Host Cell Chaperones Hsp70/Hsp90 and Peptidyl-Prolyl Cis/Trans Isomerases Are Required for the Membrane Translocation of Bacterial ADP-Ribosylating Toxins

  • Katharina Ernst
  • Leonie Schnell
  • Holger BarthEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 406)


Bacterial ADP-ribosylating toxins are the causative agents for several severe human and animal diseases such as diphtheria, cholera, or enteric diseases. They display an AB-type structure: The enzymatically active A-domain attaches to the binding/translocation B-domain which then binds to a receptor on the cell surface. After receptor-mediated endocytosis, the B-domain facilitates the membrane translocation of the unfolded A-domain into the host cell cytosol. Here, the A-domain transfers an ADP-ribose moiety onto its specific substrate which leads to characteristic cellular effects and thus to severe clinical symptoms. Since the A-domain has to reach the cytosol to achieve a cytotoxic effect, the membrane translocation represents a crucial step during toxin uptake. Host cell chaperones including Hsp90 and protein-folding helper enzymes of the peptidyl-prolyl cis/trans isomerase (PPIase) type facilitate this membrane translocation of the unfolded A-domain for ADP-ribosylating toxins but not for toxins with a different enzyme activity. This review summarizes the uptake mechanisms of the ADP-ribosylating clostridial binary toxins, diphtheria toxin (DT) and cholera toxin (CT), with a special focus on the interaction of these toxins with the chaperones Hsp90 and Hsp70 and PPIases of the cyclophilin and FK506-binding protein families during the membrane translocation of their ADP-ribosyltransferase domains into the host cell cytosol. Moreover, the medical implications of host cell chaperones and PPIases as new drug targets for the development of novel therapeutic strategies against diseases caused by bacterial ADP-ribosylating toxins are discussed.

List of Abbreviations (Optional)




