Clostridium difficile Toxin Biology

Annual Review of Microbiology

Volumn 71, Issue , 2017, Pages 281-307

  Aktories, Klaus ^a   Schwan, Carsten ^a   Jank, Thomas ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

Author keywords

Actin; ADP ribosylation; CDT; Clostridium difficile infection; Clostridium difficile toxins; Clostridium difficile transferase toxin; Glucosylation; Microtubules; Rho proteins; Toxin receptors; Toxin uptake

Indexed keywords

ACTIN; ADENOSINE DIPHOSPHATE; CHONDROITIN SULFATE PROTEOGLYCAN 4; CLOSTRIDIUM DIFFICILE TRANSFERASE TOXIN; CLOSTRIDIUM TOXIN; COMBINED REPETITIVE PEPTIDE; FRIZZLED PROTEIN; G ACTIN; GLUCOSYLTRANSFERASE; GLYCOSYLTRANSFERASE; INFLAMMASOME; PEPTIDE; PHYTIC ACID; PROTEOCHONDROITIN SULFATE; RECEPTOR; RHO FACTOR; TCDA RECEPTOR; TCDB RECEPTOR; UNCLASSIFIED DRUG; ACTIN-SPECIFIC ADP-RIBOSYLTRANSFERASE, CLOSTRIDIUM; BACTERIAL PROTEIN; BACTERIAL TOXIN; ENTEROTOXIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; TCDA PROTEIN, CLOSTRIDIUM DIFFICILE; TOXB PROTEIN, CLOSTRIDIUM DIFFICILE; VIRULENCE FACTOR;

ADENOSINE DIPHOSPHATE RIBOSYLATION; ALLOSTERISM; APOPTOSIS; ARTICLE; CELL STRUCTURE; CLOSTRIDIUM DIFFICILE INFECTION; CYTOPATHOGENIC EFFECT; ENZYME ACTIVITY; GLYCOSYLATION; HUMAN; MICROTUBULE; NONHUMAN; PEPTOCLOSTRIDIUM DIFFICILE; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN MODIFICATION; PROTEIN TARGETING; PROTEIN TRANSPORT; PYROPTOSIS; RECEPTOR BINDING; REGULATORY MECHANISM; TOXIN STRUCTURE; TOXIN SYNTHESIS; ANIMAL; CYTOSKELETON; DRUG EFFECTS; ENDOCYTOSIS; EPITHELIUM CELL; METABOLISM; PHYSIOLOGY;

ADP RIBOSE TRANSFERASES; ANIMALS; BACTERIAL PROTEINS; BACTERIAL TOXINS; CLOSTRIDIUM DIFFICILE; CYTOSKELETON; ENDOCYTOSIS; ENTEROTOXINS; EPITHELIAL CELLS; HUMANS; MICROTUBULES; VIRULENCE FACTORS;

EID: 85029288413     PISSN: 00664227     EISSN: 15453251     Source Type: Book Series    
DOI: 10.1146/annurev-micro-090816-093458     Document Type: Article

References (180)

1. Aktories K. 2011. Bacterial protein toxins that modify host regulatory GTPases. Nat. Rev. Microbiol. 9:487-98
2. Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH, Habermann E. 1986. Botulinum C2 toxin ADP-ribosylates actin. Nature 322:390-92
3. Aktories K, Wegner A. 1989. ADP-ribosylation of actin by clostridial toxins. J. Cell Biol. 109:1385-87
4. 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 153:1198-206
5. Antonny B, Burd C, De Camilli P, Chen E, Daumke O, et al. 2016. Membrane fission by dynamin: what we know and what we need to know. EMBO J. 35:2270-84
6. Barroso LA, Moncrief JS, Lyerly DM, Wilkins TD. 1994. Mutagenesis of the Clostridium difficile toxin B gene and effect on cytotoxic activity. Microb. Pathog. 16:297-303
7. 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. 68:373-402
8. BarthH, Bl ockerD, Behlke J, Bergsma-SchutterW, Brisson A, et al. 2000. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J. Biol. Chem. 275:18704-11
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. 276:10670-76
10. Biname F. 2014. Transduction of extracellular cues into cell polarity: the role of the transmembrane proteoglycan NG2. Mol. Neurobiol. 50:482-93
11. Bouillaut L, Dubois T, Sonenshein AL, Dupuy B. 2015. Integration of metabolism and virulence in Clostridium difficile. Res. Microbiol. 166:375-83
12. Braun V,Hundsberger T, Leukel P, SauerbornM, Von Eichel-Streiber C. 1996. Definition of the single integration site of the pathogenicity locus in Clostridium difficile. Gene 181:29-38
13. 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. 186:1438-47
14. Burridge K,Wennerberg K. 2004. Rho and Rac take center stage. Cell 116:167-79
15. 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. 275:13228-34
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. 273:19566-72
