1887

Journal of Medical Microbiology logo

Volume 57, Issue 6

Processing of toxins Free

Abstract

The pathogenicity of depends on the large clostridial glucosylating toxins A and B (TcdA and TcdB). The proteins accomplish their own uptake by a modular structure comprising a catalytic and a binding/translocation domain. Based on a proteolytic processing step solely the catalytic domain reaches the cytosol. Within the cells, the glucosyltransferases inactivate small GTPases by mono--glucosylation. Here, a short overview is given regarding latest insights into the intramolecular processing, which is mediated by an intrinsic protease activity.

  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.47742-0
2008-06-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jmm/57/6/690.html?itemId=/content/journal/jmm/10.1099/jmm.0.47742-0&mimeType=html&fmt=ahah

References

  1. Aktories K. 2007; Self-cutting to kill: new insights into the processing of Clostridium difficile toxins. ACS Chem Biol 2:228–230 [CrossRef]
     [Google Scholar]
  2. Barroso L. A., Moncrief J. S., Lyerly D. M., Wilkins T. D. 1994; Mutagenesis of the Clostridium difficile toxin B gene and effect on cytotoxic activity. Microb Pathog 16:297–303 [CrossRef]
     [Google Scholar]
  3. 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 276:10670–10676 [CrossRef]
     [Google Scholar]
  4. Bartlett J. G., Perl T. M. 2005; The new Clostridium difficile – what does it mean?. N Engl J Med 353:2503–2505 [CrossRef]
     [Google Scholar]
  5. Bartlett J. G., Onderdonk A. B., Cisneros R. L., Kasper D. L. 1977; Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J Infect Dis 136:701–705 [CrossRef]
     [Google Scholar]
  6. 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 273:19566–19572 [CrossRef]
     [Google Scholar]
  7. Dvorsky R., Ahmadian M. R. 2004; Always look on the bright site of Rho: structural implications for a conserved intermolecular interface. EMBO Rep 5:1130–1136 [CrossRef]
     [Google Scholar]
  8. Egerer M., Giesemann T., Jank T., Satchell K. J., Aktories K. 2007; Auto-catalytic cleavage of Clostridium difficile toxins A and B depends on a cysteine protease activity. J Biol Chem 282:25314–25321 [CrossRef]
     [Google Scholar]
  9. Etienne-Manneville S., Hall A. 2002; Rho GTPases in cell biology. Nature 420:629–635 [CrossRef]
     [Google Scholar]
  10. Faust C., Ye B., Song K.-P. 1998; The enzymatic domain of Clostridium difficile toxin A is located within its N-terminal region. Biochem Biophys Res Commun 251:100–105 [CrossRef]
     [Google Scholar]
  11. Florin I., Thelestam M. 1983; Internalization of Clostridium difficile cytotoxin into cultured human lung fibroblasts. Biochim Biophys Acta 763:383–392 [CrossRef]
     [Google Scholar]
  12. 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 300:706–711 [CrossRef]
     [Google Scholar]
  13. Geyer M., Wilde C., Selzer J., Aktories K., Kalbitzer H. R. 2003; Glucosylation of Ras by Clostridium sordellii lethal toxin: consequences for the effector loop conformations observed by NMR spectroscopy. Biochemistry 42:11951–11959 [CrossRef]
     [Google Scholar]
  14. 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 281:10808–10815 [CrossRef]
     [Google Scholar]
  15. Greco A., Ho J. G., Lin S. J., Palcic M. M., Rupnik M., Ng K. K. 2006; Carbohydrate recognition by Clostridium difficile toxin A. Nat Struct Mol Biol 13:460–461 [CrossRef]
     [Google Scholar]
  16. Hammond G. A., Johnson J. L. 1995; The toxigenic element of Clostridium difficile strain VPI 10463. Microb Pathog 19:203–213 [CrossRef]
     [Google Scholar]
  17. Ho J. G., Greco A., Rupnik M., Ng K. K. 2005; Crystal structure of receptor-binding C-terminal repeats from Clostridium difficile toxin A. Proc Natl Acad Sci U S A 102:18373–18378 [CrossRef]
     [Google Scholar]
  18. 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 272:11074–11078 [CrossRef]
     [Google Scholar]
  19. Hundsberger T., Braun V., Weidmann M., Leukel P., Sauerborn M., von Eichel-Streiber C. 1997; Transcription analysis of the genes tcdA-E of the pathogenicity locus of Clostridium difficile . Eur J Biochem 244:735–742 [CrossRef]
     [Google Scholar]
  20. Jank T., Reinert D. J., Giesemann T., Schulz G. E., Aktories K. 2005; Change of the donor substrate specificity of Clostridium difficile toxin B by site-directed mutagenesis. J Biol Chem 280:37833–37838 [CrossRef]
     [Google Scholar]
  21. Jank T., Giesemann T., Aktories K. 2007a; Clostridium difficile glucosyltransferase toxin B – essential amino acids for substrate-binding. J Biol Chem 282:35222–35331 [CrossRef]
     [Google Scholar]
  22. Jank T., Giesemann T., Aktories K. 2007b; Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 17:15R–22R [CrossRef]
     [Google Scholar]
  23. Just I., Gerhard R. 2004; Large clostridial cytotoxins. Rev Physiol Biochem Pharmacol 152:23–47
     [Google Scholar]
  24. 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 375:500–503 [CrossRef]
     [Google Scholar]
  25. Krivan H. C., Clark G. F., Smith D. F., Wilkins T. D. 1986; Cell surface binding site for Clostridium difficile enterotoxin: evidence for a glycoconjugate containing the sequence Gal α 1-3Gal β 1-4GlcNAc. Infect Immun 53:573–581
     [Google Scholar]
  26. Larsen R. D., Rivera-Marrero C. A., Ernst L. K., Cummings R. D., Lowe J. B. 1990; Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal: β -d-Gal(1,4)-d-GlcNAc α (1,3)-galactosyltransferase cDNA. J Biol Chem 265:7055–7061
     [Google Scholar]
  27. Mani N., Dupuy B. 2001; Regulation of toxin synthesis in Clostridium difficile by an alternative RNA polymerase sigma factor. Proc Natl Acad Sci U S A 98:5844–5849 [CrossRef]
     [Google Scholar]
  28. McDonald L. C., Killgore G. E., Thompson A., Owens R. C. Jr, Kazakova S. V., Sambol S. P., Johnson S., Gerding D. N. 2005; An epidemic, toxin gene-variant strain of Clostridium difficile . N Engl J Med 353:2433–2441 [CrossRef]
     [Google Scholar]
  29. Pfeifer G., Schirmer J., Leemhuis J., Busch C., Meyer D. K., 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 278:44535–44541 [CrossRef]
     [Google Scholar]
  30. Popoff M. R., Rubin E. J., Gill D. M., Boquet P. 1988; Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect Immun 56:2299–2306
     [Google Scholar]
  31. Pothoulakis C., Gilbert R. J., Cladaras C., Castagliuolo I., Semenza G., Hitti Y., Montcrief J. S., Linevsky J., Kelly C. P. other authors 1996; Rabbit sucrase-isomaltase contains a functional intestinal receptor for Clostridium difficile toxin A. J Clin Invest 98:641–649 [CrossRef]
     [Google Scholar]
  32. Qa'Dan M., Spyres L. M., Ballard J. D. 2000; pH-induced conformational changes in Clostridium difficile toxin B. Infect Immun 68:2470–2474 [CrossRef]
     [Google Scholar]
  33. Reineke J., Tenzer S., Rupnik M., Koschinski A., Hasselmayer O., Schrattenholz A., Schild H., von Eichel-Streiber C. 2007; Autocatalytic cleavage of Clostridium difficile toxin B. Nature 446:415–419 [CrossRef]
     [Google Scholar]
  34. Reinert D. J., Jank T., Aktories K., Schulz G. E. 2005; Structural basis for the function of Clostridium difficile toxin B. J Mol Biol 351:973–981 [CrossRef]
     [Google Scholar]
  35. Rifkin G. D., Fekety F. R., Silva J., Sack R. B. 1977; Antibiotic-induced colitis. Implication of a toxin neutralised by Clostridium sordellii antitoxin. Lancet 310:1103–1106 [CrossRef]
     [Google Scholar]
  36. Rolfe R. D., Song W. 1993; Purification of a functional receptor for Clostridium difficile toxin A from intestinal brush border membranes of infant hamsters. Clin Infect Dis 16:S219–227 [CrossRef]