Cyclosporine A, inhibitor of cyclophilins


Cholera toxin




Diphtheria toxin


Inhibitor of FK506-binding proteins


FK506-binding protein


Geldanamycin, inhibitor of Hsp90


Peptidyl-prolyl cis/trans isomerase


Radicicol, inhibitor of Hsp90


  1. Abrami L, Liu S, Cosson P, Leppla SH, van der Goot FG (2003) Anthrax toxin triggers endocytosis of its receptor via a lipid raft-mediated clathrin-dependent process. J Cell Biol 160:321–328PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abrami L, Lindsay M, Parton RG, Leppla SH, van der Goot FG (2004) Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J Cell Biol 166:645–651PubMedPubMedCentralCrossRefGoogle Scholar
  3. Abrami L, Bischofberger M, Kunz B, Groux R, van der Goot FG (2010) Endocytosis of the anthrax toxin is mediated by clathrin, actin and unconventional adaptors. PLoS Pathog 6:e1000792PubMedPubMedCentralCrossRefGoogle Scholar
  4. Aktories K, Wegner A (1992) Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. Mol Microbiol 6:2905–2908PubMedCrossRefGoogle Scholar
  5. Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH, Habermann E (1986) Botulinum C2 toxin ADP-ribosylates actin. Nature 322:390–392ADSPubMedCrossRefGoogle Scholar
  6. Aktories K, Lang AE, Schwan C, Mannherz HG (2011) Actin as target for modification by bacterial protein toxins. FEBS J 278:4526–4543PubMedCrossRefGoogle Scholar
  7. Ampapathi RS, Creath AL, Lou DI, Craft JW, Blanke SR, Legge GB (2008) Order-disorder-order transitions mediate the activation of cholera toxin. J Mol Biol 377:748–760PubMedPubMedCentralCrossRefGoogle Scholar
  8. Ariansen S, Afanasiev BN, Moskaug JO, Stenmark H, Madshus IH, Olsnes S (1993) Membrane translocation of diphtheria toxin A-fragment: role of carboxy-terminal region. Biochemistry (Mosc) 32:83–90CrossRefGoogle Scholar
  9. Arndt V, Rogon C, Höhfeld J (2007) To be, or not to be–molecular chaperones in protein degradation. Cell Mol Life Sci CMLS 64:2525–2541PubMedCrossRefGoogle Scholar
  10. Arora N, Leppla SH (1994) Fusions of anthrax toxin lethal factor with shiga toxin and diphtheria toxin enzymatic domains are toxic to mammalian cells. Infect Immun 62:4955–4961PubMedPubMedCentralGoogle Scholar
  11. Atkinson W, Hamborsky J, McIntyre L, Wolfe S (2007) Diphtheria. In: Epidemiology and prevention of vaccine-preventable diseases (the pink book). Public Health Foundation, Washington DC, pp 59–70Google Scholar
  12. Bacha P, Williams DP, Waters C, Williams JM, Murphy JR, Strom TB (1988) Interleukin 2 receptor-targeted cytotoxicity. Interleukin 2 receptor-mediated action of a diphtheria toxin-related interleukin 2 fusion protein. J Exp Med 167:612–622PubMedCrossRefGoogle Scholar
  13. Bade S, Rummel A, Alves J, Bigalke H, Binz T (2002) New insights into the translocation process of botulinum neurotoxins. Naunyn Schmiedebergs Arch Pharmacol 365(Sup 2):R13Google Scholar
  14. Bagola K, Mehnert M, Jarosch E, Sommer T (2011) Protein dislocation from the ER. Biochim Biophys Acta 1808:925–936PubMedCrossRefGoogle Scholar
  15. Banerjee T, Pande A, Jobling MG, Taylor M, Massey S, Holmes RK, Tatulian SA, Teter K (2010) Contribution of subdomain structure to the thermal stability of the cholera toxin A1 subunit. Biochemistry (Mosc) 49:8839–8846CrossRefGoogle Scholar
  16. Banerjee T, Taylor M, Jobling MG, Burress H, Yang Z, Serrano A, Holmes RK, Tatulian SA, Teter K (2014) ADP-ribosylation factor 6 acts as an allosteric activator for the folded but not disordered cholera toxin A1 polypeptide. Mol Microbiol 94:898–912PubMedPubMedCentralCrossRefGoogle Scholar
  17. Barbieri JT, Collier RJ (1987) Expression of a mutant, full-length form of diphtheria toxin in Escherichia coli. Infect Immun 55:1647–1651PubMedPubMedCentralGoogle Scholar
  18. Barth H (2011) Exploring the role of host cell chaperones/PPIases during cellular up-take of bacterial ADP-ribosylating toxins as basis for novel pharmacological strategies to protect mammalian cells against these virulence factors. Naunyn Schmiedebergs Arch Pharmacol 383:237–245PubMedCrossRefGoogle Scholar
  19. Barth H, Aktories K (2011) New insights into the mode of action of the actin ADP-ribosylating virulence factors Salmonella enterica SpvB and Clostridium botulinum C2 toxin. Eur J Cell Biol 90:944–950PubMedCrossRefGoogle Scholar
  20. Barth H, Stiles BG (2008) Binary actin-ADP-ribosylating toxins and their use as molecular Trojan horses for drug delivery into eukaryotic cells. Curr Med Chem 15:459–469PubMedCrossRefGoogle Scholar
  21. Barth H, Hofmann F, Olenik C, Just I, Aktories K (1998a) The n-terminal part of the enzyme component (C2I) of the binary clostridium botulinum C2 toxin interacts with the binding component C2II and functions as a carrier system for a Rho ADP-ribosylating C3-like fusion toxin. Infect Immun 66:1364–1369PubMedPubMedCentralGoogle Scholar
  22. Barth H, Preiss JC, Hofmann F, Aktories K (1998b) Characterization of the catalytic site of the ADP-ribosyltransferase clostridium botulinum C2 toxin by site-directed mutagenesis. J Biol Chem 273:29506–29511PubMedCrossRefGoogle Scholar
  23. Barth H, Blocker D, Behlke J, Bergsma-Schutter W, Brisson A, Benz R, Aktories K (2000) Cellular uptake of clostridium botulinum C2 toxin requires oligomerization and acidification. J Biol Chem 275:18704–18711PubMedCrossRefGoogle Scholar
