Skip to main content
SpringerLink
Log in
Book cover

Microbial Toxins pp 1–22Cite as

Chaperones and ADP-Ribosylating Bacterial Toxins

  • Living reference work entry
  • First Online:

Part of the book series: Toxinology ((TOXI))

Abstract

Clostridial binary actin ADP-ribosylating toxins are protein toxins, which consist of an enzymatic active (A-) subunit and a separate binding/transport (B-) subunit. The A- and B-components are secreted by the clostridia as two individual, nontoxic proteins, which assemble on the surface of mammalian target cells to form biologically active AB7 toxin complexes. The heptameric barrel-shaped B-components mediate the transport of the A-components into the host cell cytosol, where the A-components mono-ADP-ribosylate G-actin which results in depolymerization of actin filaments and cell rounding. When the cellular uptake of these toxins was investigated in more detail, it became evident that cell-bound B-components bind their A-components and mediate the receptor-mediated endocytosis of the AB7 toxin complexes. After internalization, the B-components have another crucial function for the transport of the A-components into the cytosol: They form transmembrane pores in the membranes of acidified endosomes and serve as channels for the transport of the A-components across endosomal membranes. The A-components unfold during this transport step and require the assistance of host cell chaperones and protein-folding helper enzymes of the family of peptidyl-prolyl cis/trans isomerases (PPIases) for their translocation and/or refolding. In this review article, the current model of the cellular uptake of binary actin ADP-ribosylating toxins from Clostridium (C.) botulinum, C. perfringens, and C. difficile; their interaction with host cell chaperones/PPIases during intracellular membrane transport of their A-components; and the role of host cell chaperones as drug targets for development of novel pharmacological strategies against diseases associated with these medically relevant toxins are summarized.

This is a preview of subscription content, log in via an institution.

References

  • Aktories K, Wegner A. Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. Mol Microbiol. 1992;6:2905–8.

    Article  CAS  PubMed  Google Scholar 

  • Aktories K, Bärmann M, Ohishi I, Tsuyama S, Jakobs KH, Habermann E. Botulinum C2 toxin ADP-ribosylates actin. Nature. 1986;322:390–2.

    Article  CAS  PubMed  Google Scholar 

  • Aktories K, Lang AE, Schwan C, Mannherz HG. Actin as target for modification by bacterial protein toxins. FEBS J. 2011;278:4526–43.

    Article  CAS  PubMed  Google Scholar 

  • Barth H. 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. 2011;383:237–45.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Aktories K. 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. 2011;90:944–50.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Stiles BG. Binary actin-ADP-ribosylating toxins and their use as molecular Trojan horses for drug delivery into eukaryotic cells. Curr Med Chem. 2008;15:459–69.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Hofmann F, Olenik C, Just I, Aktories K. 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. 1998a;66:1364–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barth H, Preiss JC, Hofmann F, Aktories K. Characterization of the catalytic site of the ADP-ribosyltransferase Clostridium botulinum C2 toxin by site-directed mutagenesis. J Biol Chem. 1998b;273:29506–11.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Blocker D, Behlke J, Bergsma-Schutter W, Brisson A, Benz R, Aktories K. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J Biol Chem. 2000;275:18704–11.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Roebling R, Fritz M, Aktories K. 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. 2002;277:5074–81.

    Article  CAS  PubMed  Google Scholar 

  • Barth H, Aktories K, Popoff MR, Stiles BG. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol Mol Biol Rev. 2004;68:373–402, table of contents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Billington SJ, Wieckowski EU, Sarker MR, Bueschel D, Songer JG, McClane BA. Clostridium perfringens Type E animal enteritis isolates with highly conserved, silent enterotoxin gene sequences. Infect Immun. 1998;66:4531–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Blöcker D, Barth H, Maier E, Benz R, Barbieri JT, Aktories K. The C terminus of component C2II of Clostridium botulinum C2 toxin is essential for receptor binding. Infect Immun. 2000;68:4566–73.

