1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Microbiology
  4. Volume 71, 2017
  5. Article

Annual Review of Microbiology

Volume 71, 2017

Toxin Biology

Abstract

is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins: toxins A (TcdA) and B (TcdB), and transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell membrane receptors and are internalized. The N-terminal glucosyltransferase and autoprotease domains of the toxins translocate from low-pH endosomes into the cytosol. After activation by inositol hexakisphosphate (InsP6), the autoprotease cleaves and releases the glucosyltransferase domain into the cytosol, where GTP-binding proteins of the Rho/Ras family are mono--glucosylated and, thereby, inactivated. Inactivation of Rho proteins disturbs the organization of the cytoskeleton and affects multiple Rho-dependent cellular processes, including loss of epithelial barrier functions, induction of apoptosis, and inflammation. CDT, the third toxin, is a binary actin-ADP-ribosylating toxin that causes depolymerization of actin, thereby inducing formation of the microtubule-based protrusions. Recent progress in understanding of the toxins’ actions include insights into the toxin structures, their interaction with host cells, and functional consequences of their actions.

Keyword(s): actin, ADP ribosylation, CDT, Clostridium difficile infection, Clostridium difficile toxins, Clostridium difficile transferase toxin, glucosylation, microtubules, Rho proteins, toxin receptors, toxin uptake
Loading

Article metrics loading...

/content/journals/10.1146/annurev-micro-090816-093458
2017-09-08
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/micro/71/1/annurev-micro-090816-093458.html?itemId=/content/journals/10.1146/annurev-micro-090816-093458&mimeType=html&fmt=ahah

Literature Cited

  1. Aktories K. 1.  2011. Bacterial protein toxins that modify host regulatory GTPases. Nat. Rev. Microbiol. 9:487–98 [Google Scholar]
  2. Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH, Habermann E. 2.  1986. Botulinum C2 toxin ADP-ribosylates actin. Nature 322:390–92 [Google Scholar]
  3. Aktories K, Wegner A. 3.  1989. ADP-ribosylation of actin by clostridial toxins. J. Cell Biol. 109:1385–87 [Google Scholar]
  4. Amimoto K, Noro T, Oishi E, Shimizu M. 4.  2007. A novel toxin homologous to large clostridial cytotoxins found in culture supernatant of Clostridium perfringens type C. Microbiology 153:1198–206 [Google Scholar]
  5. Antonny B, Burd C, De Camilli P, Chen E, Daumke O. 5.  et al. 2016. Membrane fission by dynamin: what we know and what we need to know. EMBO J 35:2270–84 [Google Scholar]
  6. Barroso LA, Moncrief JS, Lyerly DM, Wilkins TD. 6.  1994. Mutagenesis of the Clostridium difficile toxin B gene and effect on cytotoxic activity. Microb. Pathog. 16:297–303 [Google Scholar]
  7. Barth H, Aktories K, Popoff MR, Stiles BG. 7.  2004. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol. Mol. Biol. Rev. 68:373–402 [Google Scholar]
  8. Barth H, Blöcker D, Behlke J, Bergsma-Schutter W, Brisson A. 8.  et al. 2000. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J. Biol. Chem. 275:18704–11 [Google Scholar]
  9. Barth H, Pfeifer G, Hofmann F, Maier E, Benz R, Aktories K. 9.  2001. Low pH-induced formation of ion channels by Clostridium difficile toxin B in target cells. J. Biol. Chem. 276:10670–76 [Google Scholar]
  10. Biname F. 10.  2014. Transduction of extracellular cues into cell polarity: the role of the transmembrane proteoglycan NG2. Mol. Neurobiol. 50:482–93 [Google Scholar]
  11. Bouillaut L, Dubois T, Sonenshein AL, Dupuy B. 11.  2015. Integration of metabolism and virulence in Clostridium difficile. Res. Microbiol. 166:375–83 [Google Scholar]
  12. Braun V, Hundsberger T, Leukel P, Sauerborn M, Von Eichel-Streiber C. 12.  1996. Definition of the single integration site of the pathogenicity locus in Clostridium difficile. Gene 181:29–38 [Google Scholar]
  13. Brito GAC, Fujji J, Carneiro-Filho BA, Lima AAM, Obrig T, Guerrant RL. 13.  2002. Mechanism of Clostridium difficile toxin A—induced apoptosis in T84 cells. J. Infect. Dis. 186:1438–47 [Google Scholar]
  14. Burridge K, Wennerberg K. 14.  2004. Rho and Rac take center stage. Cell 116:167–79 [Google Scholar]
  15. Busch C, Hofmann F, Gerhard R, Aktories K. 15.  2000. Involvement of a conserved tryptophan residue in the UDP-glucose binding of large clostridial cytotoxin glycosyltransferases. J. Biol. Chem. 275:13228–34 [Google Scholar]