  24. Barth H, Roebling R, Fritz M, Aktories K (2002) The binary Clostridium botulinum C2 toxin as a protein delivery system: identification of the minimal protein region necessary for interaction of toxin components. J Biol Chem 277:5074–5081PubMedCrossRefGoogle Scholar
  25. 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 MMBR 68:373–402, table of contentsGoogle Scholar
  26. Beitzinger C, Stefani C, Kronhardt A, Rolando M, Flatau G, Lemichez E, Benz R (2012) Role of N-terminal His6-Tags in binding and efficient translocation of polypeptides into cells using anthrax protective antigen (PA). PLoS ONE 7:e46964ADSPubMedPubMedCentralCrossRefGoogle Scholar
  27. Billington SJ, Wieckowski EU, Sarker MR, Bueschel D, Songer JG, McClane BA (1998) Clostridium perfringens type E animal enteritis isolates with highly conserved, silent enterotoxin gene sequences. Infect Immun 66:4531–4536PubMedPubMedCentralGoogle Scholar
  28. Blanke SR, Milne JC, Benson EL, Collier RJ (1996) Fused polycationic peptide mediates delivery of diphtheria toxin A chain to the cytosol in the presence of anthrax protective antigen. Proc Natl Acad Sci USA 93:8437–8442ADSPubMedPubMedCentralCrossRefGoogle Scholar
  29. Blaustein RO, Koehler TM, Collier RJ, Finkelstein A (1989) Anthrax toxin: channel-forming activity of protective antigen in planar phospholipid bilayers. Proc Natl Acad Sci USA 86:2209–2213ADSPubMedPubMedCentralCrossRefGoogle Scholar
  30. Blöcker D, Barth H, Maier E, Benz R, Barbieri JT, Aktories K (2000) The C terminus of component C2II of clostridium botulinum C2 toxin is essential for receptor binding. Infect Immun 68:4566–4573PubMedPubMedCentralCrossRefGoogle Scholar
  31. Boquet P, Silverman MS, Pappenheimer AM, Vernon WB (1976) Binding of triton X-100 to diphtheria toxin, crossreacting material 45, and their fragments. Proc Natl Acad Sci USA 73:4449–4453ADSPubMedPubMedCentralCrossRefGoogle Scholar
  32. Borel JF, Feurer C, Gubler HU, Stähelin H (1976) Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 6:468–475PubMedCrossRefGoogle Scholar
  33. Brown JG, Almond BD, Naglich JG, Eidels L (1993) Hypersensitivity to diphtheria toxin by mouse cells expressing both diphtheria toxin receptor and CD9 antigen. Proc Natl Acad Sci USA 90:8184–8188ADSPubMedPubMedCentralCrossRefGoogle Scholar
  34. Burress H, Taylor M, Banerjee T, Tatulian SA, Teter K (2014) Co- and post-translocation roles for HSP90 in cholera intoxication. J Biol Chem 289:33644–33654PubMedPubMedCentralCrossRefGoogle Scholar
  35. Carroll KC, Bartlett JG (2011) Biology of Clostridium difficile: implications for epidemiology and diagnosis. Annu Rev Microbiol 65:501–521PubMedCrossRefGoogle Scholar
  36. Carroll SF, Collier RJ (1984) NAD binding site of diphtheria toxin: identification of a residue within the nicotinamide subsite by photochemical modification with NAD. Proc Natl Acad Sci USA 81:3307–3311ADSPubMedPubMedCentralCrossRefGoogle Scholar
  37. Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF (2005) Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol 19:1654–1666PubMedCrossRefGoogle Scholar
  38. Choe S, Bennett MJ, Fujii G, Curmi PM, Kantardjieff KA, Collier RJ, Eisenberg D (1992) The crystal structure of diphtheria toxin. Nature 357:216–222ADSPubMedCrossRefGoogle Scholar
  39. Clemens J, Shin S, Sur D, Nair GB, Holmgren J (2011) New-generation vaccines against cholera. Nat Rev Gastroenterol Hepatol 8:701–710PubMedCrossRefGoogle Scholar
  40. Clerico EM, Tilitsky JM, Meng W, Gierasch LM (2015) How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J Mol Biol 427:1575–1588PubMedPubMedCentralCrossRefGoogle Scholar
  41. Clipstone NA, Crabtree GR (1992) Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357:695–697ADSPubMedCrossRefGoogle Scholar
  42. Collier RJ (1975) Diphtheria toxin: mode of action and structure. Bacteriol Rev 39:54–85PubMedPubMedCentralGoogle Scholar
  43. Collier RJ (2001) Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon 39:1793–1803PubMedCrossRefGoogle Scholar
  44. Collier RJ (2009) Membrane translocation by anthrax toxin. Mol Aspects Med 30:413–422PubMedPubMedCentralCrossRefGoogle Scholar
  45. Collier RJ, Cole HA (1969) Diphtheria toxin subunit active in vitro. Science 164:1179–1181ADSPubMedCrossRefGoogle Scholar
  46. Collier RJ, Kandel J (1971) Structure and activity of diphtheria toxin I. Thiol-dependent dissociation of a fraction of toxin into enzymically active and inactive fragments. J Biol Chem 246:1496–1503PubMedGoogle Scholar
  47. Davis TL, Walker JR, Campagna-Slater V, Finerty PJ Jr, Paramanathan R, Bernstein G, MacKenzie F, Tempel W, Ouyang H, Lee WH et al (2010) Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases. PLoS Biol 8:e1000439PubMedPubMedCentralCrossRefGoogle Scholar
  48. De Haan L, Hirst TR (2004) Cholera toxin: a paradigm for multi-functional engagement of cellular mechanisms (Review). Mol Membr Biol 21:77–92PubMedCrossRefGoogle Scholar
  49. Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG (2000) Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology 141:4107–4113PubMedCrossRefGoogle Scholar
  50. Dmochewitz L, Lillich M, Kaiser E, Jennings LD, Lang AE, Buchner J, Fischer G, Aktories K, Collier RJ, Barth H (2011) Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. Cell Microbiol 13:359–373PubMedPubMedCentralCrossRefGoogle Scholar
  51. Donovan JJ, Simon MI, Draper RK, Montal M (1981) Diphtheria toxin forms transmembrane channels in planar lipid bilayers. Proc Natl Acad Sci USA 78:172–176ADSPubMedPubMedCentralCrossRefGoogle Scholar