    Article  PubMed  PubMed Central  Google Scholar 

  • Blöcker D, Behlke J, Aktories K, Barth H. Cellular uptake of the Clostridium perfringens binary iota-toxin. Infect Immun. 2001;69:2980–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blöcker D, Pohlmann K, Haug G, Bachmeyer C, Benz R, Aktories K, Barth H. Clostridium botulinum C2 toxin: low pH-induced pore formation is required for translocation of the enzyme component C2I into the cytosol of host cells. J Biol Chem. 2003;278:37360–7.

    Article  PubMed  CAS  Google Scholar 

  • Blonder J, Hale ML, Chan KC, Yu L-R, Lucas DA, Conrads TP, Zhou M, Popoff MR, Issaq HJ, Stiles BG, et al. Quantitative profiling of the detergent-resistant membrane proteome of iota-b toxin induced vero cells. J Proteome Res. 2005;4:523–31.

    Article  CAS  PubMed  Google Scholar 

  • Borel JF, Feurer C, Gubler HU, Stähelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976;6:468–75.

    Article  CAS  PubMed  Google Scholar 

  • Bronnhuber A, Maier E, Riedl Z, Hajós G, Benz R, Barth H. Inhibitions of the translocation pore of Clostridium botulinum C2 toxin by tailored azolopyridinium salts protects human cells from intoxication. Toxicology. 2014;316:25–33.

    Article  CAS  PubMed  Google Scholar 

  • Carroll KC, Bartlett JG. Biology of Clostridium difficile: implications for epidemiology and diagnosis. Annu Rev Microbiol. 2011;65:501–21.

    Article  CAS  PubMed  Google Scholar 

  • Carroll SF, Collier RJ. NAD binding site of diphtheria toxin: identification of a residue within the nicotinamide subsite by photochemical modification with NAD. Proc Natl Acad Sci U S A. 1984;81:3307–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF. Physiological role for the cochaperone FKBP52 in androgen receptor signaling. Mol Endocrinol. 2005;19:1654–66.

    Article  CAS  PubMed  Google Scholar 

  • Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992;357:695–7.

    Article  CAS  PubMed  Google Scholar 

  • Collier RJ. Three-dimensional structure of diphtheria toxin. In: Moss J, Iglewski B, Vaughan M, Tu A, editors. Bacterial toxins and virulence factors in disease. New York: Marcel Dekker; 1995.

    Google Scholar 

  • Collier RJ. Membrane translocation by anthrax toxin. Mol Aspects Med. 2009;30:413–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daum S, Schumann M, Mathea S, Aumüller T, Balsley MA, Constant SL, de Lacroix BF, Kruska F, Braun M, Schiene-Fischer C. Isoform-specific inhibition of cyclophilins. Biochemistry (Mosc). 2009;48:6268–77.

    Article  CAS  Google Scholar 

  • Denny WB, Valentine DL, Reynolds PD, Smith DF, Scammell JG. Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding. Endocrinology. 2000;141:4107–13.

    CAS  PubMed  Google Scholar 

  • Dmochewitz L, Lillich M, Kaiser E, Jennings LD, Lang AE, Buchner J, Fischer G, Aktories K, Collier RJ, Barth H. Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. Cell Microbiol. 2011;13:359–73.

    Article  CAS  PubMed  Google Scholar 

  • Eckhardt M, Barth H, Blöcker D, Aktories K. Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid carbohydrates. J Biol Chem. 2000;275:2328–34.

    Article  CAS  PubMed  Google Scholar 

  • Elliott JF, Lin Y, Mizel SB, Bleackley RC, Harnish DG, Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984;226:1439–41.

    Article  CAS  PubMed  Google Scholar 

  • Ernst K, Langer S, Kaiser E, Osseforth C, Michaelis J, Popoff MR, Schwan C, Aktories K, Kahlert V, Malesevic M, et al. Cyclophilin-facilitated membrane translocation as pharmacological target to prevent intoxication of mammalian cells by binary clostridial actin ADP-ribosylated toxins. J Mol Biol. 2015;427:1224–38.