17. Bustelo XR, Sauzeau V, Berenjeno IM. 2007. GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29:356-70
18. Carter GP, Chakravorty A, Pham Nguyen TA, Mileto S, Schreiber F, 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
19. Chandrasekaran R, Kenworthy AK, Lacy DB. 2016. Clostridium difficile toxin A undergoes clathrinindependent, PACSIN2-dependent endocytosis. PLOS Pathog. 12:e1006070
20. Chaves-Olarte E, Freer E, Parra A, Guzmán-Verri C, Moreno E, Thelestam M. 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
21. Chaves-Olarte E,LowP, Freer E, Norlin T, WeidmannM,et al. 1999.Anovel cytotoxin from Clostridium difficile serogroup F is a functional hybrid between two other large clostridial cytotoxins. J. Biol. Chem. 274:11046-52
22. Chaves-Olarte E, Weidmann M, Von Eichel-Streiber C, Thelestam M. 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
23. Chen ML, Pothoulakis C, LaMont JT. 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
24. Cherfils J, Zeghouf M. 2013. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol. Rev. 93:269-309
25. Chumbler NM, Rutherford SA, Zhang Z, Farrow MA, Lisher JP, et al. 2016. Crystal structure of Clostridium difficile toxin A. Nat. Microbiol. 1:15002
26. Cowardin CA, Buonomo EL, Saleh MM, Wilson MG, Burgess SL, et al. 2016. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia. Nat. Microbiol. 1:16108
27. Ding J, Wang K, LiuW, She Y, Sun Q, et al. 2016. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111-16
28. Donald RG, Flint M, Kalyan N, Johnson E, Witko SE, et al. 2013. A novel approach to generate a recombinant toxoid vaccine against Clostridium difficile. Microbiology 159:1254-66
29. Dove CH, Wang SZ, Price SB, Phelps CJ, Lyerly DM, et al. 1990. Molecular characterization of the Clostridium difficile toxin A gene. Infect. Immun. 58:480-88
30. EgererM, Giesemann T, Herrmann C, Aktories K. 2009. Autocatalytic processing of Clostridium difficile toxin B: binding of inositol hexakisphosphate. J. Biol. Chem. 284:3389-95
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. 282:25314-21
32. Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J, 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
33. Farrow MA, Chumbler NM, Lapierre LA, Franklin JL, Rutherford SA, et al. 2013. Clostridium difficile toxin B-induced necrosis is mediated by the host epithelial cell NADPH oxidase complex. PNAS 110:18674-79
34. Fiorentini C, Fabbri A, Falzano L, Fattorossi A, Matarrese P, et al. 1998. Clostridium difficile toxin B induces apoptosis in intestinal cultured cells. Infect. Immun. 66:2660-65
35. Fiorentini C, Falzano L, Travaglione S, Fabbri A. 2003. Hijacking Rho GTPases by protein toxins and apoptosis: molecular strategies of pathogenic bacteria. Cell Death Differ. 10:147-52
36. Fiorentini C, Thelestam M. 1991. Clostridium difficile toxin A and its effects on cells. Toxicon 29:543-67
37. Frey SM,Wilkins TD. 1992. Localization of two epitopes recognized by monoclonal antibody PCG-4 on Clostridium difficile toxin A. Infect. Immun. 60:2488-92
38. Fukumoto Y, Kaibuchi K, Hori Y, FujiokaH, Araki S, 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
39. GaoW, Yang J, Liu W, Wang Y, Shao F. 2016. Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. PNAS 113:E4857-66
40. Garcia-Mata R, Burridge K. 2007. Catching a GEF by its tail. Trends Cell Biol. 17:36-43
41. Geissler B, Tungekar R, Satchell KJ. 2010. Identification of a conserved membrane localization domain within numerous large bacterial protein toxins. PNAS 107:5581-86
42. 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. 79:1643-54
43. GenthH,AktoriesK, Just I. 1999. Monoglucosylation ofRhoA at threonine-37 blocks cytosol-membrane cycling. J. Biol. Chem. 274:29050-56
44. Genth H, Pauillac S, Schelle I, Bouvet P, Bouchier C, 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