  52. Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, Ahn NG, Oskarsson MK, Fukasawa K, Paull KD et al (1998) Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science 280:734–737ADSPubMedCrossRefGoogle Scholar
  53. Eckhardt M, Barth H, Blöcker D, Aktories K (2000) Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid carbohydrates. J Biol Chem 275:2328–2334PubMedCrossRefGoogle Scholar
  54. Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J, Popoff MR, Schwan C, Aktories K, Kahlert V, Malesevic M 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
  55. Ernst K, Liebscher M, Mathea S, Granzhan A, Schmid J, Popoff MR, Ihmels H, Barth H, Schiene-Fischer C (2016) A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin. Sci Rep 6Google Scholar
  56. Falnes PO, Olsnes S (1995) Cell-mediated reduction and incomplete membrane translocation of diphtheria toxin mutants with internal disulfides in the A fragment. J Biol Chem 270:20787–20793PubMedCrossRefGoogle Scholar
  57. Falnes PO, Choe S, Madshus IH, Wilson BA, Olsnes S (1994) Inhibition of membrane translocation of diphtheria toxin A-fragment by internal disulfide bridges. J Biol Chem 269:8402–8407PubMedGoogle Scholar
  58. Finka A, Sharma SK, Goloubinoff P (2015) Multi-layered molecular mechanisms of polypeptide holding, unfolding and disaggregation by HSP70/HSP110 chaperones. Front. Mol, Biosci 2Google Scholar
  59. Friedlander AM (1986) Macrophages are sensitive to anthrax lethal toxin through an acid-dependent process. J Biol Chem 261:7123–7126PubMedGoogle Scholar
  60. Fruman DA, Burakoff SJ, Bierer BE (1994) Immunophilins in protein folding and immunosuppression. FASEB. J Off Publ Fed Am Soc Exp Biol 8:391–400Google Scholar
  61. Galat A (2003) Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity–targets–functions. Curr Top Med Chem 3:1315–1347PubMedCrossRefGoogle Scholar
  62. Galigniana MD, Radanyi C, Renoir J-M, Housley PR, Pratt WB (2001) Evidence that the peptidylprolyl isomerase domain of the hsp90-binding immunophilin FKBP52 is involved in both dynein interaction and glucocorticoid receptor movement to the nucleus. J Biol Chem 276:14884–14889PubMedCrossRefGoogle Scholar
  63. Galigniana MD, Harrell JM, Murphy PJM, Chinkers M, Radanyi C, Renoir J-M, Zhang M, Pratt WB (2002) Binding of hsp90-associated immunophilins to cytoplasmic dynein: direct binding and in vivo evidence that the peptidylprolyl isomerase domain is a dynein interaction domain†. Biochemistry (Mosc) 41:13602–13610CrossRefGoogle Scholar
  64. Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G (2010) The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol 30:1285–1298PubMedPubMedCentralCrossRefGoogle Scholar
  65. Geipel U, Just I, Schering B, Haas D, Aktories K (1989) ADP-ribosylation of actin causes increase in the rate of ATP exchange and inhibition of ATP hydrolysis. Eur J Biochem FEBS 179:229–232CrossRefGoogle Scholar
  66. Gibert M, Marvaud JC, Pereira Y, Hale ML, Stiles BG, Boquet P, Lamaze C, Popoff MR (2007) Differential requirement for the translocation of clostridial binary toxins: iota toxin requires a membrane potential gradient. FEBS Lett 581:1287–1296PubMedCrossRefGoogle Scholar
  67. Gill DM, Pappenheimer AM (1971) Structure-activity relationships in diphtheria toxin. J Biol Chem 246:1492–1495PubMedGoogle Scholar
  68. Göthel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci CMLS 55:423–436PubMedCrossRefGoogle Scholar
  69. Greenfield L, Bjorn MJ, Horn G, Fong D, Buck GA, Collier RJ, Kaplan DA (1983) Nucleotide sequence of the structural gene for diphtheria toxin carried by corynebacteriophage beta. Proc Natl Acad Sci USA 80:6853–6857ADSPubMedPubMedCentralCrossRefGoogle Scholar
  70. Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E et al (1997) The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 272:23843–23850PubMedCrossRefGoogle Scholar
  71. Gülke I, Pfeifer G, Liese J, Fritz M, Hofmann F, Aktories K, Barth H (2001) Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect Immun 69:6004–6011PubMedPubMedCentralCrossRefGoogle Scholar
  72. Hale ML, Marvaud J-C, 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
  73. Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW (1984) Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226:544–547ADSPubMedCrossRefGoogle Scholar
  74. Harding MW, Galat A, Uehling DE, Schreiber SL (1989) A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase. Nature 341:758–760ADSPubMedCrossRefGoogle Scholar
  75. Harris JB, LaRocque RC, Qadri F, Ryan ET, Calderwood SB (2012) Cholera. Lancet Lond Engl 379:2466–2476CrossRefGoogle Scholar
  76. Haug G, Wilde C, Leemhuis J, Meyer DK, Aktories K, Barth H (2003a) Cellular uptake of Clostridium botulinum C2 toxin: membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain. Biochemistry (Mosc) 42:15284–15291CrossRefGoogle Scholar
  77. Haug G, Leemhuis J, Tiemann D, Meyer DK, Aktories K, Barth H (2003b) The host cell chaperone Hsp90 is essential for translocation of the binary Clostridium botulinum C2 toxin into the cytosol. J Biol Chem 278:32266–32274PubMedCrossRefGoogle Scholar
  78. Haug G, Aktories K, Barth H (2004) The host cell chaperone Hsp90 is necessary for cytotoxic action of the binary iota-like toxins. Infect Immun 72:3066–3068PubMedPubMedCentralCrossRefGoogle Scholar
  79. Hazes B, Read RJ (1997) Accumulating evidence suggests that several AB-toxins subvert the endoplasmic reticulum-associated protein degradation pathway to enter target cells. Biochemistry (Mosc) 36:11051–11054CrossRefGoogle Scholar