    Article  CAS  PubMed  Google Scholar 

  • Fischer G, Aumüller T. Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes. Rev Physiol Biochem Pharmacol. 2003;148:105–50.

    CAS  PubMed  Google Scholar 

  • Fischer G, Bang H, Mech C. Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides. Biomed Biochim Acta. 1984;43:1101–11.

    CAS  PubMed  Google Scholar 

  • Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature. 1989;337:476–8.

    Article  CAS  PubMed  Google Scholar 

  • Fischer G, Gallay P, Hopkins S. Cyclophilin inhibitors for the treatment of HCV infection. Curr Opin Investig Drugs. 2010;2000(11):911–8.

    Google Scholar 

  • Fritz G, Schroeder P, Aktories K. Isolation and characterization of a Clostridium botulinum C2 toxin-resistant cell line: evidence for possible involvement of the cellular C2II receptor in growth regulation. Infect Immun. 1995;63:2334–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fruman DA, Burakoff SJ, Bierer BE. Immunophilins in protein folding and immunosuppression. FASEB J. 1994;8:391–400.

    CAS  PubMed  Google Scholar 

  • Galat A. Peptidylprolyl cis/trans isomerases (immunophilins): biological diversity – targets – functions. Curr Top Med Chem. 2003;3:1315–47.

    Article  CAS  PubMed  Google Scholar 

  • Galigniana MD, Radanyi C, Renoir J-M, Housley PR, Pratt WB. 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. 2001;276:14884–9.

    Article  CAS  PubMed  Google Scholar 

  • Galigniana MD, Harrell JM, Murphy PJM, Chinkers M, Radanyi C, Renoir J-M, Zhang M, Pratt WB. 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). 2002;41:13602–10.

    Article  CAS  Google Scholar 

  • Galigniana MD, Erlejman AG, Monte M, Gomez-Sanchez C, Piwien-Pilipuk G. The hsp90-FKBP52 complex links the mineralocorticoid receptor to motor proteins and persists bound to the receptor in early nuclear events. Mol Cell Biol. 2010;30:1285–98.

    Article  CAS  PubMed  Google Scholar 

  • Gatsogiannis C, Lang AE, Meusch D, Pfaumann V, Hofnagel O, Benz R, Aktories K, Raunser S. A syringe-like injection mechanism in Photorhabdus luminescens toxins. Nature. 2013;495:520–3.

    Article  CAS  PubMed  Google Scholar 

  • Geipel U, Just I, Schering B, Haas D, Aktories K. ADP-ribosylation of actin causes increase in the rate of ATP exchange and inhibition of ATP hydrolysis. Eur J Biochem. 1989;179:229–32.

    Article  CAS  PubMed  Google Scholar 

  • Gibert M, Petit L, Raffestin S, Okabe A, Popoff MR. Clostridium perfringens iota-toxin requires activation of both binding and enzymatic components for cytopathic activity. Infect Immun. 2000;68:3848–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gibert M, Marvaud JC, Pereira Y, Hale ML, Stiles BG, Boquet P, Lamaze C, Popoff MR. Differential requirement for the translocation of clostridial binary toxins: iota toxin requires a membrane potential gradient. FEBS Lett. 2007;581:1287–96.

    Article  CAS  PubMed  Google Scholar 

  • Gibert M, Monier M-N, Ruez R, Hale ML, Stiles BG, Benmerah A, Johannes L, Lamaze C, Popoff MR. Endocytosis and toxicity of clostridial binary toxins depend on a clathrin-independent pathway regulated by Rho-GDI. Cell Microbiol. 2011;13:154–70.

    Article  CAS  PubMed  Google Scholar 

  • Göthel SF, Marahiel MA. Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci. 1999;55:423–36.

    Article  PubMed  Google Scholar 

  • Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, et al. 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. 1997;272:23843–50.

