 PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Urbina P, Collado MI, Alonso A, Goni FM, Flores-Diaz M, Alape-Giron A, Ruysschaert JM, Lensink MF (2011) Unexpected wide substrate specificity of C. perfringens alpha-toxin phospholipase C. Biochim Biophys Acta 1808:2618–2627. doi: 10.1016/j.bbamem.2011.06.008 PubMedCrossRefGoogle Scholar
  130. 130.
    Uzal FA, Freedman JC, Shrestha A, Theoret JR, Garcia J, Awad MM, Adams V, Moore RJ, Rood JI, McClane BA (2014) Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease. Future Microbiol 9:361–377. doi: 10.2217/fmb.13.168 PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Uzal FA, Saputo J, Sayeed S, Vidal JE, Fisher DJ, Poon R, Adams V, Fernandez-Miyakawa ME, Rood JI, McClane BA (2009) Development and application of new mouse models to study the pathogenesis of Clostridium perfringens type C enterotoxemias. Infect Immun 77:5291–5299. doi: 10.1128/IAI.00825-09 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Uzzau S, Cappuccinelli P, Fasano A (1999) Expression of Vibrio cholerae zonula occludens toxin and analysis of its subcellular localization. Microb Pathog 27:377–385. doi: 10.1006/mpat.1999.0312 PubMedCrossRefGoogle Scholar
  133. 133.
    Van Itallie CM, Betts L, Smedley JG, McClane BA, Anderson JM (2008) Structure of the claudin-binding domain of Clostridium perfringens enterotoxin. J Biol Chem 283:268–274. doi: 10.1074/jbc.M708066200 PubMedCrossRefGoogle Scholar
  134. 134.
    Veshnyakova A, Piontek J, Protze J, Waziri N, Heise I, Krause G (2012) Mechanism of Clostridium perfringens enterotoxin interaction with claudin-3/-4 protein suggests structural modifications of the toxin to target specific claudins. J Biol Chem 287:1698–1708PubMedCrossRefGoogle Scholar
  135. 135.
    Veshnyakova A, Protze J, Rossa J, Blasig I, Krause G, Piontek J (2010) On the interaction of Clostridium perfringens enterotoxin with claudins. Toxins 2:1336–1356. doi: 10.1074/jbc.M111.312165 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Vidal JE, McClane BA, Saputo J, Parker J, Uzal FA (2008) Effects of Clostridium perfringens beta-toxin on the rabbit small intestine and colon. Infect Immun 76:4396–4404. doi: 10.1128/IAI.00547-08 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Viswanathan VK, Koutsouris A, Lukic S, Pilkinton M, Simonovic I, Simonovic M, Hecht G (2004) Comparative analysis of EspF from enteropathogenic and enterohemorrhagic Escherichia coli in alteration of epithelial barrier function. Infect Immun 72:3218–3227. doi: 10.1128/IAI.72.6.3218-3227.2004 PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Walther W, Petkov S, Kuvardina ON, Aumann J, Kobelt D, Fichtner I, Lemm M, Piontek J, Blasig IE, Stein U, Schlag PM (2012) Novel Clostridium perfringens enterotoxin suicide gene therapy for selective treatment of claudin-3- and -4-overexpressing tumors. Gene Ther 19:494–503. doi: 10.1038/gt.2011.136 PubMedCrossRefGoogle Scholar
  139. 139.
    Winkler L, Gehring C, Wenzel A, Muller SL, Piehl C, Krause G, Blasig IE, Piontek J (2009) Molecular determinants of the interaction between Clostridium perfringens enterotoxin fragments and claudin-3. J Biol Chem 284:18863–18872. doi: 10.1074/jbc.M109.008623 PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Wu Z, Nybom P, Magnusson KE (2000) Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell Microbiol 2:11–17. doi: 10.1046/j.1462-5822.2000.00025.x PubMedCrossRefGoogle Scholar
  141. 141.
    Yamahashi Y, Saito Y, Murata-Kamiya N, Hatakeyama M (2011) Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization. J Biol Chem 286:44576–44584. doi: 10.1074/jbc.M111.267021 PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Yelland TS, Naylor CE, Bagoban T, Savva CG, Moss DS, McClane BA, Blasig IE, Popoff M, Basak AK (2014) Structure of a C. perfringens enterotoxin mutant in complex with a modified claudin-2 extracellular loop 2. J Mol Biol 426:3134–3147. doi: 10.1016/j.jmb.2014.07.001 PubMedCrossRefGoogle Scholar
  143. 143.
    Yuan XQ, Lin XJ, Manorek G, Kanatani I, Cheung LH, Rosenblum MG, Howell SB (2009) Recombinant CPE fused to tumor necrosis factor targets human ovarian cancer cells expressing the claudin-3 and claudin-4 receptors. Mol Cancer Ther 8:1906–1915. doi: 10.1158/1535-7163.MCT-09-0106 PubMedCrossRefGoogle Scholar
  144. 144.
    Zhang J, Ni C, Yang Z, Piontek A, Chen H, Wang S, Fan Y, Qin Z, Piontek J (2015) Specific binding of Clostridium perfringens enterotoxin fragment to claudin-b and modulation of zebrafish epidermal barrier. Exp Dermatol 24:605–610. doi: 10.1111/exd.12728 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Miriam Eichner
    • 1
  • Jonas Protze
    • 2
  • Anna Piontek
    • 2
  • Gerd Krause
    • 2
  • Jörg Piontek
    • 1
    Email author
  1. 1.Institute of Clinical PhysiologyCharité–Universitätsmedizin BerlinBerlinGermany
  2. 2.Leibniz-Institut für Molekulare Pharmakologie (FMP)BerlinGermany

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