45. Geny B, Grassart A, Manich M, Chicanne G, Payrastre B, et al. 2010. Rac1 inactivation by lethal toxin from Clostridium sordellii modifies focal adhesions upstream of actin depolymerization. Cell. Microbiol. 12:217-32
46. GerdingDN, Johnson S, Rupnik M, Aktories K. 2014. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5:15-27
47. 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. 62:1414-22
48. 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. 57:765-70
49. Giesemann T, Jank T, Gerhard R, Maier E, Just I, et al. 2006. Cholesterol-dependent pore formation of Clostridium difficile toxin A. J. Biol. Chem. 281:10808-15
50. Govind R, Dupuy B. 2012. Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLOS Pathog. 8:e1002727
51. Greco A,Ho JG, Lin SJ, Palcic MM, Rupnik M, Ng KK. 2006. Carbohydrate recognition by Clostridium difficile toxin A. Nat. Struct. Mol. Biol. 13:460-1
52. Gulke I, Pfeifer G, Liese J, Fritz M, Hofmann F, et al. 2001. Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect. Immun. 69:6004-11
53. Guttenberg G, Hornei S, Jank T, Schwan C, LuW, 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
54. Guttenberg G, Papatheodorou P, Genisyuerek S, LuW, Jank T, et al. 2011. Inositol hexakisphosphatedependent processing of Clostridium sordellii lethal toxin and Clostridium novyi ?-toxin. J. Biol. Chem. 286:14779-86
55. Halabi-Cabezon I, Huelsenbeck J, May M, Ladwein M, Rottner K, et al. 2008. Prevention of the cytopathic effect induced by Clostridium difficile toxin B by active Rac1. FEBS Lett. 582:3751-56
56. Hall A. 1994. Small GTP-binding proteins and the regulation of the actin cytoskeleton. Annu. Rev. Cell Biol. 10:31-54
57. Hammond GA, Johnson JL. 1995. The toxigenic element of Clostridium difficile strain VPI 10463. Microb. Pathog. 19:203-13
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. 6:932-36
59. Haug G, Leemhuis J, Tiemann D, Meyer DK, Aktories K, Barth H. 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
60. Heasman SJ, Ridley AJ. 2008. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9:690-701
61. HechtG,Koutsouris A, Pothoulakis C, LaMont JT,Madara JL. 1992. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102:416-23
62. Hecht G, Pothoulakis C, LaMont JT,Madara JL. 1988. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J. Clin. Investig. 82:1516-24
63. 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. 290:14031-44
64. Henriques B, Florin I, Thelestam M. 1987. Cellular internalisation of Clostridium difficile toxin A. Microb. Pathogen. 2:455-63
65. Higashi T, Tokuda S, Kitajiri SI, Masuda S, Nakamura H, 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
66. Hippenstiel S, Schmeck B, N'Guessan PD, Seybold J, Kr ull M, et al. 2002. Rho protein inactivation induced apoptosis of cultured human endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 283:L830-38
67. Hirase T, Kawashima S, Wong EY, Ueyama T, Rikitake Y, et al. 2001. Regulation of tight junction permeability and occludin phosphorylation by Rhoa-p160ROCK-dependent and-independent mechanisms. J. Biol. Chem. 276:10423-31
68. Ho JG, Greco A, Rupnik M, Ng KK. 2005. Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. PNAS 102:18373-78
69. Ihara K, Muraguchi S, Kato M, Shimizu T, Shirakawa M, et al. 1998. Crystal structure of human RhoA in a dominantly active form complexed with a GTP analogue. J. Biol. Chem. 273:9656-66
70. 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. 171:939-45
71. Ishida Y,Maegawa T, Kondo T, Kimura A, Iwakura Y, et al. 2004. Essential involvement of IFN-gamma in Clostridium difficile toxin A-induced enteritis. J. Immunol. 172:3018-25
72. Jafari NV, Kuehne SA, Bryant CE, Elawad M, Wren BW, et al. 2013. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLOS ONE 8:e69846