    Article  CAS  PubMed  Google Scholar 

  • Gülke I, Pfeifer G, Liese J, Fritz M, Hofmann F, Aktories K, Barth H. Characterization of the enzymatic component of the ADP-ribosyltransferase toxin CDTa from Clostridium difficile. Infect Immun. 2001;69:6004–11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hale ML, Marvaud J-C, Popoff MR, Stiles BG. Detergent-resistant membrane microdomains facilitate Ib oligomer formation and biological activity of Clostridium perfringens iota-toxin. Infect Immun. 2004;72:2186–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han S, Craig JA, Putnam CD, Carozzi NB, Tainer JA. Evolution and mechanism from structures of an ADP-ribosylating toxin and NAD complex. Nat Struct Mol Biol. 1999;6:932–6.

    Article  CAS  Google Scholar 

  • Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984;226:544–7.

    Article  CAS  PubMed  Google Scholar 

  • Harding MW, Galat A, Uehling DE, Schreiber SL. A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase. Nature. 1989;341:758–60.

    Article  CAS  PubMed  Google Scholar 

  • Haug G, Leemhuis J, Tiemann D, Meyer DK, Aktories K, Barth H. The host cell chaperone Hsp90 is essential for translocation of the binary Clostridium botulinum C2 toxin into the cytosol. J Biol Chem. 2003a;278:32266–74.

    Article  CAS  PubMed  Google Scholar 

  • Haug G, Wilde C, Leemhuis J, Meyer DK, Aktories K, Barth H. Cellular uptake of Clostridium botulinum C2 toxin: membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain. Biochemistry (Mosc). 2003b;42:15284–91.

    Article  CAS  Google Scholar 

  • Haug G, Aktories K, Barth H. The host cell chaperone Hsp90 is necessary for cytotoxic action of the binary iota-like toxins. Infect Immun. 2004;72:3066–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffmann H, Schiene-Fischer C. Functional aspects of extracellular cyclophilins. Biol Chem. 2014;395:721–35.

    CAS  PubMed  Google Scholar 

  • Kaiser E, Haug G, Hliscs M, Aktories K, Barth H. Formation of a biologically active toxin complex of the binary Clostridium botulinum C2 toxin without cell membrane interaction. Biochemistry (Mosc). 2006;45:13361–8.

    Article  CAS  Google Scholar 

  • Kaiser E, Pust S, Kroll C, Barth H. Cyclophilin A facilitates translocation of the Clostridium botulinum C2 toxin across membranes of acidified endosomes into the cytosol of mammalian cells. Cell Microbiol. 2009;11:780–95.

    Article  CAS  PubMed  Google Scholar 

  • Kaiser E, Kroll C, Ernst K, Schwan C, Popoff M, Fischer G, Buchner J, Aktories K, Barth H. Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by cyclophilin A and Hsp90. Infect Immun. 2011;79:3913–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaiser E, Böhm N, Ernst K, Langer S, Schwan C, Aktories K, Popoff M, Fischer G, Barth H. FK506-binding protein 51 interacts with Clostridium botulinum C2 toxin and FK506 inhibits membrane translocation of the toxin in mammalian cells. Cell Microbiol. 2012;14:1193–205.

    Article  CAS  PubMed  Google Scholar 

  • Knapp O, Maier E, Waltenberger E, Mazuet C, Benz R, Popoff MR. Residues involved in the pore-forming activity of the Clostridium perfringens iota toxin. Cell Microbiol. 2015;17:288–302.

    Article  CAS  PubMed  Google Scholar 

  • Krönke M, Leonard WJ, Depper JM, Arya SK, Wong-Staal F, Gallo RC, Waldmann TA, Greene WC. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984;81:5214–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kurazono H, Hosokawa M, Matsuda H, Sakaguchi G. 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. 1987;42:349–53.

    CAS  PubMed  Google Scholar 

  • Lang K, Schmid FX, Fischer G. Catalysis of protein folding by prolyl isomerase. Nature. 1987;329:268–70.

    Article  CAS  PubMed  Google Scholar 

  • Lang AE, Schmidt G, Schlosser A, Hey TD, Larrinua IM, Sheets JJ, Mannherz HG, Aktories K. Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering. Science. 2010;327:1139–42.