     [Google Scholar]
  37. Rupnik M., Braun V., Soehn F., Janc M., Hofstetter M., Laufenberg-Feldmann R., von Eichel-Streiber C. 1997; Characterization of polymorphisms in the toxin A and B genes of Clostridium difficile . FEMS Microbiol Lett 148:197–202 [CrossRef]
     [Google Scholar]
  38. 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 36:2240–2247
     [Google Scholar]
  39. Rupnik M., Pabst S., Rupnik M., von Eichel-Streiber C., Urlaub H., Soling H. D. 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 [CrossRef]
     [Google Scholar]
  40. Sandvig K., Spilsberg B., Lauvrak S. U., Torgersen M. L., Iversen T. G., van Deurs B. 2004; Pathways followed by protein toxins into cells. Int J Med Microbiol 293:483–490 [CrossRef]
     [Google Scholar]
  41. 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 37:5296–5304 [CrossRef]
     [Google Scholar]
  42. Selzer J., Hofmann F., Rex G., Wilm M., Mann M., Just I., Aktories K. 1996; Clostridium novyi α -toxin-catalyzed incorporation of GlcNAc into Rho subfamily proteins. J Biol Chem 271:25173–25177 [CrossRef]
     [Google Scholar]
  43. Sheahan K.-L., Cordero C. L., Fullner Satchell K. J. 2007; Autoprocessing of the Vibrio cholerae RTX toxin by the cysteine protease domain. EMBO J 26:2552–2561 [CrossRef]
     [Google Scholar]
  44. Shears S. B. 2001; Assessing the omnipotence of inositol hexakisphosphate. Cell Signal 13:151–158 [CrossRef]
     [Google Scholar]
  45. Sullivan N. M., Pellett S., Wilkins T. D. 1982; Purification and characterization of toxins A and B of Clostridium difficile . Infect Immun 35:1032–1040
     [Google Scholar]
  46. Torres J. F. 1991; Purification and characterisation of toxin B from a strain of Clostridium difficile that does not produce toxin A. J Med Microbiol 35:40–44 [CrossRef]
     [Google Scholar]
  47. Tucker K. D., Wilkins T. D. 1991; Toxin A of Clostridium difficile binds to the human carbohydrate antigens I, X, and Y. Infect Immun 59:73–78
     [Google Scholar]
  48. Vetter I. R., 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 301:1091–1095 [CrossRef]
     [Google Scholar]
  49. von Eichel-Streiber C. 1992; A dual model for the architecture of Clostridium difficile toxins A and B. In Bacterial Protein Toxins pp 113–122 Edited by Witholt B. Stuttgart, Jena, New York: Fischer;
     [Google Scholar]
  50. von Eichel-Streiber C., Laufenberg-Feldmann R., Sartingen S., Schulze J., Sauerborn M. 1992; Comparative sequence analysis of the Clostridium difficile toxins A and B. Mol Gen Genet 233:260–268 [CrossRef]
     [Google Scholar]
  51. von Eichel-Streiber C., Boquet P., Sauerborn M., Thelestam M. 1996; Large clostridial cytotoxins – a family of glycosyltransferases modifying small GTP-binding proteins. Trends Microbiol 4:375–382 [CrossRef]
     [Google Scholar]
  52. Voth D. E., Ballard J. D. 2005; Clostridium difficile toxins: mechanism of action and role in disease. Clin Microbiol Rev 18:247–263 [CrossRef]
     [Google Scholar]
  53. Warny M., Pepin J., Fang A., Killgore G., Thompson A., Brazier J., Frost E., McDonald L. C. 2005; Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366:1079–1084 [CrossRef]
     [Google Scholar]
  54. Wren B. W. 1991; A family of clostridial and streptococcal ligand-binding proteins with conserved C-terminal repeat sequences. Mol Microbiol 5:797–803 [CrossRef]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.47742-0
Loading
Processing of Clostridium difficile toxins
J. Med. Microbiol. 57, 690 (2008); https://doi.org/10.1099/jmm.0.47742-0
/content/journal/jmm/10.1099/jmm.0.47742-0
/content/journal/jmm/10.1099/jmm.0.47742-0
Loading

Data & Media loading...

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