73. Jaffe AB, Hall A. 2005. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21:247-69
74. Jank T, Aktories K. 2008. Structure and mode of action of clostridial glucosylating toxins: the ABCD model. Trends Microbiol. 16:222-29
75. Jank T, Giesemann T, Aktories K. 2007. Clostridium difficile glucosyltransferase toxin B-essential amino acids for substrate binding. J. Biol. Chem. 282:35222-31
76. Jank T, Reinert DJ, GiesemannT, Schulz GE, Aktories K. 2005. Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J. Biol. Chem. 280:37833-38
77. Johal SS, Solomon K, Dodson S, Borriello SP,Mahida YR. 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
78. Jorgensen I,Miao EA. 2015. Pyroptotic cell death defends against intracellular pathogens. Immunol. Rev. 265:130-42
79. Just I, Selzer J, Wilm M, Von Eichel-Streiber C, Mann M, Aktories K. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375:500-3
80. Just I, Wilm M, Selzer J, Rex G, Von Eichel-Streiber C, et al. 1995. The enterotoxin from Clostridium difficile (ToxA) monoglucosylates the Rho proteins. J. Biol. Chem. 270:13932-36
81. Kaiser E, Bohm N, Ernst K, Langer S, Schwan C, 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
82. Karlsson S, Burman LG, Akerlund T. 1999. Suppression of toxin production in Clostridium difficile VPI 10463 by amino acids. Microbiology 145(Part 7):1683-93
83. Karlsson S, Lindberg A, Norin E, Burman LG, Akerlund T. 2000. Toxins, butyric acid, and other shortchain fatty acids are coordinately expressed and down-regulated by cysteine in Clostridium difficile. Infect. Immun. 68:5881-88
84. Kelly CP, LaMont JT. 2008. Clostridium difficile-more difficult than ever. N. Engl. J.Med. 359:1932-40
85. Kishida S, Yamamoto H, Kikuchi A. 2004. Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Mol. Cell. Biol. 24:4487-501
86. Klaus A, Birchmeier W. 2008. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8:387-98
87. 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 ?1-3Gal?1-4GlcNAc. Infect. Immun. 53:573-81
88. 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 467:711-13
89. LaFrance ME, FarrowMA, Chandrasekaran R, Sheng J, Rubin DH, Lacy DB. 2015. Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. PNAS 112:7073-78
90. Lambert GS, Baldwin MR. 2016. Evidence for dual receptor-binding sites in Clostridium difficile toxin A. FEBS Lett. 590:4550-63
91. Le SS, Loucks FA, Udo H, Richardson-Burns S, Phelps RA, 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
92. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, et al. 2015. Burden of Clostridium difficile infection in the United States. N. Engl. J. Med. 372:825-34
93. Leuzzi R, Spencer J, Buckley A, Brettoni C, Martinelli M, et al. 2013. Protective efficacy induced by recombinant Clostridium difficile toxin fragments. Infect. Immun. 81:2851-60
94. Lima AAM, Lyerly DM, Wilkins TD, Innes DJ, Guerrant RL. 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
95. Linevsky JK, Pothoulakis C, Keates S, Warny M, Keates AC, et al. 1997. IL-8 release and neutrophil activation by Clostridium difficile toxin-exposed human monocytes. Am. J. Physiol. 273:G1333-40
96. Lord MS,Whitelock JM. 2013. Recombinant production of proteoglycans and their bioactive domains. FEBS J. 280:2490-510
97. Lu A, Wu H. 2015. Structural mechanisms of inflammasome assembly. FEBS J. 282:435-44
98. Lyras D, O'Connor JR, Howarth PM, Sambol SP, Carter GP, et al. 2009. Toxin B is essential for virulence of Clostridium difficile. Nature 458(7242):1176-79
99. Madshus IH, Stenmark H, Sandvig K, Olsnes S. 1991. Entry of diphtheria toxin-protein A chimeras into cells. J. Biol. Chem. 266:17446-53
100. 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 38:337-47
101. Mani N, Dupuy B. 2001. Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. PNAS 98:5844-49
102. Masuda S, Oda Y, Sasaki H, Ikenouchi J, Higashi T, et al. 2011. LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 124:548-55
103. Matamouros S, England P, Dupuy B. 2007. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol. Microbiol. 64:1274-88
104. McCormack J, Welsh NJ, Braga VM. 2013. Cycling around cell-cell adhesion with Rho GTPase regulators. J. Cell. Sci. 126:379-91
105. Mesli S, Javorschi S, Berard AM,LandryM, PriddleH, 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
106. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, et al. 2010. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11:1136-42
107. Mitchell TJ, Ketley JM, Haslam SC, Stephen J, Burdon DW, et al. 1986. Effect of toxin A and B of Clostridium difficile on rabbit ileum and colon. Gut 27:78-85
108. Miyoshi J, Takai Y. 2007. Nectin and nectin-like molecules: biology and pathology. Am. J. Nephrol. 27:590-604
109. Monot M, Eckert C, Lemire A, Hamiot A, Dubois T, et al. 2015. Clostridium difficile: new insights into the evolution of the pathogenicity locus. Sci. Rep. 5:15023
110. Moorman JP, LuuD,Wickham J, Bobak DA, Hahn CS. 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
111. Murase T, Eugenio L, SchorrM, Hussack G, Tanha J, 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
112. Na X, Kim H, Moyer MP, Pothoulakis C, LaMont JT. 2008. gp96 is a human colonocyte plasma membrane binding protein for Clostridium difficile toxin A. Infect. Immun. 76:2862-71
113. Nagahama M, Ohkubo A, Oda M, Kobayashi K, Amimoto K, et al. 2011. Clostridium perfringens TpeL glycosylates the Rac and Ras subfamily proteins. Infect. Immun. 79(2):905-10
114. 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. 72:3267-75
115. Ng J, Hirota SA, Gross O, Li Y, Ulke-Lemee A, et al. 2010. Clostridium difficile toxin-induced inflammation and intestinal injury are mediated by the inflammasome. Gastroenterology 139:542-52.e3
116. 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). PNAS 113:7870-75
117. Nusrat A, Giry M, Turner JR, Colgan SP, Parkos CA, et al. 1995. Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. PNAS 92:10629-33
118. 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. 69:1329-36
119. Orth P, Xiao L, Hernandez LD, Reichert P, Sheth PR, 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
120. OttlingerME, Lin S. 1988. Clostridium difficile toxin B induces reorganization of actin, vinculin, and talin in cultures cells. Exp. Cell. Res. 174:215-29
121. Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G, et al. 2011. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). PNAS 108:16422-27
122. Papatheodorou P, Hornuss D, Nolke T, Hemmasi S, Castonguay J, et al. 2013. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. mBio 4:e00244-13
123. Papatheodorou P, Zamboglou C, Genisyuerek S, Guttenberg G, Aktories K. 2010. Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLOS ONE 5:e10673
124. Park YH,Wood G, Kastner DL, Chae JJ. 2016. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17:914-21
125. Pfeifer G, Schirmer J, Leemhuis J, Busch C, Meyer DK, 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
126. Pothoulakis C, Gilbert RJ, Cladaras C, Castagliuolo I, Semenza G, et al. 1996. Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J. Clin. Investig. 98:641-49
127. Pruitt RN, Chagot B, Cover M, Chazin WJ, SpillerB,Lacy DB. 2009. Structure-function analysis of inositol hexakisphosphate-induced autoprocessing in Clostridium difficile toxin A. J. Biol. Chem. 284:21934-40
128. Pruitt RN, Chambers MG, Ng KK, Ohi MD, Lacy DB. 2010. Structural organization of the functional domains of Clostridium difficile toxins A and B. PNAS 107:13467-72
129. Pruitt RN, Chumbler NM, Rutherford SA, Farrow MA, Friedman DB, et al. 2012. Structural determinants of Clostridium difficile toxin A glucosyltransferase activity. J. Biol. Chem. 287:8013-20
