Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells

Scientific Reports

Volumn 7, Issue 1, 2017, Pages

  Ernst, Katharina ^a   Schmid, Johannes ^a   Beck, Matthias ^a   Hägele, Marlen ^b   Hohwieler, Meike ^b   Hauff, Patricia ^a   Ückert, Anna Katharina ^a   Anastasia, Anna ^a   Fauler, Michael ^b   Jank, Thomas ^c   Aktories, Klaus ^c   Popoff, Michel R ^d   Schiene Fischer, Cordelia ^e   Kleger, Alexander ^b   Müller, Martin ^b   Frick, Manfred ^b   Barth, Holger ^a  

^a UNIVERSITY HOSPITAL ULM   (Germany)

^b UNIVERSITY OF ULM   (Germany)

^c UNIVERSITY OF FREIBURG   (Germany)

^d INSTITUT PASTEUR   (France)

^e MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CARRIER PROTEIN; ENTEROTOXIN; HEAT SHOCK PROTEIN 70; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROTEIN BINDING;

ANIMAL; ANTAGONISTS AND INHIBITORS; BACTERIUM; CHLOROCEBUS AETHIOPS; HUMAN; METABOLISM; PH; VERO CELL LINE;

ADP RIBOSE TRANSFERASES; ANIMALS; BACTERIA; CERCOPITHECUS AETHIOPS; ENTEROTOXINS; HSP70 HEAT-SHOCK PROTEINS; HUMANS; HYDROGEN-ION CONCENTRATION; MEMBRANE TRANSPORT PROTEINS; PROTEIN BINDING; VERO CELLS;

EID: 85019974593     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/s41598-017-02882-y     Document Type: Article

References (70)

1. Gerding, D. N., Johnson, S., Rupnik, M. & Aktories, K. Clostridium difficile binary toxin CDT: mechanism, epidemiology, and potential clinical importance. Gut Microbes 5, 15-27 (2014).
2. 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. 42, 349-353 (1987).
3. Ohishi, I. Lethal and vascular permeability activities of botulinum C2 toxin induced by separate injections of the two toxin components. Infect. Immun. 40, 336-339 (1983).
4. Songer, J. G. Clostridial enteric diseases of domestic animals. Clin. Microbiol. Rev. 9, 216-234 (1996).
5. Aktories, K. et al. Botulinum C2 toxin ADP-ribosylates actin. Nature 322, 390-392 (1986).
6. Popoff, M. R., Rubin, E. J., Gill, D. M. & Boquet, P. Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect. Immun. 56, 2299-2306 (1988).
7. Schering, B., Bärmann, M., Chhatwal, G. S., Geipel, U. & Aktories, K. ADP-ribosylation of skeletal muscle and non-muscle actin by Clostridium perfringens iota toxin. Eur. J. Biochem. FEBS 171, 225-229 (1988).
8. Aktories, K. & Wegner, A. Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. Mol. Microbiol. 6, 2905-2908 (1992).
9. 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. FEBS 179, 229-232 (1989).
10. Reuner, K. H., Presek, P., Boschek, C. B. & Aktories, K. Botulinum C2 toxin ADP-ribosylates actin and disorganizes the microfilament network in intact cells. Eur. J. Cell Biol. 43, 134-140 (1987).
11. Wegner, A. & Aktories, K. ADP-ribosylated actin caps the barbed ends of actin filaments. J. Biol. Chem. 263, 13739-13742 (1988).
12. Sterthoff, C., Lang, A. E., 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. 78, 1468-1474 (2010).
13. Barth, H. et al. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J. Biol. Chem. 275, 18704-18711 (2000).
14. Blöcker, D. et al. The C terminus of component C2II of Clostridium botulinum C2 toxin is essential for receptor binding. Infect. Immun. 68, 4566-4573 (2000).
15. Eckhardt, M., Barth, H., Blöcker, D. & Aktories, K. Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid carbohydrates. J. Biol. Chem. 275, 2328-2334 (2000).
16. Ohishi, I., Miyake, M., Ogura, H. & Nakamura, S. Cytopathic effect of botulinum C2 toxin on tissue-culture cells. FEMS Microbiol. Lett 23, 281-284 (1984).
17. Haug, G. et al. Cellular uptake of Clostridium botulinum C2 toxin: membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain. Biochemistry (Mosc.) 42, 15284-15291 (2003).
18. Schleberger, C., Hochmann, H., Barth, H., Aktories, K. & Schulz, G. E. Structure and action of the binary C2 toxin from Clostridium botulinum. J. Mol. Biol. 364, 705-715 (2006).
19. Barth, H. & Stiles, B. G. Binary actin-ADP-ribosylating toxins and their use as molecular Trojan horses for drug delivery into eukaryotic cells. Curr. Med. Chem. 15, 459-469 (2008).
20. Stiles, B. G. & Wilkins, T. D. Purification and characterization of Clostridium perfringens iota toxin: dependence on two nonlinked proteins for biological activity. Infect. Immun. 54, 683-688 (1986).
21. Barth, H., Aktories, K., Popoff, M. R. & Stiles, B. G. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol. Mol. Biol. Rev. 68, 373-402 (2004).
22. Perelle, S., Gibert, M., Bourlioux, P., Corthier, G. & Popoff, M. R. Production of a complete binary toxin (actin-specific ADPribosyltransferase) by Clostridium difficile CD196. Infect. Immun. 65, 1402-1407 (1997).
23. Papatheodorou, P. et al. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc. Natl. Acad. Sci. USA 108, 16422-16427 (2011).
24. Papatheodorou, P. et al. Clostridium difficile binary toxin CDT induces clustering of the lipolysis-stimulated lipoprotein receptor into lipid rafts. mBio 4, e00244-00213 (2013).
25. Wigelsworth, D. J. et al. CD44 promotes intoxication by the clostridial iota-family toxins. PLoS ONE 7 (2012).
26. Ernst, K. 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. 427, 1224-1238 (2015).
27. Haug, G. et al. The host cell chaperone Hsp90 is essential for translocation of the binary Clostridium botulinum C2 toxin into the cytosol. J. Biol. Chem. 278, 32266-32274 (2003).
28. Haug, G., Aktories, K. & Barth, H. The host cell chaperone Hsp90 is necessary for cytotoxic action of the binary iota-like toxins. Infect. Immun. 72, 3066-3068 (2004).
29. 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 11, 780-795 (2009).
30. Kaiser, E. et al. Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by cyclophilin A and Hsp90. Infect. Immun. 79, 3913-3921 (2011).
31. Kaiser, E. et al. FK506-binding protein 51 interacts with Clostridium botulinum C2 toxin and FK506 inhibits membrane translocation of the toxin in mammalian cells. Cell. Microbiol. 14, 1193-1205 (2012).
32. Barth, H. & Ernst, K. In Microbial Toxins (eds. Gopalakrishnakone, P., Stiles, B., Alape-Girón, A., Dubreuil, J. D. & Mandal, M.) 1-22 (Springer Netherlands, 2016).
33. Ernst, K. et al. A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin. Sci. Rep 6, 20301 (2016).
34. Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T. & Pfanner, N. Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628-644 (2009).
35. Clerico, E. M., Tilitsky, J. M., Meng, W. & Gierasch, L. M. How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J. Mol. Biol. 427, 1575-1588 (2015).
36. Li, J., Soroka, J. & Buchner, J. The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim. Biophys. Acta 1823, 624-635 (2012).
37. Pirkl, F. & Buchner, J. Functional analysis of the Hsp90-Associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. J. Mol. Biol. 308, 795-806 (2001).
38. Pratt, W. B. & Toft, D. O. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306-360 (1997).
39. Williamson, D. S. et al. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J. Med. Chem. 52, 1510-1513 (2009).
40. Ernst, K., Schnell, L. & Barth, H. Host cell chaperones Hsp70/Hsp90 and peptidyl-prolyl cis/trans isomerases are required for the membrane translocation of bacterial ADP-ribosylating toxins. Curr. Top. Microbiol. Immunol. doi:10.1007/82-2016-14 (2016).
41. Beitzinger, C. et al. Role of N-terminal His6-Tags in binding and efficient translocation of polypeptides into cells using anthrax protective antigen (PA). PloS One 7, e46964 (2012).
42. Blanke, S. R., Milne, J. C., Benson, E. L. & Collier, R. J. 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, 8437-8442 (1996).
43. Jank, T. et al. A bacterial toxin catalyzing tyrosine glycosylation of Rho and deamidation of Gq and Gi proteins. Nat. Struct. Mol. Biol. 20, 1273-1280 (2013).
44. Jank, T. et al. Tyrosine glycosylation of Rho by Yersinia toxin impairs blastomere cell behaviour in zebrafish embryos. Nat. Commun. 6, 7807 (2015).
45. Lang, A. E. et al. Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering. Science 327, 1139-1142 (2010).
46. Hohwieler, M. et al. 'Miniguts' from plucked human hair meet Crohn's disease. Z. Für Gastroenterol 54, 748-759 (2016).
47. Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262-265 (2009).
48. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105-109 (2011).
49. Ratts, R. et al. The cytosolic entry of diphtheria toxin catalytic domain requires a host cell cytosolic translocation factor complex. J. Cell Biol. 160, 1139-1150 (2003).
50. Dmochewitz, L. et al. Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. Cell. Microbiol 13, 359-373 (2011).
51. Mayer, M. P. & Kityk, R. Insights into the molecular mechanism of allostery in Hsp70s. Front. Mol. Biosci 2, 58 (2015).
52. Burress, H., Taylor, M., Banerjee, T., Tatulian, S. A. & Teter, K. Co-And post-translocation roles for HSP90 in cholera intoxication. J. Biol. Chem. 289, 33644-33654 (2014).
53. Murphy, J. R. Mechanism of diphtheria toxin catalytic domain delivery to the eukaryotic cell cytosol and the cellular factors that directly participate in the process. Toxins 3, 294-308 (2011).
54. Taylor, M. et al. Hsp90 is required for transfer of the cholera toxin A1 subunit from the endoplasmic reticulum to the cytosol. J. Biol. Chem. 285, 31261-31267 (2010).
55. Lang, A. E. et al. The chaperone Hsp90 and PPIases of the cyclophilin and FKBP families facilitate membrane translocation of Photorhabdus luminescens ADP-ribosyltransferases. Cell. Microbiol. 16, 490-503 (2014).
56. Azarnia Tehran, D. et al. Hsp90 is involved in the entry of clostridial neurotoxins into the cytosol of nerve terminals. Cell. Microbiol. doi:10.1111/cmi.12647 (2016).
57. Söderberg, O. et al. Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat. Methods 3, 995-1000 (2006).
58. Goloubinoff, P. & De Los Rios, P. The mechanism of Hsp70 chaperones: (entropic) pulling the models together. Trends Biochem. Sci. 32, 372-380 (2007).
59. McCracken, K. W. et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 516, 400-404 (2014).
60. Braga, V. Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton. Curr. Opin. Cell Biol. 42, 138-145 (2016).
61. Leslie, J. L. et al. Persistence and toxin production by Clostridium difficile within human intestinal organoids result in disruption of epithelial paracellular barrier function. Infect. Immun. 83, 138-145 (2015).
62. Barth, H., Preiss, J. C., Hofmann, F. & Aktories, K. Characterization of the catalytic site of the ADP-ribosyltransferase Clostridium botulinum C2 toxin by site-directed mutagenesis. J. Biol. Chem. 273, 29506-29511 (1998).
63. Fahrer, J. et al. Selective and specific internalization of clostridial C3 ADP-ribosyltransferases into macrophages and monocytes. Cell. Microbiol 12, 233-247 (2010).
64. Papatheodorou, P., Zamboglou, C., Genisyuerek, S., Guttenberg, G. & Aktories, K. Clostridial glucosylating toxins enter cells via clathrin-mediated endocytosis. PLOS ONE 5, e10673 (2010).
65. Gatsogiannis, C. et al. A syringe-like injection mechanism in Photorhabdus luminescens toxins. Nature 495, 520-523 (2013).
66. Freeman, B. C., Michels, A., Song, J., Kampinga, H. H. & Morimoto, R. I. Analysis of molecular chaperone activities using in vitro and in vivo approaches. Methods Mol. Biol. Clifton NJ 99, 393-419 (2000).
67. Edlich, F. et al. The specific FKBP38 inhibitor N-(N?,N?-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. J. Biol. Chem. 281, 14961-14970 (2006).
68. Wesche, J., Elliott, J. L., Falnes, P. O., Olsnes, S. & Collier, R. J. Characterization of membrane translocation by anthrax protective antigen. Biochemistry (Mosc.) 37, 15737-15746 (1998).
69. Granzhan, A., Ihmels, H. & Viola, G. 9-donor-substituted acridizinium salts: versatile environment-sensitive fluorophores for the detection of biomacromolecules. J. Am. Chem. Soc. 129, 1254-1267 (2007).
70. Schlecht, R. et al. Functional analysis of Hsp70 inhibitors. PLOS ONE 8, e78443 (2013).