  80. Hirst TR, Holmgren J (1987) Conformation of protein secreted across bacterial outer membranes: a study of enterotoxin translocation from Vibrio cholerae. Proc Natl Acad Sci USA 84:7418–7422ADSPubMedPubMedCentralCrossRefGoogle Scholar
  81. Hoffmann H, Schiene-Fischer C (2014) Functional aspects of extracellular cyclophilins. Biol Chem 395:721–735PubMedGoogle Scholar
  82. Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E (1994) Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J 13:2322–2330PubMedPubMedCentralGoogle Scholar
  83. Kaczorek M, Delpeyroux F, Chenciner N, Streeck RE, Murphy JR, Boquet P, Tiollais P (1983) Nucleotide sequence and expression of the diphtheria tox228 gene in Escherichia coli. Science 221:855–858ADSPubMedCrossRefGoogle Scholar
  84. Kagan BL, Finkelstein A, Colombini M (1981) Diphtheria toxin fragment forms large pores in phospholipid bilayer membranes. Proc Natl Acad Sci USA 78:4950–4954ADSPubMedPubMedCentralCrossRefGoogle Scholar
  85. Kahn RA, Gilman AG (1984) Purification of a protein cofactor required for ADP-ribosylation of the stimulatory regulatory component of adenylate cyclase by cholera toxin. J Biol Chem 259:6228–6234PubMedGoogle Scholar
  86. Kaiser E, Haug G, Hliscs M, Aktories K, Barth H (2006) Formation of a biologically active toxin complex of the binary Clostridium botulinum C2 toxin without cell membrane interaction. Biochemistry (Mosc) 45:13361–13368CrossRefGoogle Scholar
  87. Kaiser E, Pust S, Kroll C, Barth H (2009) Cyclophilin A facilitates translocation of the Clostridium botulinum C2 toxin across membranes of acidified endosomes into the cytosol of mammalian cells. Cell Microbiol 11:780–795PubMedCrossRefGoogle Scholar
  88. Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M, Fischer G, Buchner J, Aktories K, Barth H (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
  89. Kaiser E, Böhm N, Ernst K, Langer S, Schwan C, Aktories K, Popoff M, Fischer G, Barth H (2012) FK506-binding protein 51 interacts with Clostridium botulinum C2 toxin and FK506 inhibits membrane translocation of the toxin in mammalian cells. Cell Microbiol 14:1193–1205PubMedCrossRefGoogle Scholar
  90. Krantz BA, Trivedi AD, Cunningham K, Christensen KA, Collier RJ (2004) Acid-induced unfolding of the amino-terminal domains of the lethal and edema factors of anthrax toxin. J Mol Biol 344:739–756PubMedCrossRefGoogle Scholar
  91. Kurazono H, Hosokawa M, Matsuda H, Sakaguchi G (1987) Fluid accumulation in the ligated intestinal loop and histopathological changes of the intestinal mucosa caused by Clostridium botulinum C2 toxin in the pheasant and chicken. Res Vet Sci 42:349–353PubMedGoogle Scholar
  92. Laing S, Unger M, Koch-Nolte F, Haag F (2011) ADP-ribosylation of arginine. Amino Acids 41:257–269PubMedPubMedCentralCrossRefGoogle Scholar
  93. Lang AE, Schmidt G, Schlosser A, Hey TD, Larrinua IM, Sheets JJ, Mannherz HG, Aktories K (2010) Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering. Science 327:1139–1142ADSPubMedCrossRefGoogle Scholar
  94. Lang AE, Ernst K, Lee H, Papatheodorou P, Schwan C, Barth H, Aktories K (2014) The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP-ribosyltransferases. Cell Microbiol 16:490–503PubMedCrossRefGoogle Scholar
  95. Lemichez E, Bomsel M, Devilliers G, van der Spek J, Murphy JR, Lukianov EV, Olsnes S, Boquet P (1997) Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery. Mol Microbiol 23:445–457Google Scholar
  96. Leppla SH (1982) Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc Natl Acad Sci USA 79:3162–3166ADSPubMedPubMedCentralCrossRefGoogle Scholar
  97. Leppla SH (1991) Purification and characterization of adenylyl cyclase from Bacillus anthracis. Methods Enzymol 195:153–168PubMedCrossRefGoogle Scholar
  98. Lessa FC, Mu Y, Bamberg WM, Beldavs ZG, Dumyati GK, Dunn JR, Farley MM, Holzbauer SM, Meek JI, Phipps EC et al (2015) Burden of Clostridium difficile infection in the United States. N Engl J Med 372:825–834PubMedCrossRefGoogle Scholar
  99. Li J, Buchner J (2013) Structure, function and regulation of the hsp90 machinery. Biomed J 36:106–117PubMedCrossRefGoogle Scholar
  100. Li J, Soroka J, Buchner J (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta 1823:624–635PubMedCrossRefGoogle Scholar
  101. Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815PubMedCrossRefGoogle Scholar
  102. Love JF, Murphy JR (2006) Corynebacterium diphtheriae: iron-mediated activation of DtxR and regulation of diphtheria toxin expression. 726–737Google Scholar
  103. Madshus IH (1994) The N-terminal alpha-helix of fragment B of diphtheria toxin promotes translocation of fragment A into the cytoplasm of eukaryotic cells. J Biol Chem 269:17723–17729PubMedGoogle Scholar
  104. Majoul I, Ferrari D, Söling H-D (1997) Reduction of protein disulfide bonds in an oxidizing environment: The disulfide bridge of cholera toxin A-subunit is reduced in the endoplasmic reticulum. FEBS Lett 401:104–108PubMedCrossRefGoogle Scholar
  105. Malesevic M, Gutknecht D, Prell E, Klein C, Schumann M, Nowak RA, Simon JC, Schiene-Fischer C, Saalbach A (2013) Anti-inflammatory effects of extracellular cyclosporins are exclusively mediated by CD147. J Med Chem 56:7302–7311PubMedCrossRefGoogle Scholar
  106. Mamane Y, Sharma S, Petropoulos L, Lin R, Hiscott J (2000) Posttranslational regulation of IRF-4 activity by the immunophilin FKBP52. Immunity 12:129–140PubMedCrossRefGoogle Scholar