    Article  CAS  PubMed  Google Scholar 

  • Lang AE, Ernst K, Lee H, Papatheodorou P, Schwan C, Barth H, Aktories K. The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP-ribosyltransferases. Cell Microbiol. 2014;16:490–503.

    Article  CAS  PubMed  Google Scholar 

  • Lemichez E, Bomsel M, Devilliers G, vander Spek J, Murphy JR, Lukianov EV, Olsnes S, Boquet P. Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery. Mol Microbiol. 1997;23:445–57.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Buchner J. Structure, function and regulation of the hsp90 machinery. Biomed J. 2013;36:106–17.

    Article  PubMed  Google Scholar 

  • Li J, Soroka J, Buchner J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta. 2012;1823:624–35.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–15.

    Article  CAS  PubMed  Google Scholar 

  • Malesevic M, Gutknecht D, Prell E, Klein C, Schumann M, Nowak RA, Simon JC, Schiene-Fischer C, Saalbach A. Anti-inflammatory effects of extracellular cyclosporins are exclusively mediated by CD147. J Med Chem. 2013;56:7302–11.

    Article  CAS  PubMed  Google Scholar 

  • Mamane Y, Sharma S, Petropoulos L, Lin R, Hiscott J. Posttranslational regulation of IRF-4 activity by the immunophilin FKBP52. Immunity. 2000;12:129–40.

    Article  CAS  PubMed  Google Scholar 

  • Masignani V, Pizza M, Rappuoli R. Common features of ADP-ribosyltransferases. In: Aktories PDK, Just DI, editors. Bacterial protein toxins. Berlin/Heidelberg: Springer; 2000. p. 21–44.

    Chapter  Google Scholar 

  • Masignani V, Pizza M, Rappuoli R. Molecular, functional and evolutionary aspects of ADP-ribosylating toxins. In: Ladant D, Alouf JE, Popoff MR, editors. The comprehensive sourcebook of bacterial protein toxins. Paris: Academic Press; 2006 (3rd ed.):213–244.

    Google Scholar 

  • Meusch D, Gatsogiannis C, Efremov RG, Lang AE, Hofnagel O, Vetter IR, Aktories K, Raunser S. Mechanism of Tc toxin action revealed in molecular detail. Nature. 2014;508:61–5.

    Article  CAS  PubMed  Google Scholar 

  • Murphy JR. Mechanism of diphtheria toxin catalytic domain delivery to the eukaryotic cell cytosol and the cellular factors that directly participate in the process. Toxins. 2011;3:294–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagahama M, Nagayasu K, Kobayashi K, Sakurai J. Binding component of Clostridium perfringens iota-toxin induces endocytosis in Vero cells. Infect Immun. 2002;70:1909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagahama M, Yamaguchi A, Hagiyama T, Ohkubo N, Kobayashi K, Sakurai J. Binding and internalization of Clostridium perfringens iota-toxin in lipid rafts. Infect Immun. 2004;72:3267–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagahama M, Hagiyama T, Kojima T, Aoyanagi K, Takahashi C, Oda M, Sakaguchi Y, Oguma K, Sakurai J. Binding and internalization of Clostridium botulinum C2 toxin. Infect Immun. 2009;77:5139–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagahama M, Takahashi C, Aoyanagi K, Tashiro R, Kobayashi K, Sakaguchi Y, Ishidoh K, Sakurai J. Intracellular trafficking of Clostridium botulinum C2 toxin. Toxicon. 2014;82:76–82.

    Article  CAS  PubMed  Google Scholar 

  • Nestorovich EM, Karginov VA, Popoff MR, Bezrukov SM, Barth H. Tailored ß-cyclodextrin blocks the translocation pores of binary exotoxins from C. botulinum and C. perfringens and protects cells from intoxication. PLoS One. 2011;6:e23927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neumeyer T, Schiffler B, Maier E, Lang AE, Aktories K, Benz R. Clostridium botulinum C2 toxin. Identification of the binding site for chloroquine and related compounds and influence of the binding site on properties of the C2II channel. J Biol Chem. 2008;283:3904–14.