130. Qa'Dan M, Christensen KA, Zhang L, Roberts TM, Collier RJ. 2005. Membrane insertion by anthrax protective antigen in cultured cells. Mol. Cell. Biol. 25:5492-98
131. Qa'Dan M, Spyres LM, Ballard JD. 2000. pH-induced conformational changes in Clostridium difficile toxin B. Infect. Immun. 68:2470-74
132. Qasba PK, Ramakrishnan B, Boeggeman E. 2005. Substrate-induced conformational changes in glycosyltransferases. Trends Biochem. Sci. 30:53-62
133. Qiu B, Pothoulakis C, Castagliuolo I, Nikulasson S, LaMont JT. 1999. Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats. Am. J. Physiol. 276:G485-90
134. Qualmann B, Kelly RB. 2000. Syndapin isoforms participate in receptor-mediated endocytosis and actin organization. J. Cell Biol. 148:1047-62
135. Reineke J, Tenzer S, Rupnik M, Koschinski A, Hasselmayer O, et al. 2007. Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446:415-19
136. Reinert DJ, Jank T, Aktories K, Schulz GE. 2005. Structural basis for the function of Clostridium difficile toxin B. J. Mol. Biol. 351:973-81
137. Riegler M, Sedivy R, Pothoulakis C, Hamilton G, Zacheri J, 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
138. Rupnik M, Janezic S. 2016. An update on Clostridium difficile toxinotyping. J. Clin. Microbiol. 54:13-18
139. 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 151:199-208
140. Sandvig K, Skotland T, van Deurs B, Klokk TI. 2013. Retrograde transport of protein toxins through the Golgi apparatus. Histochem. Cell. Biol. 140:317-26
141. Savidge TC, Pan W-H, Newman P, O'Brien M, Anton PM, Pothoulakis C. 2003. Clostridium difficile toxin B is an inflammatory enterotoxin in human intestine. Gastroenterology 125:413-20
142. Savidge TC, Urvil P, Oezguen N, Ali K, Choudhury A, et al. 2011. Host S-nitrosylation inhibits clostridial small molecule-activated glucosylating toxins. Nat. Med. 17:1136-41
143. Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, et al. 2016. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35:1766-78
144. Schorch B, Song S, van Diemen FR, Bock HH, May P, 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
145. Schulte G. 2010. International Union of Basic and Clinical Pharmacology: LXXX. The class Frizzled receptors. Pharmacol. Rev. 62:632-67
146. Schwan C, Kruppke AS, Nolke T, Schumacher L, Koch-Nolte F, et al. 2014. Clostridium difficile toxin CDThijacksmicrotubule organization and reroutes vesicle traffic to increase pathogen adherence. PNAS 111:2313-18
147. Schwan C, Stecher B, Tzivelekidis T, van Ham M, RohdeM, et al. 2009. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLOS Pathog. 5:e1000626
148. Sehr P, Joseph G, GenthH, Just I, Pick E, Aktories K. 1998. Glucosylation and ADP ribosylation of Rho proteins: effects on nucleotide binding,GTPase activity, and effector coupling. Biochemistry 37:5296-304
149. Selzer J, Hofmann F, Rex G,Wilm M, Mann M, et al. 1996. Clostridium novyi ?-toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J. Biol. Chem. 271:25173-77
150. Sheahan K-L, Cordero CL, Fullner Satchell KJ. 2007. Autoprocessing of the Vibrio cholerae RTX toxin by the cysteine protease domain. EMBO J. 26:2552-61
151. Shen A, Lupardus PJ, Gersch MM, Puri AW, Albrow VE, et al. 2011. Defining an allosteric circuit in the cysteine protease domain of Clostridium difficile toxins. Nat. Struct. Mol. Biol. 18:364-71
152. Shi J, Gao W, Shao F. 2017. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42:245-54
153. Shi J, Zhao Y, Wang K, Shi X, Wang Y, et al. 2015. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660-65
154. Slimings C, Riley TV. 2014. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J. Antimicrob. Chemother. 69:881-91
155. Smith JA, Cooke DL, Hyde S, Borriello SP, Long RG. 1997. Clostridium difficile toxin A binding to human intestinal epithelial cells. J. Med. Microbiol. 46:953-58
156. Stankiewicz TR, Ramaswami SA, Bouchard RJ, Aktories K, Linseman DA. 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(15):9363-76
157. Staub E,Hinzmann B, Rosenthal A. 2002. A novel repeat in themelanoma-associated chondroitin sulfate proteoglycan defines a new protein family. FEBS Lett. 527:114-18
158. Tan KS, Wee BY, Song KP. 2001. Evidence for holin function of tcdE gene in the pathogenicity of Clostridium difficile. J. Med. Microbiol. 50:613-19
159. Tao L, Zhang J, Meraner P, Tovaglieri A, Wu X, et al. 2016. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538:350-55
160. Tcherkezian J, Lamarche-Vane N. 2007. Current knowledge of the large RhoGAP family of proteins. Biol. Cell 99:67-86
161. Teneberg S, Lönnroth I, Lopez JFT, Galili U, Halvarsson MÖ, et al. 1996. Molecular mimicry in the recognition of glycosphingolipids byGal?3Gal?4GlcNAc?-binding Clostridium difficile toxin A, human natural anti ?-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
162. Triadafilopoulos G, Pothoulakis C, O'Brien MJ, LaMont JT. 1987. Differential effects of Clostridium difficile toxins A and B on rabbit ileum. Gastroenterology 93:273-79
163. Tucker KD, Wilkins TD. 1991. Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y. Infect. Immun. 59:73-78
164. van Leeuwen HC, Bakker D, Steindel P, Kuijper EJ, Corver J. 2013. Clostridium difficile TcdC protein binds four-stranded G-quadruplex structures. Nucleic Acids Res. 41:2382-93
165. Vandekerckhove J, Schering B, Bärmann M, Aktories K. 1988. Botulinum C2 toxin ADP-ribosylates cytoplasmic ?/?-actin in arginine J. Biol. Chem. 263:696-700
166. Vetter IR, Hofmann F, Wohlgemuth S, Herrmann C, Just I. 2000. Structural consequences of monoglucosylation of Ha-Ras by Clostridium sordellii lethal toxin. J. Mol. Biol. 301:1091-95
167. Von Eichel-Streiber C, Laufenberg-Feldmann R, Sartingen S, Schulze J, SauerbornM. 1992. Comparative sequence analysis of the Clostridium difficile toxins A and B. Mol. Gen. Genet. 233:260-68
168. 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 96:107-13
169. Wang Q, Navarro MV, Peng G, Molinelli E, Goh SL, et al. 2009. Molecular mechanism of membrane constriction and tubulation mediated by the F-BAR protein Pacsin/Syndapin. PNAS 106:12700-5
170. Wegner A, Aktories K. 1988. ADP-ribosylated actin caps the barbed ends of actin filaments. J. Biol. Chem. 263:13739-42
171. Wei Y, Zhang Y, Derewenda U, Liu X, Minor W, et al. 1997. Crystal structure of RhoA-GDP and its functional implications. Nat. Struct. Biol. 4:699-703
172. Wohlan K, Goy S, Olling A, Srivaratharajan S, Tatge H, 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
173. Xu H, Yang J, GaoW, Li L, Li P, et al. 2014. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513:237-41
174. Yen FT, Mann CJ, Guermani LM, Hannouche NF, Hubert N, et al. 1994. Identification of a lipolysisstimulated receptor that is distinct from the LDL receptor and the LDL receptor-related protein. Biochemistry 33:1172-80
175. Yen FT, Roitel O, Bonnard L, Notet V, Pratte D, 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
176. Young JA, CollierRJ. 2007. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 76:243-65
177. Yuan P, Zhang H, Cai C, Zhu S, Zhou Y, et al. 2015. Chondroitin sulfate proteoglycan 4 functions as the cellular receptor for Clostridium difficile toxin B. Cell Res. 25:157-68
178. 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. 12:1604-18
179. Zhang Z, ParkM, Tam J, Auger A, Beilhartz GL, et al. 2014. Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore. PNAS 111:3721-26
180. Ziegler MO, Jank T, Aktories K, Schulz GE. 2008. Conformational changes and reaction of clostridial glycosylating toxins. J. Mol. Biol. 377:1346-56