  107. Mandel R, Ryser HJ, Ghani F, Wu M, Peak D (1993) Inhibition of a reductive function of the plasma membrane by bacitracin and antibodies against protein disulfide-isomerase. Proc Natl Acad Sci USA 90:4112–4116ADSPubMedPubMedCentralCrossRefGoogle Scholar
  108. Massey S, Banerjee T, Pande AH, Taylor M, Tatulian SA, Teter K (2009) Stabilization of the tertiary structure of the cholera toxin A1 subunit inhibits toxin dislocation and cellular intoxication. J Mol Biol 393:1083–1096PubMedPubMedCentralCrossRefGoogle Scholar
  109. Miller CJ, Elliott JL, Collier RJ (1999) Anthrax protective antigen: prepore-to-pore conversion. Biochemistry (Mosc) 38:10432–10441CrossRefGoogle Scholar
  110. Mitamura T, Iwamoto R, Umata T, Yomo T, Urabe I, Tsuneoka M, Mekada E (1992) The 27-kD diphtheria toxin receptor-associated protein (DRAP27) from vero cells is the monkey homologue of human CD9 antigen: expression of DRAP27 elevates the number of diphtheria toxin receptors on toxin-sensitive cells. J Cell Biol 118:1389–1399PubMedCrossRefGoogle Scholar
  111. Moskaug JO, Sandvig K, Olsnes S (1987) Cell-mediated reduction of the interfragment disulfide in nicked diphtheria toxin. A new system to study toxin entry at low pH. J Biol Chem 262:10339–10345PubMedGoogle Scholar
  112. Moya M, Dautry-Varsat A, Goud B, Louvard D, Boquet P (1985) Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not that of ricin toxin. J Cell Biol 101:548–559PubMedCrossRefGoogle Scholar
  113. 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
  114. Nagahama M, Hagiyama T, Kojima T, Aoyanagi K, Takahashi C, Oda M, Sakaguchi Y, Oguma K, Sakurai J (2009) Binding and internalization of Clostridium botulinum C2 toxin. Infect Immun 77:5139–5148PubMedPubMedCentralCrossRefGoogle Scholar
  115. Naglich JG, Metherall JE, Russell DW, Eidels L (1992) Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69:1051–1061PubMedCrossRefGoogle Scholar
  116. Nakatsukasa K, Brodsky JL (2008) The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic Cph Den 9:861–870CrossRefGoogle Scholar
  117. Nigro P, Pompilio G, Capogrossi MC (2013) Cyclophilin A: a key player for human disease. Cell Death Dis 4:e888PubMedPubMedCentralCrossRefGoogle Scholar
  118. O’Neal CJ, Jobling MG, Holmes RK, Hol WGJ (2005) Structural basis for the activation of cholera toxin by human ARF6-GTP. Science 309:1093–1096ADSPubMedCrossRefGoogle Scholar
  119. Ohishi I (1983a) Lethal and vascular permeability activities of botulinum C2 toxin induced by separate injections of the two toxin components. Infect Immun 40:336–339PubMedPubMedCentralGoogle Scholar
  120. Ohishi I (1983b) Response of mouse intestinal loop to botulinum C2 toxin: enterotoxic activity induced by cooperation of nonlinked protein components. Infect Immun 40:691–695PubMedPubMedCentralGoogle Scholar
  121. Ohishi I, Iwasaki M, Sakaguchi G (1980) Purification and characterization of two components of botulinum C2 toxin. Infect Immun 30:668–673PubMedPubMedCentralGoogle Scholar
  122. Ohishi I, Miyake M, Ogura H, Nakamura S (1984) Cytopathic effect of botulinum C2 toxin on tissue-culture cells. FEMS Microbiol Lett 23:281–284CrossRefGoogle Scholar
  123. Orlandi PA (1997) Protein-disulfide isomerase-mediated reduction of the A subunit of cholera toxin in a human intestinal cell line. J Biol Chem 272:4591–4599PubMedGoogle Scholar
  124. Orlowski M, Wilk S (2003) Ubiquitin-independent proteolytic functions of the proteasome. Arch Biochem Biophys 415:1–5PubMedCrossRefGoogle Scholar
  125. Owens-Grillo JK, Hoffmann K, Hutchison KA, Yem AW, Deibel MR, Handschumacher RE, Pratt WB (1995) The cyclosporin A-binding immunophilin CyP-40 and the FK506-binding immunophilin hsp56 bind to a common site on hsp90 and exist in independent cytosolic heterocomplexes with the untransformed glucocorticoid receptor. J Biol Chem 270:20479–20484PubMedCrossRefGoogle Scholar
  126. Pande AH, Scaglione P, Taylor M, Nemec KN, Tuthill S, Moe D, Holmes RK, Tatulian SA, Teter K (2007) Conformational instability of the cholera toxin A1 polypeptide. J Mol Biol 374:1114–1128PubMedPubMedCentralCrossRefGoogle Scholar
  127. 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 USA 108:16422–16427ADSPubMedPubMedCentralCrossRefGoogle Scholar
  128. Papatheodorou P, Hornuss D, Nölke 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:e00244–00213Google Scholar
  129. Papini E, Cabrini G, Montecucco C (1993a) The sensitivity of cystic fibrosis cells to diphtheria toxin. Toxicon Off J Int Soc Toxinol 31:359–362CrossRefGoogle Scholar
  130. Papini E, Rappuoli R, Murgia M, Montecucco C (1993b) Cell penetration of diphtheria toxin. Reduction of the interchain disulfide bridge is the rate-limiting step of translocation in the cytosol. J Biol Chem 268:1567–1574PubMedGoogle Scholar
  131. Pappenheimer AM (1977) Diphtheria toxin. Annu Rev Biochem 46:69–94PubMedCrossRefGoogle Scholar
  132. 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
  133. Popoff MR, Rubin EJ, Gill DM, Boquet P (1988) Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect Immun 56:2299–2306PubMedPubMedCentralGoogle Scholar
  134. Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18:306–360PubMedGoogle Scholar
  135. Pratt WB, Toft DO (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med Maywood NJ 228:111–133CrossRefGoogle Scholar