    Article  CAS  PubMed  Google Scholar 

  • Ni L, Yang C-S, Gioeli D, Frierson H, Toft DO, Paschal BM. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010;30:1243–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nigro P, Pompilio G, Capogrossi MC. Cyclophilin A: a key player for human disease. Cell Death Dis. 2013;4:e888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I. Response of mouse intestinal loop to botulinum C2 toxin: enterotoxic activity induced by cooperation of nonlinked protein components. Infect Immun. 1983a;40:691–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I. Lethal and vascular permeability activities of botulinum C2 toxin induced by separate injections of the two toxin components. Infect Immun. 1983b;40:336–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I. Activation of botulinum C2 toxin by trypsin. Infect Immun. 1987;55:1461–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I, Miyake M. Binding of the two components of C2 toxin to epithelial cells and brush borders of mouse intestine. Infect Immun. 1985;48:769–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I, Yanagimoto A. Visualizations of binding and internalization of two nonlinked protein components of botulinum C2 toxin in tissue culture cells. Infect Immun. 1992;60:4648–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I, Iwasaki M, Sakaguchi G. Purification and characterization of two components of botulinum C2 toxin. Infect Immun. 1980;30:668–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ohishi I, Miyake M, Ogura H, Nakamura S. Cytopathic effect of botulinum C2 toxin on tissue-culture cells. FEMS Microbiol Lett. 1984;23:281–4.

    Article  CAS  Google Scholar 

  • Owens-Grillo JK, Hoffmann K, Hutchison KA, Yem AW, Deibel MR, Handschumacher RE, Pratt WB. 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. 1995;270:20479–84.

    Article  CAS  PubMed  Google Scholar 

  • Papatheodorou P, Carette JE, Bell GW, Schwan C, Guttenberg G, Brummelkamp TR, Aktories K. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc Natl Acad Sci U S A. 2011;108:16422–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Papatheodorou P, Hornuss D, Nölke T, Hemmasi S, Castonguay J, Picchianti M, Aktories K. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. mBio. 2013;4:e00244–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perelle S, Gibert M, Bourlioux P, Corthier G, Popoff MR. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect Immun. 1997a;65:1402–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Perelle S, Scalzo S, Kochi S, Mock M, Popoff MR. Immunological and functional comparison between Clostridium perfringens iota toxin, C. spiroforme toxin, and anthrax toxins. FEMS Microbiol Lett. 1997b;146:117–21.

    Article  CAS  PubMed  Google Scholar 

  • Pirkl F, Buchner J. Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. J Mol Biol. 2001;308:795–806.

    Article  CAS  PubMed  Google Scholar 

  • Popoff MR. Molecular biology of actin-ADP-ribosylating toxins. In: Aktories PDK, Just DI, editors. Bacterial protein toxins. Berlin/Heidelberg: Springer; 2000. p. 275–306.

    Chapter  Google Scholar 

  • Popoff MR, Rubin EJ, Gill DM, Boquet P. Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect Immun. 1988;56:2299–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18:306–60.

    CAS  PubMed  Google Scholar 

  • Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med. 2003;228:111–33.

    CAS  Google Scholar 

  • Prell E, Kahlert V, Rücknagel KP, Malešević M, Fischer G. Fine tuning the inhibition profile of cyclosporine a by derivatization of the MeBmt residue. Chembiochem. 2013;14:63–5.

    Article  CAS  PubMed  Google Scholar 

  • Pust S, Hochmann H, Kaiser E, von Figura G, Heine K, Aktories K, Barth H. 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. 2007;282:10272–82.

    Article  CAS  PubMed  Google Scholar 

  • Pust S, Barth H, Sandvig K. Clostridium botulinum C2 toxin is internalized by clathrin- and Rho-dependent mechanisms. Cell Microbiol. 2010;12:1809–20.

    Article  CAS  PubMed  Google Scholar 

  • Ratajczak T, Carrello A. Cyclophilin 40 (CyP-40), mapping of its hsp90 binding domain and evidence that FKBP52 competes with CyP-40 for hsp90 binding. J Biol Chem. 1996;271:2961–5.

