Cellular Uptake and Mode-of-Action of Clostridium difficile Toxins

  • Panagiotis Papatheodorou
  • Holger Barth
  • Nigel Minton
  • Klaus Aktories
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1050)


Research on the human gut pathogen Clostridium difficile and its toxins has gained much attention, particularly as a consequence of the increasing threat to human health presented by emerging hypervirulent strains. Toxin A (TcdA) and B (TcdB) are the two major virulence determinants of C. difficile. Both are single-chain proteins with a similar multidomain architecture. Certain hypervirulent C. difficile strains also produce a third toxin, namely binary toxin CDT (Clostridium difficile transferase). As C. difficile toxins are the causative agents of C. difficile-associated diseases (CDAD), such as antibiotics-associated diarrhea and pseudomembranous colitis, considerable efforts have been expended to unravel their molecular mode-of-action and the cellular mechanisms responsible for their uptake. Notably, a high proportion of studies on C. difficile toxins were performed in European laboratories. In this chapter we will highlight important recent advances in C. difficile toxins research.


Clostridium difficile Bacterial disease Bacterial toxins Toxin uptake Toxin receptor 


  1. Aktories K (2011) Bacterial protein toxins that modify host regulatory GTPases. Nat Rev Microbiol 9:487–498PubMedCrossRefGoogle Scholar
  2. Aktories K, Wegner A (1989) ADP-ribosylation of actin by clostridial toxins. J Cell Biol 109:1385–1387PubMedCrossRefGoogle Scholar
  3. Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH, Habermann E (1986) Botulinum C2 toxin ADP-ribosylates actin. Nature 322:390–392PubMedCrossRefGoogle Scholar
  4. Aktories K, Schwan C, Jank T (2017) Clostridium difficile toxin biology. Annu Rev Microbiol 71:281–307PubMedCrossRefGoogle Scholar
  5. Albesa-Jove D, Bertrand T, Carpenter EP, Swain GV, Lim J, Zhang J et al (2010) Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS. J Mol Biol 396:1260–1270PubMedCrossRefGoogle Scholar
  6. Alvin JW, Lacy DB (2017) Clostridium difficile toxin glucosyltransferase domains in complex with a non-hydrolyzable UDP-glucose analogue. J Struct Biol 198:203–209PubMedCrossRefGoogle Scholar
  7. Amimoto K, Noro T, Oishi E, Shimizu M (2007) A novel toxin homologous to large clostridial cytotoxins found in culture supernatant of Clostridium perfringens type C. Microbiology 153:1198–1206PubMedCrossRefGoogle Scholar
  8. Barroso LA, Moncrief JS, Lyerly DM, Wilkins TD (1994) Mutagenesis of the Clostridium difficile toxin B gene and effect on cytotoxic activity. Microb Pathog 16:297–303PubMedCrossRefGoogle Scholar
  9. Barth H, Pfeifer G, Hofmann F, Maier E, Benz R, Aktories K (2001) Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells. J Biol Chem 276:10670–10676PubMedCrossRefGoogle Scholar
  10. Barth H, Aktories K, Popoff MR, Stiles BG (2004) Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol Mol Biol Rev 68:373–402PubMedPubMedCentralCrossRefGoogle Scholar
  11. Belyi Y, Niggeweg R, Opitz B, Vogelsgesang M, Hippenstiel S, Wilm M, Aktories K (2006) Legionella pneumophila glucosyltransferase inhibits host elongation factor 1A. Proc Natl Acad Sci U S A 103:16953–16958PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348:241–255PubMedPubMedCentralCrossRefGoogle Scholar
  13. Blonder J, Hale ML, Chan KC, Yu LR, Lucas DA, Conrads TP et al (2005) Quantitative profiling of the detergent-resistant membrane proteome of iota-b toxin induced vero cells. J Proteome Res 4:523–531PubMedCrossRefGoogle Scholar
  14. Brito GAC, Fujji J, Carneiro-Filho BA, Lima AAM, Obrig T, Guerrant RL (2002) Mechanism of Clostridium difficile toxin A – induced apoptosis in T84 cells. J Infect Dis 186:1438–1447PubMedCrossRefGoogle Scholar
  15. Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–179PubMedCrossRefGoogle Scholar
  16. Busch C, Hofmann F, Selzer J, Munro J, Jeckel D, Aktories K (1998) A common motif of eukaryotic glycosyltransferases is essential for the enzyme activity of large clostridial cytotoxins. J Biol Chem 273:19566–19572PubMedCrossRefGoogle Scholar
  17. Busch C, Hofmann F, Gerhard R, Aktories K (2000) Involvement of a conserved tryptophan residue in the UDP-glucose binding of large clostridial cytotoxin glycosyltransferases. J Biol Chem 275:13228–13234PubMedCrossRefGoogle Scholar
  18. Chandrasekaran R, Kenworthy AK, Lacy DB (2016) Clostridium difficile toxin A undergoes clathrin-independent, PACSIN2-dependent endocytosis. PLoS Pathog 12:e1006070PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93:269–309PubMedCrossRefGoogle Scholar
  20. Chumbler NM, Rutherford SA, Zhang Z, Farrow MA, Lisher JP, Farquhar E et al (2016) Crystal structure of Clostridium difficile toxin A. Nat Microbiol 1:15002PubMedPubMedCentralCrossRefGoogle Scholar
  21. Collery MM, Kuehne SA, McBride SM, Kelly ML, Monot M, Cockayne A et al (2017) What’s a SNP between friends: the influence of single nucleotide polymorphisms on virulence and phenotypes of Clostridium difficile strain 630 and derivatives. Virulence 8:767–781PubMedPubMedCentralCrossRefGoogle Scholar
  22. Considine RV, Simpson LL (1991) Cellular and molecular actions of binary toxins possessing ADP-ribosyltransferase activity. Toxicon 29:913–936PubMedCrossRefGoogle Scholar
  23. Cowardin CA, Buonomo EL, Saleh MM, Wilson MG, Burgess SL, Kuehne SA et al (2016) The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat Microbiol 1:16108PubMedPubMedCentralCrossRefGoogle Scholar
  24. Czulkies BA, Mastroianni J, Lutz L, Lang S, Schwan C, Schmidt G et al (2017) Loss of LSR affects epithelial barrier integrity and tumor xenograft growth of CaCo-2 cells. Oncotarget 8:37009–37022PubMedCrossRefGoogle Scholar
  25. D’Urzo N, Malito E, Biancucci M, Bottomley MJ, Maione D, Scarselli M, Martinelli M (2012) The structure of Clostridium difficile toxin A glucosyltransferase domain bound to Mn2+ and UDP provides insights into glucosyltransferase activity and product release. FEBS J 279:3085–3097PubMedCrossRefGoogle Scholar
  26. Dingle T, Wee S, Mulvey GL, Greco A, Kitova EN, Sun J et al (2008) Functional properties of the carboxy-terminal host cell-binding domains of the two toxins, TcdA and TcdB, expressed by Clostridium difficile. Glycobiology 18:698–706PubMedCrossRefGoogle Scholar
  27. Dominguez R, Holmes KC (2011) Actin structure and function. Annu Rev Biophys 40:169–186PubMedPubMedCentralCrossRefGoogle Scholar
  28. Donald RG, Flint M, Kalyan N, Johnson E, Witko SE, Kotash C et al (2013) A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 159:1254–1266PubMedPubMedCentralCrossRefGoogle Scholar
  29. Dove CH, Wang SZ, Price SB, Phelps CJ, Lyerly DM, Wilkins TD, Johnson JL (1990) Molecular characterization of the Clostridium difficile toxin A gene. Infect Immun 58:480–488PubMedPubMedCentralGoogle Scholar
  30. Drabek K, van HM, Stepanova T, Draegestein K, van HR, Sayas CL et al (2006) Role of CLASP2 in microtubule stabilization and the regulation of persistent motility. Curr Biol 16:2259–2264PubMedCrossRefGoogle Scholar
  31. Egerer M, Giesemann T, Jank T, Satchell KJ, Aktories K (2007) Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on a cysteine protease activity. J Biol Chem 282:25314–25321PubMedCrossRefGoogle Scholar
  32. Egerer M, Giesemann T, Herrmann C, Aktories K (2009) Autocatalytic processing of Clostridium difficile toxin B. Binding of inositol hexakisphosphate. J Biol Chem 284:3389–3395Google Scholar
  33. Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J, Popoff MR et al (2015) Cyclophilin-facilitated membrane translocation as pharmacological target to prevent intoxication of mammalian cells by binary clostridial actin ADP-ribosylated toxins. J Mol Biol 427:1224–1238PubMedCrossRefGoogle Scholar
  34. Ernst K, Schnell L, Barth H (2016) Host cell chaperones Hsp70/Hsp90 and peptidyl-prolyl cis/trans isomerases are required for the membrane translocation of bacterial ADP-ribosylating toxins. Curr Top Microbiol Immunol. May 20. [Epub ahead of print]Google Scholar
  35. Ernst K, Schmid J, Beck M, Hagele M, Hohwieler M, Hauff P et al (2017) Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells. Sci Rep 7:2724PubMedPubMedCentralCrossRefGoogle Scholar
  36. Farrow MA, Chumbler NM, Lapierre LA, Franklin JL, Rutherford SA, Goldenring JR, Lacy DB (2013) Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. Proc Natl Acad Sci U S A 110:18674–18679PubMedPubMedCentralCrossRefGoogle Scholar
  37. Fiorentini C, Thelestam M (1991) Clostridium difficile toxin A and its effects on cells. Toxicon 29:543–567PubMedCrossRefGoogle Scholar
  38. Fiorentini C, Fabbri A, Falzano L, Fattorossi A, Matarrese P, Rivabene R, Donelli G (1998) Clostridium difficile toxin B induces apoptosis in intestinal cultured cells. Infect Immun 66:2660–2665PubMedPubMedCentralGoogle Scholar
  39. Frey SM, Wilkins TD (1992) Localization of two epitopes recognized by monoclonal antibody PCG-4 on Clostridium difficile toxin A. Infect Immun 60:2488–2492PubMedPubMedCentralGoogle Scholar
  40. Frisch C, Gerhard R, Aktories K, Hofmann F, Just I (2003) The complete receptor-binding domain of Clostridium difficile toxin A is required for endocytosis. Biochem Biophys Res Commun 300:706–711PubMedCrossRefGoogle Scholar
  41. Furuse M, Oda Y, Higashi T, Iwamoto N, Masuda S (2012) Lipolysis-stimulated lipoprotein receptor: a novel membrane protein of tricellular tight junctions. Ann N Y Acad Sci 1257:54–58PubMedCrossRefGoogle Scholar
  42. Gao W, Yang J, Liu W, Wang Y, Shao F (2016) Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. Proc Natl Acad Sci U S A 113:E4857–E4866PubMedPubMedCentralCrossRefGoogle Scholar
  43. Garcia-Mata R, Burridge K (2007) Catching a GEF by its tail. Trends Cell Biol 17:36–43PubMedCrossRefGoogle Scholar
  44. Geissler B, Tungekar R, Satchell KJ (2010) Identification of a conserved membrane localization domain within numerous large bacterial protein toxins. Proc Natl Acad Sci U S A 107:5581–5586PubMedPubMedCentralCrossRefGoogle Scholar
  45. Genisyuerek S, Papatheodorou P, Guttenberg G, Schubert R, Benz R, Aktories K (2011) Structural determinants for membrane insertion, pore formation and translocation of Clostridium difficile toxin B. Mol Microbiol 79:1643–1654PubMedCrossRefGoogle Scholar
  46. Genth H, Aktories K, Just I (1999) Monoglucosylation of RhoA at threonine-37 blocks cytosol-membrane cycling. J Biol Chem 274:29050–29056PubMedCrossRefGoogle Scholar
  47. Gerding DN, Johnson S, Rupnik M, Aktories K (2014) Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5:15–27PubMedCrossRefGoogle Scholar
  48. Gerhard R (2016) Receptors and binding structures for Clostridium difficile toxins A and B. Curr Top Microbiol Immunol. [Epub ahead of print]Google Scholar
  49. Gerhard R, Nottrott S, Schoentaube J, Tatge H, Olling A, Just I (2008) Glucosylation of Rho GTPases by Clostridium difficile toxin A triggers apoptosis in intestinal epithelial cells. J Med Microbiol 57:765–770PubMedCrossRefGoogle Scholar
  50. Gerhard R, Frenzel E, Goy S, Olling A (2013) Cellular uptake of Clostridium difficile TcdA and truncated TcdA lacking the receptor binding domain. J Med Microbiol 62:1414–1422PubMedCrossRefGoogle Scholar
  51. Geyer M, Wilde C, Selzer J, Aktories K, Kalbitzer HR (2003) Glucosylation of Ras by Clostridium sordellii lethal toxin: consequences for the effector loop conformations observed by NMR spectroscopy. Biochemistry 42:11951–11959PubMedCrossRefGoogle Scholar
  52. Gibert M, Monier MN, Ruez R, Hale ML, Stiles BG, Benmerah A et al (2011) Endocytosis and toxicity of clostridial binary toxins depend on a clathrin-independent pathway regulated by Rho-GDI. Cell Microbiol 13:154–170PubMedCrossRefGoogle Scholar
  53. Giesemann T, Jank T, Gerhard R, Maier E, Just I, Benz R, Aktories K (2006) Cholesterol-dependent pore formation of Clostridium difficile toxin A. J Biol Chem 281:10808–10815PubMedCrossRefGoogle Scholar
  54. Greco A, Ho JG, Lin SJ, Palcic MM, Rupnik M, Ng KK (2006) Carbohydrate recognition by Clostridium difficile toxin A. Nat Struct Mol Biol 13:460–461PubMedCrossRefGoogle Scholar
  55. Guttenberg G, Hornei S, Jank T, Schwan C, Lu W, Einsle O et al (2012) Molecular characteristics of Clostridium perfringens TpeL toxin and consequences of mono-O-GlcNAcylation of Ras in living cells. J Biol Chem 287:24929–24940PubMedPubMedCentralCrossRefGoogle Scholar
  56. Halabi-Cabezon I, Huelsenbeck J, May M, Ladwein M, Rottner K, Just I, Genth H (2008) Prevention of the cytopathic effect induced by Clostridium difficile toxin B by active Rac1. FEBS Lett 582:3751–3756PubMedCrossRefGoogle Scholar
  57. Hale ML, Marvaud JC, Popoff MR, Stiles BG (2004) Detergent-resistant membrane microdomains facilitate Ib oligomer formation and biological activity of Clostridium perfringens iota-toxin. Infect Immun 72:2186–2193PubMedPubMedCentralCrossRefGoogle Scholar
  58. Han S, Craig JA, Putnam CD, Carozzi NB, Tainer JA (1999) Evolution and mechanism from structures of an ADP-ribosylating toxin and NAD complex. Nat Struct Biol 6:932–936PubMedCrossRefGoogle Scholar
  59. Hecht G, Pothoulakis C, LaMont JT, Madara JL (1988) Clostridium difficile toxin A pertubs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 82:1516–1524PubMedPubMedCentralCrossRefGoogle Scholar
  60. Hecht G, Koutsouris A, Pothoulakis C, LaMont JT, Madara JL (1992) Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102:416–423PubMedCrossRefGoogle Scholar
  61. Heine K, Pust S, Enzenmuller S, Barth H (2008) ADP-ribosylation of actin by the Clostridium botulinum C2 toxin in mammalian cells results in delayed caspase-dependent apoptotic cell death. Infect Immun 76:4600–4608PubMedPubMedCentralCrossRefGoogle Scholar
  62. 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 290:14031–14044PubMedPubMedCentralCrossRefGoogle Scholar
  63. Hirase T, Kawashima S, Wong EY, Ueyama T, Rikitake Y, Tsukita S et al (2001) Regulation of tight junction permeability and occludin phosphorylation by Rhoa-p160ROCK-dependent and -independent mechanisms. J Biol Chem 276:10423–10431PubMedCrossRefGoogle Scholar
  64. Ho JG, Greco A, Rupnik M, Ng KK (2005) Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. Proc Natl Acad Sci U S A 102:18373–18378PubMedPubMedCentralCrossRefGoogle Scholar
  65. Hofmann F, Busch C, Prepens U, Just I, Aktories K (1997) Localization of the glucosyltransferase activity of Clostridium difficile toxin B to the N-terminal part of the holotoxin. J Biol Chem 272:11074–11078PubMedCrossRefGoogle Scholar
  66. Hofmann F, Busch C, Aktories K (1998) Chimeric clostridial cytotoxins: identification of the N-terminal region involved in protein substrate recognition. Infect Immun 66:1076–1081PubMedPubMedCentralGoogle Scholar
  67. Holmes KC, Popp D, Gebhard W, Kabsch W (1990) Atomic model of the actin filament. Nature 347:44–49PubMedCrossRefGoogle Scholar
  68. Ishida Y, Maegawa T, Kondo T, Kimura A, Iwakura Y, Nakamura S, Mukaida N (2004) Essential involvement of IFN-gamma in Clostridium difficile toxin A-induced enteritis. J Immunol 172:3018–3025PubMedCrossRefGoogle Scholar
  69. Jafari NV, Kuehne SA, Bryant CE, Elawad M, Wren BW, Minton NP et al (2013) Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS One 8:e69846PubMedPubMedCentralCrossRefGoogle Scholar
  70. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269PubMedCrossRefGoogle Scholar
  71. Jank T, Aktories K (2008) Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol 16:222–229PubMedCrossRefGoogle Scholar
  72. Jank T, Reinert DJ, Giesemann T, Schulz GE, Aktories K (2005) Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J Biol Chem 280:37833–37838PubMedCrossRefGoogle Scholar
  73. Jank T, Giesemann T, Aktories K (2007) Clostridium difficile glucosyltransferase toxin B – essential amino acids for substrate-binding. J Biol Chem 282:35222–35231PubMedCrossRefGoogle Scholar
  74. Jank T, Bogdanovic X, Wirth C, Haaf E, Spoerner M, Bohmer KE et al (2013) A bacterial toxin catalyzing tyrosine glycosylation of Rho and deamidation of Gq and Gi proteins. Nat Struct Mol Biol 20:1273–1280PubMedCrossRefGoogle Scholar
  75. Jank T, Belyi Y, Aktories K (2015a) Bacterial glycosyltransferase toxins. Cell Microbiol 17:1752–1765PubMedCrossRefGoogle Scholar
  76. Jank T, Eckerle S, Steinemann M, Trillhaase C, Schimpl M, Wiese S et al (2015b) Tyrosine glycosylation of Rho by Yersinia toxin impairs blastomere cell behaviour in zebrafish embryos. Nat Commun 6:7807PubMedPubMedCentralCrossRefGoogle Scholar
  77. Jorgensen I, Miao EA (2015) Pyroptotic cell death defends against intracellular pathogens. Immunol Rev 265:130–142PubMedPubMedCentralCrossRefGoogle Scholar
  78. Just I, Gerhard R (2004) Large clostridial cytotoxins. Rev Physiol Biochem Pharmacol 152:23–47PubMedCrossRefGoogle Scholar
  79. Just I, Selzer J, Wilm M, Von Eichel-Streiber C, Mann M, Aktories K (1995a) Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500–503PubMedCrossRefGoogle Scholar
  80. Just I, Wilm M, Selzer J, Rex G, Von Eichel-Streiber C, Mann M, Aktories K (1995b) The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J Biol Chem 270:13932–13936PubMedCrossRefGoogle Scholar
  81. Just I, Selzer J, Hofmann F, Green GA, Aktories K (1996) Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation. J Biol Chem 271:10149–10153PubMedCrossRefGoogle Scholar
  82. Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M, Fischer G et al (2011) Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by cyclophilin A and Hsp90. Infect Immun 79:3913–3921PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kim J, Pai H, Seo MR, Kang JO (2012) Clinical and microbiologic characteristics of tcdA-negative variant Clostridium difficile infections. BMC Infect Dis 12:109PubMedPubMedCentralCrossRefGoogle Scholar
  84. Kodama A, Karakesisoglou I, Wong E, Vaezi A, Fuchs E (2003) ACF7: an essential integrator of microtubule dynamics. Cell 115:343–354PubMedCrossRefGoogle Scholar
  85. Krivan HC, Clark GF, Smith DF, Wilkins TD (1986) Cell surface binding site for Clostridium difficile enterotoxin: evidence for a glycoconjugate containing the sequence Gal alpha 1-3Gal beta 1-4GlcNAc. Infect Immun 53:573–581PubMedPubMedCentralGoogle Scholar
  86. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP (2010) The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711–713PubMedPubMedCentralCrossRefGoogle Scholar
  87. 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 209:83–86PubMedCrossRefGoogle Scholar
  88. Kushnaryov VM, Sedmark JJ (1989) Effect of Clostridium difficile enterotoxin A on ultrastructure of chinese hamster ovary cells. Infect Immun 57(12):3914–3921PubMedPubMedCentralGoogle Scholar
  89. La France ME, Farrow MA, Chandrasekaran R, Sheng JS, Rubin DH, Lacy DB (2015) Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. Proc Natl Acad Sci U S A 112:7073–7078CrossRefGoogle Scholar
  90. Lamaze C, Dujeancourt A, Baba T, Lo CG, Benmerah A, Dautry-Varsat A (2001) Interleukin 2 receptors and detergent-resistant membrane domains define a clathrin-independent endocytic pathway. Mol Cell 7:661–671PubMedCrossRefGoogle Scholar
  91. Lambert GS, Baldwin MR (2016) Evidence for dual receptor-binding sites in Clostridium difficile toxin A. FEBS Lett 590:4550–4563PubMedCrossRefGoogle Scholar
  92. Lemichez E, Aktories K (2013) Hijacking of Rho GTPases during bacterial infection. Exp Cell Res 319:2329–2336PubMedCrossRefGoogle Scholar
  93. Li S, Zhang L, Yao Q, Li L, Dong N, Rong J et al (2013) Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 501:242–246PubMedCrossRefGoogle Scholar
  94. Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, LaMont JT, Kelly CP (1997) IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am J Phys 273:G1333–G1340Google Scholar
  95. Lu A, Wu H (2015) Structural mechanisms of inflammasome assembly. FEBS J 282:435–444PubMedCrossRefGoogle Scholar
  96. Lyerly DM, Krivan HC, Wilkins TD (1988) Clostridium difficile: its disease and toxins. Clin Microbiol Rev 1:1–18PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lyerly DM, Barroso LA, Wilkins TD, Depitre C, Corthier G (1992) Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile. Infect Immun 60:4633–4639PubMedPubMedCentralGoogle Scholar
  98. Lyras D, O’Connor JR, Howarth PM, Sambol SP, Carter GP, Phumoonna T et al (2009) Toxin B is essential for virulence of Clostridium difficile. Nature 458:1176–1179PubMedPubMedCentralCrossRefGoogle Scholar
  99. Mahida YR, Makh S, Hyde S, Gray T, Borriello SP (1996) Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut 38:337–347PubMedPubMedCentralCrossRefGoogle Scholar
  100. Manse JS, Baldwin MR (2015) Binding and entry of Clostridium difficile toxin B is mediated by multiple domains. FEBS Lett 589:3945–3951PubMedCrossRefGoogle Scholar
  101. Margarit SM, Davidson W, Frego L, Stebbins CE (2006) A steric antagonism of actin polymerization by a salmonella virulence protein. Structure 14:1219–1229PubMedCrossRefGoogle Scholar
  102. Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, Akashi M et al (2011) LSR defines cell corners for tricellular tight junction formation in epithelial cells. J Cell Sci 124:548–555PubMedCrossRefGoogle Scholar
  103. Mesli S, Javorschi S, Berard AM, Landry M, Priddle H, Kivlichan D et al (2004) Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSR−/− embryos at 12.5 to 14.5 days of gestation. Eur J Biochem 271:3103–3114PubMedCrossRefGoogle Scholar
  104. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A et al (2010) Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11:1136–1142PubMedPubMedCentralCrossRefGoogle Scholar
  105. Monot M, Eckert C, Lemire A, Hamiot A, Dubois T, Tessier C et al (2015) Clostridium difficile: new insights into the evolution of the pathogenicity locus. Sci Rep 5:15023PubMedPubMedCentralCrossRefGoogle Scholar
  106. Mostowy S, Cossart P (2012) Septins: the fourth component of the cytoskeleton. Nat Rev Mol Cell Biol 13:183–194PubMedCrossRefGoogle Scholar
  107. Nagahama M, Yamaguchi A, Hagiyama T, Ohkubo N, Kobayashi K, Sakurai J (2004) Binding and internalization of Clostridium perfringens iota-toxin in lipid rafts. Infect Immun 72:3267–3275PubMedPubMedCentralCrossRefGoogle Scholar
  108. Nagahama M, Ohkubo A, Oda M, Kobayashi K, Amimoto K, Miyamoto K, Sakurai J (2011) Clostridium perfringens TpeL glycosylates the Rac and Ras subfamily proteins. Infect Immun 79:905–910PubMedCrossRefGoogle Scholar
  109. Ng J, Hirota SA, Gross O, Li Y, Ulke-Lemee A, Potentier MS et al (2010) Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139:542–552CrossRefGoogle Scholar
  110. Nobes C, Hall A (1994) Regulation and function of the Rho subfamily of small GTPases. Curr Opin Genet Dev 4:77–81PubMedCrossRefGoogle Scholar
  111. Nolke T, Schwan C, Lehmann F, Ostevold K, Pertz O, Aktories K (2016) Septins guide microtubule protrusions induced by actin-depolymerizing toxins like Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A 113:7870–7875PubMedPubMedCentralCrossRefGoogle Scholar
  112. Nusrat A, Giry M, Turner JR, Colgan SP, Parkos CA, Carnes D et al (1995) Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. Proc Natl Acad Sci U S A 92:10629–10633PubMedPubMedCentralCrossRefGoogle Scholar
  113. 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 69:1329–1336PubMedPubMedCentralCrossRefGoogle Scholar
  114. Olling A, Goy S, Hoffmann F, Tatge H, Just I, Gerhard R (2011) The repetitive oligopeptide sequences modulate cytopathic potency but are not crucial for cellular uptake of Clostridium difficile toxin A. PLoS One 6:e17623PubMedPubMedCentralCrossRefGoogle Scholar
  115. Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, Beaumont M et al (2014) Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J Biol Chem 289:18008–18021PubMedPubMedCentralCrossRefGoogle Scholar
  116. Ottlinger ME, Lin S (1988) Clostridium difficile toxin B induces reorganization of actin, vinculin, and talin in cultures cells. Exp Cell Res 174:215–229PubMedCrossRefGoogle Scholar
  117. Papatheodorou P, Aktories K (2016) Receptor-binding and uptake of binary actin-ADP-ribosylating toxins. Curr Top Microbiol Immunol. Nov 6. [Epub ahead of print]Google Scholar
  118. Papatheodorou P, Zamboglou C, Genisyuerek S, Guttenberg G, Aktories K (2010) Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLoS One 5:e10673PubMedPubMedCentralCrossRefGoogle Scholar
  119. 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 108:16422–16427PubMedPubMedCentralCrossRefGoogle Scholar
  120. Papatheodorou P, Wilczek C, Nolke T, Guttenberg G, Hornuss D, Schwan C, Aktories K (2012) Identification of the cellular receptor of Clostridium spiroforme toxin. Infect Immun 80:1418–1423PubMedPubMedCentralCrossRefGoogle Scholar
  121. Papatheodorou P, Hornuss D, Nolke T, Hemmasi S, Castonguay J, Picchianti M, Aktories K (2013) Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. MBio 4:e00244–e00213PubMedPubMedCentralCrossRefGoogle Scholar
  122. Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17:914–921PubMedPubMedCentralCrossRefGoogle Scholar
  123. Perelle S, Gibert M, Bourlioux P, Corthier G, Popoff MR (1997) Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect Immun 65:1402–1407PubMedPubMedCentralGoogle Scholar
  124. Perieteanu AA, Visschedyk DD, Merrill AR, Dawson JF (2010) ADP-ribosylation of cross-linked actin generates barbed-end polymerization-deficient F-actin oligomers. Biochemistry 49:8944–8954PubMedCrossRefGoogle Scholar
  125. Petosa C, Collier RJ, Klimpel KR, Leppla SH, Liddingtom RC (1997) Crystal structure of the anthrax toxin protective antigen. Nature 385:833–838PubMedCrossRefGoogle Scholar
  126. Pfeifer G, Schirmer J, Leemhuis J, Busch C, Meyer DK, Aktories K, Barth H (2003) Cellular uptake of Clostridium difficile toxin B: translocation of the N-terminal catalytic domain into the cytosol of eukaryotic cells. J Biol Chem 278:44535–44541PubMedCrossRefGoogle Scholar
  127. Popoff MR, Boquet P (1988) Clostridium spiroforme toxin is a binary toxin which ADP- ribosylates cellular actin. Biochem Biophys Res Commun 152:1361–1368PubMedCrossRefGoogle Scholar
  128. Pruitt RN, Chagot B, Cover M, Chazin WJ, Spiller B, Lacy DB (2009) Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J Biol Chem 284:21934–21940PubMedPubMedCentralCrossRefGoogle Scholar
  129. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB (2010) Structural organization of the functional domains of Clostridium difficile toxins A and B. Proc Natl Acad Sci U S A 107:13467–13472PubMedPubMedCentralCrossRefGoogle Scholar
  130. Pruitt RN, Chumbler NM, Rutherford SA, Farrow MA, Friedman DB, Spiller B, Lacy DB (2012) Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. J Biol Chem 287:8013–8020PubMedPubMedCentralCrossRefGoogle Scholar
  131. Puri AW, Lupardus PJ, Deu E, Albrow VE, Garcia KC, Bogyo M, Shen A (2010) Rational design of inhibitors and activity-based probes targeting Clostridium difficile virulence factor TcdB. Chem Biol 17:1201–1211PubMedPubMedCentralCrossRefGoogle Scholar
  132. Qa’Dan M, Spyres LM, Ballard JD (2000) pH-induced conformational changes in Clostridium difficile toxin B. Infect Immun 68:2470–2474PubMedPubMedCentralCrossRefGoogle Scholar
  133. Qa’Dan M, Spyres LM, Ballard JD (2001) pH-enhanced cytopathic effects of Clostridium sordellii lethal toxin. Infect Immun 69:5487–5493PubMedPubMedCentralCrossRefGoogle Scholar
  134. Qa’Dan M, Christensen KA, Zhang L, Roberts TM, Collier RJ (2005) Membrane insertion by anthrax protective antigen in cultured cells. Mol Cell Biol 25:5492–5498PubMedPubMedCentralCrossRefGoogle Scholar
  135. Qiu B, Pothoulakis C, Castagliuolo I, Nikulasson S, La Mont JT (1999) Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats. Am J Phys 276:G485–G490Google Scholar
  136. Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O, Schrattenholz A et al (2007) Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446:415–419PubMedCrossRefGoogle Scholar
  137. Reinert DJ, Jank T, Aktories K, Schulz GE (2005) Structural basis for the function of Clostridium difficile toxin B. J Mol Biol 351:973–981PubMedCrossRefGoogle Scholar
  138. Roeder M, Nestorovich EM, Karginov VA, Schwan C, Aktories K, Barth H (2014) Tailored cyclodextrin pore blocker protects mammalian cells from Clostridium difficile binary toxin CDT. Toxins (Basel) 6:2097–2114CrossRefGoogle Scholar
  139. Roth BM, Godoy-Ruiz R, Varney KM, Rustandi RR, Weber DJ (2016a) 1H, 13C, and 15N resonance assignments of an enzymatically active domain from the catalytic component (CDTa, residues 216-420) of a binary toxin from Clostridium difficile. Biomol NMR Assign 10:213–217PubMedPubMedCentralCrossRefGoogle Scholar
  140. Roth BM, Varney KM, Rustandi RR, Weber DJ (2016b) (1)H(N), (13)C, and (15)N resonance assignments of the CDTb-interacting domain (CDTaBID) from the Clostridium difficile binary toxin catalytic component (CDTa, residues 1–221). Biomol NMR Assign 10:335–339PubMedPubMedCentralCrossRefGoogle Scholar
  141. Rupnik M, Janezic S (2016) An update on Clostridium difficile toxinotyping. J Clin Microbiol 54:13–18CrossRefPubMedGoogle Scholar
  142. Rupnik M, Avesani V, Janc M, Von Eichel-Streiber C, Delmée M (1998) A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates. J Clin Microbiol 36:2240–2247PubMedPubMedCentralGoogle Scholar
  143. Rupnik M, Pabst S, Rupnik M, Von Eichel-Streiber C, Urlaub H, Soling HD (2005) Characterization of the cleavage site and function of resulting cleavage fragments after limited proteolysis of Clostridium difficile toxin B (TcdB) by host cells. Microbiology 151:199–208PubMedCrossRefGoogle Scholar
  144. Russo HM, Rathkey J, Boyd-Tressler A, Katsnelson MA, Abbott DW, Dubyak GR (2016) Active caspase-1 induces plasma membrane pores that precede pyroptotic lysis and are blocked by lanthanides. J Immunol 197:1353–1367PubMedPubMedCentralCrossRefGoogle Scholar
  145. Sauerborn M, Leukel P, Von Eichel-Streiber C (1997) The C-terminal ligand-binding domain of Clostridium difficile toxin A (TcdA) abrogates TcdA-specific binding to cells and prevents mouse lethality. FEMS Microbiol Lett 155:45–54PubMedCrossRefGoogle Scholar
  146. Schering B, Bärmann M, Chhatwal GS, Geipel U, Aktories K (1988) ADP-ribosylation of skeletal muscle and non- muscle actin by Clostridium perfringens iota toxin. Eur J Biochem 171:225–229PubMedCrossRefGoogle Scholar
  147. Schleberger C, Hochmann H, Barth H, Aktories K, Schulz GE (2006) Structure and action of the binary C2 toxin from Clostridium botulinum. J Mol Biol 364:705–715PubMedCrossRefGoogle Scholar
  148. Schorch B, Song S, van Diemen FR, Bock HH, May P, Herz J et al (2014) LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. Proc Natl Acad Sci U S A 111:6431–6436PubMedPubMedCentralCrossRefGoogle Scholar
  149. Schwan C, Stecher B, Tzivelekidis T, Van HM, Rohde M, Hardt WD et al (2009) Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 5:e1000626PubMedPubMedCentralCrossRefGoogle Scholar
  150. Schwan C, Kruppke AS, Nolke T, Schumacher L, Koch-Nolte F, Kudryashev M et al (2014) Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. Proc Natl Acad Sci U S A 111:2313–2318PubMedPubMedCentralCrossRefGoogle Scholar
  151. Sehr P, Joseph G, Genth H, Just I, Pick E, Aktories K (1998) Glucosylation and ADP-ribosylation of Rho proteins – effects on nucleotide binding, GTPase activity, and effector-coupling. Biochemistry 37:5296–5304PubMedCrossRefGoogle Scholar
  152. Selzer J, Hofmann F, Rex G, Wilm M, Mann M, Just I, Aktories K (1996) Clostridium novyi alpha-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J Biol Chem 271:25173–25177Google Scholar
  153. Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE, Garcia KC, Bogyo M (2011) Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat Struct Mol Biol 18:364–371PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sohet F, Lin C, Munji RN, Lee SY, Ruderisch N, Soung A et al (2015) LSR/angulin-1 is a tricellular tight junction protein involved in blood-brain barrier formation. J Cell Biol 208:703–711PubMedPubMedCentralCrossRefGoogle Scholar
  155. Steiner TS, Flores CA, Pizarro TT, Guerrant RL (1997) Fecal lactoferrin, interleukin-1beta, and interleukin-8 are elevated in patients with severe Clostridium difficile colitis. Clin Diagn Lab Immunol 4:719–722PubMedPubMedCentralGoogle Scholar
  156. Stiles BG, Hale ML, Marvaud J-C, Popoff M (2000) Clostridium perfringens iota toxin: binding studies and characterization of cell surface receptor by fluorescence-activated cytometry. Infect Immun 68:3475–3484PubMedPubMedCentralCrossRefGoogle Scholar
  157. Tao L, Zhang J, Meraner P, Tovaglieri A, Wu X, Gerhard R et al (2016) Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538:350–355PubMedPubMedCentralCrossRefGoogle Scholar
  158. Tcherkezian J, Lamarche-Vane N (2007) Current knowledge of the large RhoGAP family of proteins. Biol Cell 99:67–86PubMedCrossRefGoogle Scholar
  159. Tsuge H, Nagahama M, Oda M, Iwamoto S, Utsunomiya H, Marquez VE et al (2008) Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens iota-toxin. Proc Natl Acad Sci U S A 105:7399–7404PubMedPubMedCentralCrossRefGoogle Scholar
  160. Tsurumura T, Tsumori Y, Qiu H, Oda M, Sakurai J, Nagahama M, Tsuge H (2013) Arginine ADP-ribosylation mechanism based on structural snapshots of iota-toxin and actin complex. Proc Natl Acad Sci U S A 110:4267–4272PubMedCrossRefGoogle Scholar
  161. Tucker KD, Wilkins TD (1991) Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y. Infect Immun 59:73–78PubMedPubMedCentralGoogle Scholar
  162. Vandekerckhove J, Schering B, Bärmann M, Aktories K (1987) Clostridium perfringens iota toxin ADP-ribosylates skeletal muscle actin in Arg-177. FEBS Lett 225:48–52PubMedCrossRefGoogle Scholar
  163. Vandekerckhove J, Schering B, Bärmann M, Aktories K (1988) Botulinum C2 toxin ADP-ribosylates cytoplasmic b/g-actin in arginine 177. J Biol Chem 263:696–700PubMedGoogle Scholar
  164. Vetter IR, Hofmann F, Wohlgemuth S, Herrmann C, Just I (2000) Structural consequences of mono-glucosylation of Ha-Ras by Clostridium sordellii lethal toxin. J Mol Biol 301:1091–1095PubMedCrossRefGoogle Scholar
  165. Von Eichel-Streiber C, Sauerborn M (1990) Clostridium difficile toxin A carries a C-terminal repetitive structure homologous to the carbohydrate binding region of streptococcal glycosyltransferases. Gene 96:107–113PubMedCrossRefGoogle Scholar
  166. Von Eichel-Streiber C, Laufenberg-Feldmann R, Sartingen S, Schulze J, Sauerborn M (1992a) Comparative sequence analysis of the Clostridium difficile toxins A and B. Mol Gen Genet 233:260–268CrossRefGoogle Scholar
  167. Von Eichel-Streiber C, Sauerborn M, Kuramitsu HK (1992b) Evidence for a modular structure of the homologous repetitive C-terminal carbohydrate-binding sites of Clostridium difficile toxins and Streptococcus mutans glucosyltransferases. J Bacteriol 174:6707–6710CrossRefGoogle Scholar
  168. Voth DE, Ballard JD (2005) Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18:247–263PubMedPubMedCentralCrossRefGoogle Scholar
  169. Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S et al (2000) p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 105:1147–1156PubMedPubMedCentralCrossRefGoogle Scholar
  170. Wegner A, Aktories K (1988) ADP-ribosylated actin caps the barbed ends of actin filaments. J Biol Chem 263:13739–13742PubMedGoogle Scholar
  171. Weigt C, Just I, Wegner A, Aktories K (1989) Nonmuscle actin ADP-ribosylated by botulinum C2 toxin caps actin filaments. FEBS Lett 246:181–184PubMedCrossRefGoogle Scholar
  172. Wiegers W, Just I, Müller H, Hellwig A, Traub P, Aktories K (1991) Alteration of the cytoskeleton of mammalian cells cultured in vitro by Clostridium botulinum C2 toxin and C3 ADP-ribosyltransferase. Eur J Cell Biol 54:237–245PubMedGoogle Scholar
  173. Wigelsworth DJ, Ruthel G, Schnell L, Herrlich P, Blonder J, Veenstra TD et al (2012) CD44 promotes intoxication by the clostridial iota-family toxins. PLoS One 7:e51356PubMedPubMedCentralCrossRefGoogle Scholar
  174. Wille M, Just I, Wegner A, Aktories K (1992) ADP-ribosylation of the gelsolin-actin complex by clostridial toxins. J Biol Chem 267:50–55PubMedGoogle Scholar
  175. Wohlan K, Goy S, Olling A, Srivaratharajan S, Tatge H, Genth H, Gerhard R (2014) Pyknotic cell death induced by Clostridium difficile TcdB: chromatin condensation and nuclear blister are induced independently of the glucosyltransferase activity. Cell Microbiol 16:1678–1692PubMedCrossRefGoogle Scholar
  176. Wren BW (1991) A family of clostridial and streptococcal ligand-binding proteins with conserved C-terminal repeat sequences. Mol Microbiol 5:797–803PubMedCrossRefGoogle Scholar
  177. Xu H, Yang J, Gao W, Li L, Li P, Zhang L et al (2014) Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513:237–241PubMedCrossRefGoogle Scholar
  178. Yen FT, Mann CJ, Guermani LM, Hannouche NF, Hubert N, Hornick CA et al (1994) Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry 33:1172–1180PubMedCrossRefGoogle Scholar
  179. Yen FT, Masson M, Clossais-Besnard N, Andre P, Grosset JM, Bougueleret L et al (1999) Molecular cloning of a lipolysis-stimulated remnant receptor expressed in the liver. J Biol Chem 274:13390–13398PubMedCrossRefGoogle Scholar
  180. Young JA, Collier RJ (2007) Anthrax toxin: receptor-binding, internalization, pore formation, and translocation. Annu Rev Biochem 76:243–265PubMedCrossRefGoogle Scholar
  181. Yuan PF, Zhang HM, Cai CZ, Zhu SY, Zhou YX, Yang XZ et al (2015) Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. Cell Res 25:157–168PubMedCrossRefGoogle Scholar
  182. Zeiser J, Gerhard R, Just I, Pich A (2013) Substrate specificity of clostridial glucosylating toxins and their function on colonocytes analyzed by proteomics techniques. J Proteome Res 12:1604–1618PubMedCrossRefGoogle Scholar
  183. Zhang Z, Park M, Tam J, Auger A, Beilhartz GL, Lacy DB, Melnyk RA (2014) Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. Proc Natl Acad Sci U S A 111:3721–3726CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Panagiotis Papatheodorou
    • 1
    • 2
    • 3
  • Holger Barth
    • 2
  • Nigel Minton
    • 4
  • Klaus Aktories
    • 1
  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyAlbert Ludwig University of FreiburgFreiburg im BreisgauGermany
  2. 2.Institute of Pharmacology and ToxicologyUniversity of Ulm Medical CenterUlmGermany
  3. 3.Faculty of Natural SciencesUniversity of UlmUlmGermany
  4. 4.BBSRC/EPSRC Synthetic Biology Research CentreUniversity of NottinghamNottinghamUK

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