  136. Prell E, Kahlert V, Rücknagel KP, Malešević M, Fischer G (2013) Fine tuning the inhibition profile of cyclosporine A by derivatization of the MeBmt residue. Chem Bio Chem 14:63–65PubMedCrossRefGoogle Scholar
  137. Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90:65–75PubMedCrossRefGoogle Scholar
  138. Prodromou C, Siligardi G, O’Brien R, Woolfson DN, Regan L, Panaretou B, Ladbury JE, Piper PW, Pearl LH (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO J 18:754–762PubMedPubMedCentralCrossRefGoogle Scholar
  139. Pust S, Hochmann H, Kaiser E, von Figura G, Heine K, Aktories K, Barth H (2007) A cell-permeable fusion toxin as a tool to study the consequences of actin-ADP-ribosylation caused by the salmonella enterica virulence factor SpvB in intact cells. J Biol Chem 282:10272–10282PubMedCrossRefGoogle Scholar
  140. Pust S, Barth H, Sandvig K (2010) Clostridium botulinum C2 toxin is internalized by clathrin- and Rho-dependent mechanisms. Cell Microbiol 12:1809–1820PubMedCrossRefGoogle Scholar
  141. Ratajczak T, Carrello A (1996) Cyclophilin 40 (CyP-40), mapping of its hsp90 binding domain and evidence that FKBP52 competes with CyP-40 for hsp90 binding. J Biol Chem 271:2961–2965PubMedCrossRefGoogle Scholar
  142. Ratts R, van der Spek J (2002) DT: structure, function and its clinical applications. In: Lorberboum-Galski H, Lazarovici P (eds) Chimeric toxins. Taylor and Francis, London, pp 14–36Google Scholar
  143. Ratts R, Zeng H, Berg EA, Blue C, McComb ME, Costello CE, van der Spek JC, Murphy JR (2003) The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J Cell Biol 160:1139–1150PubMedPubMedCentralCrossRefGoogle Scholar
  144. Ratts R, Trujillo C, Bharti A, van der Spek J, Harrison R, Murphy JR (2005) A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol. Proc Natl Acad Sci USA 102:15635–15640Google Scholar
  145. Ray S, Taylor M, Banerjee T, Tatulian SA, Teter K (2012) Lipid rafts alter the stability and activity of the cholera toxin A1 subunit. J Biol Chem 287:30395–30405PubMedPubMedCentralCrossRefGoogle Scholar
  146. Riggs DL, Roberts PJ, Chirillo SC, Cheung-Flynn J, Prapapanich V, Ratajczak T, Gaber R, Picard D, Smith DF (2003) The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J 22:1158–1167PubMedPubMedCentralCrossRefGoogle Scholar
  147. Rodighiero C, Tsai B, Rapoport TA, Lencer WI (2002) Role of ubiquitination in retro-translocation of cholera toxin and escape of cytosolic degradation. EMBO Rep 3:1222–1227PubMedPubMedCentralCrossRefGoogle Scholar
  148. Roe SM, Prodromou C, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42:260–266PubMedCrossRefGoogle Scholar
  149. Roux E, Yersin A (1888) Contribution a l’etude de la diphtheria. Ann Inst Pasteur 629–661Google Scholar
  150. Sack DA, Sack RB, Nair GB, Siddique AK (2004) Cholera. Lancet Lond Engl 363:223–233CrossRefGoogle Scholar
  151. Sakurai J, Nagahama M, Hisatsune J, Katunuma N, Tsuge H (2003) Clostridium perfringens iota-toxin, ADP-ribosyltransferase: structure and mechanism of action. Adv Enzyme Regul 43:361–377PubMedCrossRefGoogle Scholar
  152. Sánchez J, Holmgren J (2008) Cholera toxin structure, gene regulation and pathophysiological and immunological aspects. Cell Mol Life Sci CMLS 65:1347–1360PubMedCrossRefGoogle Scholar
  153. 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 FEBS 171:225–229CrossRefGoogle Scholar
  154. Schiene-Fischer C (2014) Multidomain peptidyl prolyl cis/trans Isomerases. Biochim Biophys, ActaGoogle Scholar
  155. 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
  156. Schnell L, Dmochewitz-Kück L, Feigl P, Montecucco C, Barth H (2015) Thioredoxin reductase inhibitor auranofin prevents membrane transport of diphtheria toxin into the cytosol and protects human cells from intoxication. Toxicon Off J Int Soc, ToxinologyGoogle Scholar
  157. Schreiber SL, Liu J, Albers MW, Karmacharya R, Koh E, Martin PK, Rosen MK, Standaert RF, Wandless TJ (1991) Immunophilin-ligand complexes as probes of intracellular signaling pathways. Transplant Proc 23:2839–2844PubMedGoogle Scholar
  158. Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt W-D, Wehland J, Aktories K (2009) Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog 5:e1000626PubMedPubMedCentralCrossRefGoogle Scholar
  159. Schwan C, Nölke T, Kruppke AS, Schubert DM, Lang AE, Aktories K (2011) Cholesterol- and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase (CDT). J Biol Chem 286:29356–29365PubMedPubMedCentralCrossRefGoogle Scholar
  160. Simpson LL (1982) A comparison of the pharmacological properties of Clostridium botulinum type C1 and C2 toxins. J Pharmacol Exp Ther 223:695–701PubMedGoogle Scholar
  161. Smith WP, Tai PC, Murphy JR, Davis BD (1980) Precursor in cotranslational secretion of diphtheria toxin. J Bacteriol 141:184–189PubMedPubMedCentralGoogle Scholar
  162. Songer JG (1996) Clostridial enteric diseases of domestic animals. Clin Microbiol Rev 9:216–234PubMedPubMedCentralGoogle Scholar
  163. Stiles BG, Wilkins TD (1986) Purification and characterization of Clostridium perfringens iota toxin: dependence on two nonlinked proteins for biological activity. Infect Immun 54:683–688PubMedPubMedCentralGoogle Scholar
  164. Stiles BG, Wigelsworth DJ, Popoff MR, Barth H (2011) Clostridial binary toxins: iota and C2 family portraits. Front Cell Infect, Microbiol 1Google Scholar
  165. Tamayo AG, Bharti A, Trujillo C, Harrison R, Murphy JR (2008) COPI coatomer complex proteins facilitate the translocation of anthrax lethal factor across vesicular membranes in vitro. Proc Natl Acad Sci USA 105:5254–5259ADSPubMedPubMedCentralCrossRefGoogle Scholar
  166. Taylor M, Navarro-Garcia F, Huerta J, Burress H, Massey S, Ireton K, Teter K (2010) Hsp90 is required for transfer of the cholera toxin A1 subunit from the endoplasmic reticulum to the cytosol. J Biol Chem 285:31261–31267PubMedPubMedCentralCrossRefGoogle Scholar
  167. Taylor M, Banerjee T, Ray S, Tatulian SA, Teter K (2011a) Protein-disulfide isomerase displaces the cholera toxin A1 subunit from the holotoxin without unfolding the A1 subunit. J Biol Chem 286:22090–22100PubMedPubMedCentralCrossRefGoogle Scholar
  168. Taylor M, Banerjee T, Navarro-Garcia F, Huerta J, Massey S, Burlingame M, Pande AH, Tatulian SA, Teter K (2011b) A therapeutic chemical chaperone inhibits cholera intoxication and unfolding/translocation of the cholera toxin A1 subunit. PLoS ONE 6:e18825ADSPubMedPubMedCentralCrossRefGoogle Scholar
  169. Taylor M, Burress H, Banerjee T, Ray S, Curtis D, Tatulian SA, Teter K (2014) Substrate-induced unfolding of protein disulfide isomerase displaces the cholera toxin A1 subunit from its holotoxin. PLoS Pathog 10:e1003925PubMedPubMedCentralCrossRefGoogle Scholar
  170. Teter K, Holmes RK (2002) Inhibition of endoplasmic reticulum-associated degradation in CHO cells resistant to cholera toxin, Pseudomonas aeruginosa exotoxin A, and ricin. Infect Immun 70:6172–6179PubMedPubMedCentralCrossRefGoogle Scholar
  171. Teter K, Jobling MG, Holmes RK (2003) A class of mutant CHO cells resistant to cholera toxin rapidly degrades the catalytic polypeptide of cholera toxin and exhibits increased endoplasmic reticulum-associated degradation. Traffic Cph Den 4:232–242CrossRefGoogle Scholar
  172. Tonello F, Montecucco C (2009) The anthrax lethal factor and its MAPK kinase-specific metalloprotease activity. Mol Aspects Med 30:431–438PubMedCrossRefGoogle Scholar
  173. Tsai B, Rodighiero C, Lencer WI, Rapoport TA (2001) Protein disulfide isomerase acts as a redox-dependent chaperone to unfold cholera toxin. Cell 104:937–948PubMedCrossRefGoogle Scholar
  174. Tsuge H, Nagahama M, Oda M, Iwamoto S, Utsunomiya H, Marquez VE, Katunuma N, Nishizawa M, Sakurai J (2008) Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin. Proc Natl Acad Sci USA 105:7399–7404ADSPubMedPubMedCentralCrossRefGoogle Scholar
  175. Tsuneoka M, Nakayama K, Hatsuzawa K, Komada M, Kitamura N, Mekada E (1993) Evidence for involvement of furin in cleavage and activation of diphtheria toxin. J Biol Chem 268:26461–26465PubMedGoogle Scholar
  176. Uchida T, Gill DM, Pappenheimer AM (1971) Mutation in the structural gene for diphtheria toxin carried by temperate phage. Nat New Biol 233:8–11PubMedCrossRefGoogle Scholar
  177. Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C (1998) Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun 248:706–711PubMedCrossRefGoogle Scholar
  178. Waters CA, Schimke PA, Snider CE, Itoh K, Smith KA, Nichols JC, Strom TB, Murphy JR (1990) Interleukin 2 receptor-targeted cytotoxicity. Receptor binding requirements for entry of a diphtheria toxin-related interleukin 2 fusion protein into cells. Eur J Immunol 20:785–791PubMedCrossRefGoogle Scholar
  179. Wegner A, Aktories K (1988) ADP-ribosylated actin caps the barbed ends of actin filaments. J Biol Chem 263:13739–13742PubMedGoogle Scholar
  180. Welsh CF, Moss J, Vaughan M (1994) ADP-ribosylation factors: a family of ∼20-kDa guanine nucleotide-binding proteins that activate cholera toxin. Mol Cell Biochem 138:157–166PubMedCrossRefGoogle Scholar
  181. Wernick NLB, Chinnapen DJ-F, Cho JA, Lencer WI (2010) Cholera toxin: an intracellular journey into the cytosol by way of the endoplasmic reticulum. Toxins 2:310–325PubMedPubMedCentralCrossRefGoogle Scholar
  182. Wesche J, Elliott JL, Falnes PO, Olsnes S, Collier RJ (1998) Characterization of membrane translocation by anthrax protective antigen. Biochemistry (Mosc) 37:15737–15746CrossRefGoogle Scholar
  183. WHO position paper (2006) Diphtheria vaccine: WHO position paper. Wkly Epidemiol Rec 24–31Google Scholar
  184. WHO position paper (2010) Cholera vaccines: WHO position paper. Wkly Epidemiol Rec 117–128Google Scholar
  185. Wigelsworth DJ, Ruthel G, Schnell L, Herrlich P, Blonder J, Veenstra TD, Carman RJ, Wilkins TD, Van Nhieu GT, Pauillac S et al (2012) CD44 promotes intoxication by the clostridial iota-family Toxins. PLoS ONE 7Google Scholar
  186. Wochnik GM, Rüegg J, Abel GA, Schmidt U, Holsboer F, Rein T (2005) FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem 280:4609–4616PubMedCrossRefGoogle Scholar
  187. Young JAT, Collier RJ (2007) Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem 76:243–265PubMedCrossRefGoogle Scholar
  188. Zhang RG, Scott DL, Westbrook ML, Nance S, Spangler BD, Shipley GG, Westbrook EM (1995) The three-dimensional crystal structure of cholera toxin. J Mol Biol 251:563–573PubMedCrossRefGoogle Scholar
  189. Zornetta I, Brandi L, Janowiak B, Dal Molin F, Tonello F, Collier RJ, Montecucco C (2010) Imaging the cell entry of the anthrax oedema and lethal toxins with fluorescent protein chimeras. Cell Microbiol 12:1435–1445PubMedCrossRefGoogle Scholar

Cross References

  1. Stiles BG, Clostridial binary toxins: basic understandings that include cell-surface binding and an internal “coup de grace”Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Institute of Pharmacology and ToxicologyUniversity of Ulm Medical CenterUlmGermany

Personalised recommendations