    Article  CAS  PubMed  Google Scholar 

  • Ratts R, Zeng H, Berg EA, Blue C, McComb ME, Costello CE, vander Spek JC, Murphy JR. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J Cell Biol. 2003;160:1139–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richard JF, Mainguy G, Gibert M, Marvaud JC, Stiles BG, Popoff MR. Transcytosis of iota-toxin across polarized CaCo-2 cells. Mol Microbiol. 2002;43:907–17.

    Article  CAS  PubMed  Google Scholar 

  • Riggs DL, Roberts PJ, Chirillo SC, Cheung-Flynn J, Prapapanich V, Ratajczak T, Gaber R, Picard D, Smith DF. The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo. EMBO J. 2003;22:1158–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakurai J, Kobayashi K. Lethal and dermonecrotic activities of Clostridium perfringens lota toxin: biological activities induced by cooperation of two nonlinked components. Microbiol Immunol. 1995;39:249–53.

    Article  CAS  PubMed  Google Scholar 

  • Sakurai J, Nagahama M, Hisatsune J, Katunuma N, Tsuge H. Clostridium perfringens iota-toxin, ADP-ribosyltransferase: structure and mechanism of action. Adv Enzyme Regul. 2003;43:361–77.

    Article  CAS  PubMed  Google Scholar 

  • Schering B, Bärmann M, Chhatwal GS, Geipel U, Aktories K. ADP-ribosylation of skeletal muscle and non-muscle actin by Clostridium perfringens iota toxin. Eur J Biochem. 1988;171:225–9.

    Article  CAS  PubMed  Google Scholar 

  • Schiene-Fischer C. Multidomain peptidyl prolyl cis/trans Isomerases. Biochim Biophys Acta. 2014;10:2005–2016.

    Google Scholar 

  • Schleberger C, Hochmann H, Barth H, Aktories K, Schulz GE. Structure and action of the binary C2 toxin from Clostridium botulinum. J Mol Biol. 2006;364:705–15.

    Article  CAS  PubMed  Google Scholar 

  • Schreiber SL, Liu J, Albers MW, Karmacharya R, Koh E, Martin PK, Rosen MK, Standaert RF, Wandless TJ. Immunophilin-ligand complexes as probes of intracellular signaling pathways. Transplant Proc. 1991;23:2839–44.

    CAS  PubMed  Google Scholar 

  • Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt W-D, Wehland J, Aktories K. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog. 2009;5:e1000626.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schwan C, Nölke T, Kruppke AS, Schubert DM, Lang AE, Aktories K. Cholesterol- and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase (CDT). J Biol Chem. 2011;286:29356–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simpson LL. A comparison of the pharmacological properties of Clostridium botulinum type C1 and C2 toxins. J Pharmacol Exp Ther. 1982;223:695–701.

    CAS  PubMed  Google Scholar 

  • Songer JG. Clostridial enteric diseases of domestic animals. Clin Microbiol Rev. 1996;9:216–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stechschulte LA, Sanchez ER. FKBP51-a selective modulator of glucocorticoid and androgen sensitivity. Curr Opin Pharmacol. 2011;11:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sterthoff C, Lang AE, Schwan C, Tauch A, Aktories K. Functional characterization of an extended binding component of the actin-ADP-ribosylating C2 toxin detected in Clostridium botulinum strain (C) 2300. Infect Immun. 2010;78:1468–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stiles BG, Hale ML, Marvaud JC, Popoff MR. Clostridium perfringens iota toxin: characterization of the cell-associated iota b complex. Biochem J. 2002;367:801–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stiles BG, Wigelsworth DJ, Popoff MR, Barth H. Clostridial binary toxins: iota and C2 family portraits. Front Cell Infect Microbiol. 2011;1:1–14.

    Article  Google Scholar 

  • Sugii S, Kozaki S. Hemagglutinating and binding properties of botulinum C2 toxin. Biochim Biophys Acta. 1990;1034:176–9.