  16. Busch C, Hofmann F, Selzer J, Munro J, Jeckel D, Aktories K. 16.  1998. A common motif of eukaryotic glycosyltransferases is essential for the enzyme activity of large clostridial cytotoxins. J. Biol. Chem. 273:19566–72 [Google Scholar]
  17. Bustelo XR, Sauzeau V, Berenjeno IM. 17.  2007. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356–70 [Google Scholar]
  18. Carter GP, Chakravorty A, Pham Nguyen TA, Mileto S, Schreiber F. 18.  et al. 2015. Defining the roles of TcdA and TcdB in localized gastrointestinal disease, systemic organ damage, and the host response during Clostridium difficile infections. mBio 6:e00551 [Google Scholar]
  19. Chandrasekaran R, Kenworthy AK, Lacy DB. 19.  2016. Clostridium difficile toxin A undergoes clathrin-independent, PACSIN2-dependent endocytosis. PLOS Pathog 12:e1006070 [Google Scholar]
  20. Chaves-Olarte E, Freer E, Parra A, Guzmán-Verri C, Moreno E, Thelestam M. 20.  2003. R-Ras glucosylation and transient RhoA activation determine the cytopathic effect produced by toxin B variants from toxin A-negative strains of Clostridium difficile. J. Biol. Chem. 278:7956–63 [Google Scholar]
  21. Chaves-Olarte E, Löw P, Freer E, Norlin T, Weidmann M. 21.  et al. 1999. A novel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins. J. Biol. Chem. 274:11046–52 [Google Scholar]
  22. Chaves-Olarte E, Weidmann M, Von Eichel-Streiber C, Thelestam M. 22.  1997. Toxins A and B from Clostridium difficile differ with respect to enzymatic potencies, cellular substrate specificities, and surface binding to cultured cells. J. Clin. Investig. 100:1734–41 [Google Scholar]
  23. Chen ML, Pothoulakis C, LaMont JT. 23.  2002. Protein kinase C signaling regulates ZO-1 translocation and increased paracellular flux of T84 colonocytes exposed to Clostridium difficile toxin A. J. Biol. Chem. 277:4247–54 [Google Scholar]
  24. Cherfils J, Zeghouf M. 24.  2013. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol. Rev. 93:269–309 [Google Scholar]
  25. Chumbler NM, Rutherford SA, Zhang Z, Farrow MA, Lisher JP. 25.  et al. 2016. Crystal structure of Clostridium difficile toxin A. Nat. Microbiol. 1:15002 [Google Scholar]
  26. Cowardin CA, Buonomo EL, Saleh MM, Wilson MG, Burgess SL. 26.  et al. 2016. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat. Microbiol. 1:16108 [Google Scholar]
  27. Ding J, Wang K, Liu W, She Y, Sun Q. 27.  et al. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111–16 [Google Scholar]
  28. Donald RG, Flint M, Kalyan N, Johnson E, Witko SE. 28.  et al. 2013. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 159:1254–66 [Google Scholar]
  29. Dove CH, Wang SZ, Price SB, Phelps CJ, Lyerly DM. 29.  et al. 1990. Molecular characterization of the Clostridium difficile toxin A gene. Infect. Immun. 58:480–88 [Google Scholar]
  30. Egerer M, Giesemann T, Herrmann C, Aktories K. 30.  2009. Autocatalytic processing of Clostridium difficile toxin B: binding of inositol hexakisphosphate. J. Biol. Chem. 284:3389–95 [Google Scholar]
  31. Egerer M, Giesemann T, Jank T, Satchell KJ, Aktories K. 31.  2007. Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on a cysteine protease activity. J. Biol. Chem. 282:25314–21 [Google Scholar]
  32. Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J. 32.  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. 427:1224–38 [Google Scholar]
  33. Farrow MA, Chumbler NM, Lapierre LA, Franklin JL, Rutherford SA. 33.  et al. 2013. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. PNAS 110:18674–79 [Google Scholar]
  34. Fiorentini C, Fabbri A, Falzano L, Fattorossi A, Matarrese P. 34.  et al. 1998. Clostridium difficile toxin B induces apoptosis in intestinal cultured cells. Infect. Immun. 66:2660–65 [Google Scholar]
  35. Fiorentini C, Falzano L, Travaglione S, Fabbri A. 35.  2003. Hijacking Rho GTPases by protein toxins and apoptosis: molecular strategies of pathogenic bacteria. Cell Death Differ 10:147–52 [Google Scholar]
  36. Fiorentini C, Thelestam M. 36.  1991. Clostridium difficile toxin A and its effects on cells. Toxicon 29:543–67 [Google Scholar]
  37. Frey SM, Wilkins TD. 37.  1992. Localization of two epitopes recognized by monoclonal antibody PCG-4 on Clostridium difficile toxin A. Infect. Immun. 60:2488–92 [Google Scholar]
  38. Fukumoto Y, Kaibuchi K, Hori Y, Fujioka H, Araki S. 38.  et al. 1990. Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 5:1321–28 [Google Scholar]
  39. Gao W, Yang J, Liu W, Wang Y, Shao F. 39.  2016. Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. PNAS 113:E4857–66 [Google Scholar]
  40. Garcia-Mata R, Burridge K. 40.  2007. Catching a GEF by its tail. Trends Cell Biol 17:36–43 [Google Scholar]
  41. Geissler B, Tungekar R, Satchell KJ. 41.  2010. Identification of a conserved membrane localization domain within numerous large bacterial protein toxins. PNAS 107:5581–86 [Google Scholar]
  42. Genisyuerek S, Papatheodorou P, Guttenberg G, Schubert R, Benz R, Aktories K. 42.  2011. Structural determinants for membrane insertion, pore formation and translocation of Clostridium difficile toxin B. Mol. Microbiol. 79:1643–54 [Google Scholar]
  43. Genth H, Aktories K, Just I. 43.  1999. Monoglucosylation of RhoA at threonine-37 blocks cytosol-membrane cycling. J. Biol. Chem. 274:29050–56 [Google Scholar]
  44. Genth H, Pauillac S, Schelle I, Bouvet P, Bouchier C. 44.  et al. 2014. Haemorrhagic toxin and lethal toxin from Clostridium sordellii strain vpi9048: molecular characterization and comparative analysis of substrate specificity of the large clostridial glucosylating toxins. Cell. Microbiol. 16:1706–21 [Google Scholar]
  45. Geny B, Grassart A, Manich M, Chicanne G, Payrastre B. 45.  et al. 2010. Rac1 inactivation by lethal toxin from Clostridium sordellii modifies focal adhesions upstream of actin depolymerization. Cell. Microbiol. 12:217–32 [Google Scholar]
  46. Gerding DN, Johnson S, Rupnik M, Aktories K. 46.  2014. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5:15–27 [Google Scholar]
  47. Gerhard R, Frenzel E, Goy S, Olling A. 47.  2013. Cellular uptake of Clostridium difficile TcdA and truncated TcdA lacking the receptor binding domain. J. Med. Microbiol 621414–22 [Google Scholar]
  48. Gerhard R, Nottrott S, Schoentaube J, Tatge H, Olling A, Just I. 48.  2008. Glucosylation of Rho GTPases by Clostridium difficile toxin A triggers apoptosis in intestinal epithelial cells. J. Med. Microbiol 57765–70 [Google Scholar]
  49. Giesemann T, Jank T, Gerhard R, Maier E, Just I. 49.  et al. 2006. Cholesterol-dependent pore formation of Clostridium difficile toxin A. J. Biol. Chem. 281:10808–15 [Google Scholar]
  50. Govind R, Dupuy B. 50.  2012. Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLOS Pathog 8:e1002727 [Google Scholar]
  51. Greco A, Ho JG, Lin SJ, Palcic MM, Rupnik M, Ng KK. 51.  2006. Carbohydrate recognition by Clostridium difficile toxin A. Nat. Struct. Mol. Biol. 13:460–1 [Google Scholar]
  52. Gülke I, Pfeifer G, Liese J, Fritz M, Hofmann F. 52.  et al. 2001. Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect. Immun. 69:6004–11 [Google Scholar]
  53. Guttenberg G, Hornei S, Jank T, Schwan C, Lu W. 53.  et al. 2012. Molecular characteristics of Clostridium perfringens TpeL toxin and consequences of mono-O-GlcNAcylation of Ras in living cells. J. Biol. Chem. 287:24929–40 [Google Scholar]
  54. Guttenberg G, Papatheodorou P, Genisyuerek S, Lu W, Jank T. 54.  et al. 2011. Inositol hexakisphosphate-dependent processing of Clostridium sordellii lethal toxin and Clostridium novyi α-toxin. J. Biol. Chem. 286:14779–86 [Google Scholar]
  55. Halabi-Cabezon I, Huelsenbeck J, May M, Ladwein M, Rottner K. 55.  et al. 2008. Prevention of the cytopathic effect induced by Clostridium difficile toxin B by active Rac1. FEBS Lett 582:3751–56 [Google Scholar]
  56. Hall A. 56.  1994. Small GTP-binding proteins and the regulation of the actin cytoskeleton. Annu. Rev. Cell Biol. 10:31–54 [Google Scholar]
  57. Hammond GA, Johnson JL. 57.  1995. The toxigenic element of Clostridium difficile strain VPI 10463. Microb. Pathog. 19:203–13 [Google Scholar]
  58. Han S, Craig JA, Putnam CD, Carozzi NB, Tainer JA. 58.  1999. Evolution and mechanism from structures of an ADP-ribosylating toxin and NAD complex. Nat. Struct. Biol. 6:932–36 [Google Scholar]
  59. Haug G, Leemhuis J, Tiemann D, Meyer DK, Aktories K, Barth H. 59.  2003. The host cell chaperone Hsp90 is essential for translocation of the binary Clostridium botulinum C2 toxin into the cytosol. J. Biol. Chem. 274:32266–74 [Google Scholar]
  60. Heasman SJ, Ridley AJ. 60.  2008. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9:690–701 [Google Scholar]
  61. Hecht G, Koutsouris A, Pothoulakis C, LaMont JT, Madara JL. 61.  1992. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102:416–23 [Google Scholar]
  62. Hecht G, Pothoulakis C, LaMont JT, Madara JL. 62.  1988. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J. Clin. Investig. 82:1516–24 [Google Scholar]
  63. Hemmasi S, Czulkies BA, Schorch B, Veit A, Aktories K, Papatheodorou P. 63.  2015. Interaction of the Clostridium difficile binary toxin CDT and its host cell receptor, lipolysis-stimulated lipoprotein receptor (LSR). J. Biol. Chem. 290:14031–44 [Google Scholar]
  64. Henriques B, Florin I, Thelestam M. 64.  1987. Cellular internalisation of Clostridium difficile toxin A. Microb. Pathogen. 2:455–63 [Google Scholar]
  65. Higashi T, Tokuda S, Kitajiri SI, Masuda S, Nakamura H. 65.  et al. 2012. Analysis of the angulin family consisting of LSR, ILDR1 and ILDR2: tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. J. Cell Sci. 126:966–77 [Google Scholar]
  66. Hippenstiel S, Schmeck B, N'Guessan PD, Seybold J, Krüll M. 66.  et al. 2002. Rho protein inactivation induced apoptosis of cultured human endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 283:L830–38 [Google Scholar]
  67. Hirase T, Kawashima S, Wong EY, Ueyama T, Rikitake Y. 67.  et al. 2001. Regulation of tight junction permeability and occludin phosphorylation by Rhoa-p160ROCK-dependent and -independent mechanisms. J. Biol. Chem. 276:10423–31 [Google Scholar]
  68. Ho JG, Greco A, Rupnik M, Ng KK. 68.  2005. Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. PNAS 102:18373–78 [Google Scholar]
  69. Ihara K, Muraguchi S, Kato M, Shimizu T, Shirakawa M. 69.  et al. 1998. Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue. J. Biol. Chem. 273:9656–66 [Google Scholar]
  70. Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. 70.  2005. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J. Cell Biol. 171:939–45 [Google Scholar]
  71. Ishida Y, Maegawa T, Kondo T, Kimura A, Iwakura Y. 71.  et al. 2004. Essential involvement of IFN-gamma in Clostridium difficile toxin A-induced enteritis. J. Immunol. 172:3018–25 [Google Scholar]
  72. Jafari NV, Kuehne SA, Bryant CE, Elawad M, Wren BW. 72.  et al. 2013. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLOS ONE 8:e69846 [Google Scholar]
  73. Jaffe AB, Hall A. 73.  2005. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21:247–69 [Google Scholar]
  74. Jank T, Aktories K. 74.  2008. Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol 16:222–29 [Google Scholar]
  75. Jank T, Giesemann T, Aktories K. 75.  2007. Clostridium difficile glucosyltransferase toxin B-essential amino acids for substrate binding. J. Biol. Chem. 282:35222–31 [Google Scholar]
  76. Jank T, Reinert DJ, Giesemann T, Schulz GE, Aktories K. 76.  2005. Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J. Biol. Chem. 280:37833–38 [Google Scholar]
  77. Johal SS, Solomon K, Dodson S, Borriello SP, Mahida YR. 77.  2004. Differential effects of varying concentrations of Clostridium difficile toxin A on epithelial barrier function and expression of cytokines. J. Infect. Dis. 189:2110–19 [Google Scholar]
  78. Jorgensen I, Miao EA. 78.  2015. Pyroptotic cell death defends against intracellular pathogens. Immunol. Rev. 265:130–42 [Google Scholar]
  79. Just I, Selzer J, Wilm M, Von Eichel-Streiber C, Mann M, Aktories K. 79.  1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500–3 [Google Scholar]
  80. Just I, Wilm M, Selzer J, Rex G, Von Eichel-Streiber C. 80.  et al. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270:13932–36 [Google Scholar]
  81. Kaiser E, Bohm N, Ernst K, Langer S, Schwan C. 81.  et al. 2012. FK506-binding protein 51 interacts with Clostridium botulinum C2 toxin and FK506 inhibits membrane translocation of the toxin in mammalian cells. Cell Microbiol 14:1193–205 [Google Scholar]
  82. Karlsson S, Burman LG, Akerlund T. 82.  1999. Suppression of toxin production in Clostridium difficile VPI 10463 by amino acids. Microbiology 145:Part 71683–93 [Google Scholar]
  83. Karlsson S, Lindberg A, Norin E, Burman LG, Akerlund T. 83.  2000. Toxins, butyric acid, and other short-chain fatty acids are coordinately expressed and down-regulated by cysteine in Clostridium difficile. Infect. Immun. 68:5881–88 [Google Scholar]
  84. Kelly CP, LaMont JT. 84.  2008. Clostridium difficile—more difficult than ever. N. Engl. J. Med. 359:1932–40 [Google Scholar]
  85. Kishida S, Yamamoto H, Kikuchi A. 85.  2004. Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Mol. Cell. Biol. 24:4487–501 [Google Scholar]
  86. Klaus A, Birchmeier W. 86.  2008. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8:387–98 [Google Scholar]
  87. Krivan HC, Clark GF, Smith DF, Wilkins TD. 87.  1986. Cell surface binding site for Clostridium difficile enterotoxin: evidence for a glycoconjugate containing the sequence Gal α1-3Galβ1-4GlcNAc. Infect. Immun. 53:573–81 [Google Scholar]
  88. Kuehne SA, Cartman ST, Heap JT, Kelly ML, Cockayne A, Minton NP. 88.  2010. The role of toxin A and toxin B in Clostridium difficile infection. Nature 467:711–13 [Google Scholar]
  89. LaFrance ME, Farrow MA, Chandrasekaran R, Sheng J, Rubin DH, Lacy DB. 89.  2015. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. PNAS 112:7073–78 [Google Scholar]
  90. Lambert GS, Baldwin MR. 90.  2016. Evidence for dual receptor-binding sites in Clostridium difficile toxin A. FEBS Lett 590:4550–63 [Google Scholar]
  91. Le SS, Loucks FA, Udo H, Richardson-Burns S, Phelps RA. 91.  et al. 2005. Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons. J. Neurochem. 94:1025–39 [Google Scholar]
  92. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK. 92.  et al. 2015. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med. 372:825–34 [Google Scholar]
  93. Leuzzi R, Spencer J, Buckley A, Brettoni C, Martinelli M. 93.  et al. 2013. Protective efficacy induced by recombinant Clostridium difficile toxin fragments. Infect. Immun. 81:2851–60 [Google Scholar]
  94. Lima AAM, Lyerly DM, Wilkins TD, Innes DJ, Guerrant RL. 94.  1988. Effects of Clostridium difficile toxins A and B in rabbit small and large intestine in vivo and on cultured cells in vitro. Infect. Immun. 56:582–88 [Google Scholar]
  95. Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC. 95.  et al. 1997. IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am. J. Physiol. 273:G1333–40 [Google Scholar]
  96. Lord MS, Whitelock JM. 96.  2013. Recombinant production of proteoglycans and their bioactive domains. FEBS J 280:2490–510 [Google Scholar]
  97. Lu A, Wu H. 97.  2015. Structural mechanisms of inflammasome assembly. FEBS J 282:435–44 [Google Scholar]
  98. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP. 98.  et al. 2009. Toxin B is essential for virulence of Clostridium difficile. Nature 458:72421176–79 [Google Scholar]
  99. Madshus IH, Stenmark H, Sandvig K, Olsnes S. 99.  1991. Entry of diphtheria toxin-protein A chimeras into cells. J. Biol. Chem. 266:17446–53 [Google Scholar]
  100. Mahida YR, Makh S, Hyde S, Gray T, Borriello SP. 100.  1996. Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut 38:337–47 [Google Scholar]
  101. Mani N, Dupuy B. 101.  2001. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. PNAS 98:5844–49 [Google Scholar]
  102. Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T. 102.  et al. 2011. LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 124:548–55 [Google Scholar]
  103. Matamouros S, England P, Dupuy B. 103.  2007. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol. Microbiol. 64:1274–88 [Google Scholar]
  104. McCormack J, Welsh NJ, Braga VM. 104.  2013. Cycling around cell-cell adhesion with Rho GTPase regulators. J. Cell. Sci. 126:379–91 [Google Scholar]
  105. Mesli S, Javorschi S, Berard AM, Landry M, Priddle H. 105.  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. 271:3103–14 [Google Scholar]
  106. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M. 106.  et al. 2010. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11:1136–42 [Google Scholar]
  107. Mitchell TJ, Ketley JM, Haslam SC, Stephen J, Burdon DW. 107.  et al. 1986. Effect of toxin A and B of Clostridium difficile on rabbit ileum and colon. Gut 27:78–85 [Google Scholar]
  108. Miyoshi J, Takai Y. 108.  2007. Nectin and nectin-like molecules: biology and pathology. Am. J. Nephrol. 27:590–604 [Google Scholar]
  109. Monot M, Eckert C, Lemire A, Hamiot A, Dubois T. 109.  et al. 2015. Clostridium difficile: new insights into the evolution of the pathogenicity locus. Sci. Rep. 5:15023 [Google Scholar]
  110. Moorman JP, Luu D, Wickham J, Bobak DA, Hahn CS. 110.  1999. A balance of signaling by Rho family small GTPases RhoA, Rac1 and Cdc42 coordinates cytoskeletal morphology but not cell survival. Oncogene 18:47–57 [Google Scholar]
  111. Murase T, Eugenio L, Schorr M, Hussack G, Tanha J. 111.  et al. 2014. Structural basis for antibody recognition in the receptor-binding domains of toxins A and B from Clostridium difficile. J. Biol. Chem. 289:2331–43 [Google Scholar]
  112. Na X, Kim H, Moyer MP, Pothoulakis C, LaMont JT. 112.  2008. gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A. Infect. Immun. 76:2862–71 [Google Scholar]
  113. Nagahama M, Ohkubo A, Oda M, Kobayashi K, Amimoto K. 113.  et al. 2011. Clostridium perfringens TpeL glycosylates the Rac and Ras subfamily proteins. Infect. Immun. 79:2905–10 [Google Scholar]
  114. Nagahama M, Yamaguchi A, Hagiyama T, Ohkubo N, Kobayashi K, Sakurai J. 114.  2004. Binding and internalization of Clostridium perfringens iota-toxin in lipid rafts. Infect. Immun. 72:3267–75 [Google Scholar]
  115. Ng J, Hirota SA, Gross O, Li Y, Ulke-Lemee A. 115.  et al. 2010. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139:542–52.e3 [Google Scholar]
  116. Nolke T, Schwan C, Lehmann F, Ostevold K, Pertz O, Aktories K. 116.  2016. Septins guide microtubule protrusions induced by actin-depolymerizing toxins like Clostridium difficile transferase (CDT). PNAS 113:7870–75 [Google Scholar]
  117. Nusrat A, Giry M, Turner JR, Colgan SP, Parkos CA. 117.  et al. 1995. Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. PNAS 92:10629–33 [Google Scholar]
  118. Nusrat A, Von Eichel-Streiber C, Turner JR, Verkade P, Madara JL, Parkos CA. 118.  2001. Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect. Immun. 69:1329–36 [Google Scholar]
  119. Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR. 119.  et al. 2014. Mechanism of action and epitopes of Clostridium difficile toxin B-neutralizing antibody bezlotoxumab revealed by X-ray crystallography. J. Biol. Chem. 289:18008–21 [Google Scholar]
  120. Ottlinger ME, Lin S. 120.  1988. Clostridium difficile toxin B induces reorganization of actin, vinculin, and talin in cultures cells. Exp. Cell. Res. 174:215–29 [Google Scholar]
  121. Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G. 121.  et al. 2011. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). PNAS 108:16422–27 [Google Scholar]
  122. Papatheodorou P, Hornuss D, Nolke T, Hemmasi S, Castonguay J. 122.  et al. 2013. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. mBio 4:e00244–13 [Google Scholar]
  123. Papatheodorou P, Zamboglou C, Genisyuerek S, Guttenberg G, Aktories K. 123.  2010. Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLOS ONE 5:e10673 [Google Scholar]
  124. Park YH, Wood G, Kastner DL, Chae JJ. 124.  2016. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17:914–21 [Google Scholar]
  125. Pfeifer G, Schirmer J, Leemhuis J, Busch C, Meyer DK. 125.  et al. 2003. Cellular uptake of Clostridium difficile toxin B: translocation of the N-terminal catalytic domain into the cytosol of eukaryotic cells. J. Biol. Chem. 278:44535–41 [Google Scholar]
  126. Pothoulakis C, Gilbert RJ, Cladaras C, Castagliuolo I, Semenza G. 126.  et al. 1996. Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J. Clin. Investig. 98:641–49 [Google Scholar]
  127. Pruitt RN, Chagot B, Cover M, Chazin WJ, Spiller B, Lacy DB. 127.  2009. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J. Biol. Chem. 284:21934–40 [Google Scholar]
  128. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB. 128.  2010. Structural organization of the functional domains of Clostridium difficile toxins A and B. PNAS 107:13467–72 [Google Scholar]
  129. Pruitt RN, Chumbler NM, Rutherford SA, Farrow MA, Friedman DB. 129.  et al. 2012. Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. J. Biol. Chem. 287:8013–20 [Google Scholar]
  130. Qa'Dan M, Christensen KA, Zhang L, Roberts TM, Collier RJ. 130.  2005. Membrane insertion by anthrax protective antigen in cultured cells. Mol. Cell. Biol. 25:5492–98 [Google Scholar]
  131. Qa'Dan M, Spyres LM, Ballard JD. 131.  2000. pH-induced conformational changes in Clostridium difficile toxin B. Infect. Immun. 68:2470–74 [Google Scholar]
  132. Qasba PK, Ramakrishnan B, Boeggeman E. 132.  2005. Substrate-induced conformational changes in glycosyltransferases. Trends Biochem. Sci. 30:53–62 [Google Scholar]
  133. Qiu B, Pothoulakis C, Castagliuolo I, Nikulasson S, LaMont JT. 133.  1999. Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats. Am. J. Physiol. 276:G485–90 [Google Scholar]
  134. Qualmann B, Kelly RB. 134.  2000. Syndapin isoforms participate in receptor-mediated endocytosis and actin organization. J. Cell Biol. 148:1047–62 [Google Scholar]
  135. Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O. 135.  et al. 2007. Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446:415–19 [Google Scholar]
  136. Reinert DJ, Jank T, Aktories K, Schulz GE. 136.  2005. Structural basis for the function of Clostridium difficile toxin B. J. Mol. Biol. 351:973–81 [Google Scholar]
  137. Riegler M, Sedivy R, Pothoulakis C, Hamilton G, Zacheri J. 137.  et al. 1995. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J. Clin. Investig. 95:2004–11 [Google Scholar]
  138. Rupnik M, Janezic S. 138.  2016. An update on Clostridium difficile toxinotyping. J. Clin. Microbiol. 54:13–18 [Google Scholar]
  139. Rupnik M, Pabst S, Rupnik M, Von Eichel-Streiber C, Urlaub H, Soling HD. 139.  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 151:199–208 [Google Scholar]
  140. Sandvig K, Skotland T, van Deurs B, Klokk TI. 140.  2013. Retrograde transport of protein toxins through the Golgi apparatus. Histochem. Cell. Biol. 140:317–26 [Google Scholar]
  141. Savidge TC, Pan W-H, Newman P, O'Brien M, Anton PM, Pothoulakis C. 141.  2003. Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 125:413–20 [Google Scholar]
  142. Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A. 142.  et al. 2011. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat. Med. 17:1136–41 [Google Scholar]
  143. Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R. 143.  et al. 2016. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766–78 [Google Scholar]
  144. Schorch B, Song S, van Diemen FR, Bock HH, May P. 144.  et al. 2014. LRP1 is a receptor for Clostridium perfringens TpeL toxin indicating a two-receptor model of clostridial glycosylating toxins. PNAS 111:6431–36 [Google Scholar]
  145. Schulte G. 145.  2010. International Union of Basic and Clinical Pharmacology: LXXX. The class Frizzled receptors. Pharmacol. Rev. 62:632–67 [Google Scholar]
  146. Schwan C, Kruppke AS, Nolke T, Schumacher L, Koch-Nolte F. 146.  et al. 2014. Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. PNAS 111:2313–18 [Google Scholar]
  147. Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M. 147.  et al. 2009. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLOS Pathog 5:e1000626 [Google Scholar]
  148. Sehr P, Joseph G, Genth H, Just I, Pick E, Aktories K. 148.  1998. Glucosylation and ADP ribosylation of Rho proteins: effects on nucleotide binding, GTPase activity, and effector coupling. Biochemistry 37:5296–304 [Google Scholar]
  149. Selzer J, Hofmann F, Rex G, Wilm M, Mann M. 149.  et al. 1996. Clostridium novyi α-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J. Biol. Chem. 271:25173–77 [Google Scholar]
  150. Sheahan K-L, Cordero CL, Fullner Satchell KJ. 150.  2007. Autoprocessing of the Vibrio cholerae RTX toxin by the cysteine protease domain. EMBO J 26:2552–61 [Google Scholar]
  151. Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE. 151.  et al. 2011. Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat. Struct. Mol. Biol. 18:364–71 [Google Scholar]
  152. Shi J, Gao W, Shao F. 152.  2017. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42:245–54 [Google Scholar]
  153. Shi J, Zhao Y, Wang K, Shi X, Wang Y. 153.  et al. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–65 [Google Scholar]
  154. Slimings C, Riley TV. 154.  2014. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J. Antimicrob. Chemother. 69:881–91 [Google Scholar]
  155. Smith JA, Cooke DL, Hyde S, Borriello SP, Long RG. 155.  1997. Clostridium difficile toxin A binding to human intestinal epithelial cells. J. Med. Microbiol 46953–58 [Google Scholar]
  156. Stankiewicz TR, Ramaswami SA, Bouchard RJ, Aktories K, Linseman DA. 156.  2015. Neuronal apoptosis induced by selective inhibition of Rac GTPase versus global suppression of Rho family GTPases is mediated by alterations in distinct mitogen-activated protein kinase signaling cascades. J. Biol. Chem. 290:159363–76 [Google Scholar]
  157. Staub E, Hinzmann B, Rosenthal A. 157.  2002. A novel repeat in the melanoma-associated chondroitin sulfate proteoglycan defines a new protein family. FEBS Lett 527:114–18 [Google Scholar]
  158. Tan KS, Wee BY, Song KP. 158.  2001. Evidence for holin function of tcdE gene in the pathogenicity of Clostridium difficile. J. Med. Microbiol. 50:613–19 [Google Scholar]
  159. Tao L, Zhang J, Meraner P, Tovaglieri A, Wu X. 159.  et al. 2016. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538:350–55 [Google Scholar]
  160. Tcherkezian J, Lamarche-Vane N. 160.  2007. Current knowledge of the large RhoGAP family of proteins. Biol. Cell 99:67–86 [Google Scholar]
  161. Teneberg S, Lönnroth I, López JFT, Galili U, Halvarsson MÖ. 161.  et al. 1996. Molecular mimicry in the recognition of glycosphingolipids by Galα3Galβ4GlcNAcβ-binding Clostridium difficile toxin A, human natural anti α-galactosyl IgG and the monoclonal antibody Gal-13: characterization of a binding-active human glycosphingolipid, non-identical with the animal receptor. Glycobiology 6:599–609 [Google Scholar]
  162. Triadafilopoulos G, Pothoulakis C, O'Brien MJ, LaMont JT. 162.  1987. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 93:273–79 [Google Scholar]
  163. Tucker KD, Wilkins TD. 163.  1991. Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y. Infect. Immun. 59:73–78 [Google Scholar]
  164. van Leeuwen HC, Bakker D, Steindel P, Kuijper EJ, Corver J. 164.  2013. Clostridium difficile TcdC protein binds four-stranded G-quadruplex structures. Nucleic Acids Res 41:2382–93 [Google Scholar]
  165. Vandekerckhove J, Schering B, Bärmann M, Aktories K. 165.  1988. Botulinum C2 toxin ADP-ribosylates cytoplasmic β/γ-actin in arginine 177. J. Biol. Chem. 263:696–700 [Google Scholar]
  166. Vetter IR, Hofmann F, Wohlgemuth S, Herrmann C, Just I. 166.  2000. Structural consequences of mono-glucosylation of Ha-Ras by Clostridium sordellii lethal toxin. J. Mol. Biol. 301:1091–95 [Google Scholar]
  167. Von Eichel-Streiber C, Laufenberg-Feldmann R, Sartingen S, Schulze J, Sauerborn M. 167.  1992. Comparative sequence analysis of the Clostridium difficile toxins A and B. Mol. Gen. Genet. 233:260–68 [Google Scholar]
  168. Von Eichel-Streiber C, Sauerborn M. 168.  1990. Clostridium difficile toxin A carries a C-terminal repetitive structure homologous to the carbohydrate binding region of streptococcal glycosyltransferases. Gene 96:107–13 [Google Scholar]
  169. Wang Q, Navarro MV, Peng G, Molinelli E, Goh SL. 169.  et al. 2009. Molecular mechanism of membrane constriction and tubulation mediated by the F-BAR protein Pacsin/Syndapin. PNAS 106:12700–5 [Google Scholar]
  170. Wegner A, Aktories K. 170.  1988. ADP-ribosylated actin caps the barbed ends of actin filaments. J. Biol. Chem. 263:13739–42 [Google Scholar]
  171. Wei Y, Zhang Y, Derewenda U, Liu X, Minor W. 171.  et al. 1997. Crystal structure of RhoA-GDP and its functional implications. Nat. Struct. Biol. 4:699–703 [Google Scholar]
  172. Wohlan K, Goy S, Olling A, Srivaratharajan S, Tatge H. 172.  et al. 2014. Pyknotic cell death induced by Clostridium difficile TcdB: Chromatin condensation and nuclear blister are induced independently of the glucosyltransferase activity. Cell. Microbiol. 16:1678–92 [Google Scholar]
  173. Xu H, Yang J, Gao W, Li L, Li P. 173.  et al. 2014. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513:237–41 [Google Scholar]
  174. Yen FT, Mann CJ, Guermani LM, Hannouche NF, Hubert N. 174.  et al. 1994. Identification of a lipolysis-stimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry 33:1172–80 [Google Scholar]
  175. Yen FT, Roitel O, Bonnard L, Notet V, Pratte D. 175.  et al. 2008. Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice. J. Biol. Chem. 283:25650–59 [Google Scholar]
  176. Young JA, Collier RJ. 176.  2007. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 76:243–65 [Google Scholar]
  177. Yuan P, Zhang H, Cai C, Zhu S, Zhou Y. 177.  et al. 2015. Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. Cell Res 25:157–68 [Google Scholar]
  178. Zeiser J, Gerhard R, Just I, Pich A. 178.  2013. Substrate specificity of clostridial glucosylating toxins and their function on colonocytes analyzed by proteomics techniques. J. Proteome Res. 12:1604–18 [Google Scholar]
  179. Zhang Z, Park M, Tam J, Auger A, Beilhartz GL. 179.  et al. 2014. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. PNAS 111:3721–26 [Google Scholar]
  180. Ziegler MO, Jank T, Aktories K, Schulz GE. 180.  2008. Conformational changes and reaction of clostridial glycosylating toxins. J. Mol. Biol. 377:1346–56 [Google Scholar]
/content/journals/10.1146/annurev-micro-090816-093458
Loading
Clostridium difficile Toxin Biology
Annual Review of Microbiology 71, 281 (2017); https://doi.org/10.1146/annurev-micro-090816-093458
/content/journals/10.1146/annurev-micro-090816-093458
/content/journals/10.1146/annurev-micro-090816-093458
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error