    Article  CAS  PubMed  Google Scholar 

  • Sundriyal A, Roberts AK, Shone CC, Acharya KR. Structural basis for substrate recognition in the enzymatic component of ADP-ribosyltransferase toxin CDTa from Clostridium difficile. J Biol Chem. 2009;284:28713–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swanson SK, Born T, Zydowsky LD, Cho H, Chang HY, Walsh CT, Rusnak F. Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci U S A. 1992;89:3741–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor P, Dornan J, Carrello A, Minchin RF, Ratajczak T, Walkinshaw MD. Two structures of cyclophilin 40: folding and fidelity in the TPR domains. Structure. 2001;1993(9):431–8.

    Article  Google Scholar 

  • Taylor M, Navarro-Garcia F, Huerta J, Burress H, Massey S, Ireton K, Teter K. Hsp90 is required for transfer of the cholera toxin A1 subunit from the endoplasmic reticulum to the cytosol. J Biol Chem. 2010;285:31261–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuge H, Nagahama M, Nishimura H, Hisatsune J, Sakaguchi Y, Itogawa Y, Katunuma N, Sakurai J. Crystal structure and site-directed mutagenesis of enzymatic components from Clostridium perfringens iota-toxin. J Mol Biol. 2003;325:471–83.

    Article  CAS  PubMed  Google Scholar 

  • Tsuge H, Nagahama M, Oda M, Iwamoto S, Utsunomiya H, Marquez VE, Katunuma N, Nishizawa M, Sakurai J. Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin. Proc Natl Acad Sci U S A. 2008;105:7399–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wegner A, Aktories K. ADP-ribosylated actin caps the barbed ends of actin filaments. J Biol Chem. 1988;263:13739–42.

    CAS  PubMed  Google Scholar 

  • Wigelsworth DJ, Ruthel G, Schnell L, Herrlich P, Blonder J, Veenstra TD, Carman RJ, Wilkins TD, Van Nhieu GT, Pauillac S, et al. CD44 promotes intoxication by the clostridial iota-family toxins. PLoS One. 2012;7:e51356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wochnik GM, Rüegg J, Abel GA, Schmidt U, Holsboer F, Rein T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol Chem. 2005;280:4609–16.

    Article  CAS  PubMed  Google Scholar 

  • Young JAT, Collier RJ. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu Rev Biochem. 2007;76:243–65.

    Article  CAS  PubMed  Google Scholar 

  • Zornetta I, Brandi L, Janowiak B, Dal Molin F, Tonello F, Collier RJ, Montecucco C. Imaging the cell entry of the anthrax oedema and lethal toxins with fluorescent protein chimeras. Cell Microbiol. 2010;12:1435–45.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein Allee 11, 89081, Ulm, Germany

    Holger Barth & Katharina Ernst

Authors
  1. Holger Barth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katharina Ernst
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Holger Barth .

Editor information

Editors and Affiliations

  1. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    P. Gopalakrishnakone

  2. Biology Department, Wilson College , Chambersburg, Pennsylvania, USA

    Brad Stiles

  3. Department of Biochemistry, School of Medicine and Instituto Clodomiro Picado, Faculty of Microbiology, University of Costa Rica , San Pedro de Montes de Oca, Costa Rica

    Alberto Alape-Girón

  4. Département de pathologie et microbiologie, Faculté de médecine vétérinaire, Université de Montréal , Saint-Hyacinthe, Canada

    J. Daniel Dubreuil

  5. College of Pharmacy, Roseman University of Health Sciences, Henderson, Nevada, USA

    Manas Mandal

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Barth, H., Ernst, K. (2016). Chaperones and ADP-Ribosylating Bacterial Toxins. In: Gopalakrishnakone, P., Stiles, B., Alape-Girón, A., Dubreuil, J., Mandal, M. (eds) Microbial Toxins. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6725-6_7-1

Download citation

  • DOI: https://doi.org/10.1007/978-94-007-6725-6_7-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Dordrecht

  • Online ISBN: 978-94-007-6725-6

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation