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After receptor-mediated uptake of the toxin, DTA translocates from acidic endosomes into the cytosol, which might be assisted by host cell factors. Here we investigated the role of Hsp90 and its co-chaperones during the uptake of native diphtheria toxin into human cells and identified the components of the Hsp90 machinery including Hsp90, Hsp70, Cyp40 and the FK506 binding proteins FKBP51 and FKBP52 as DTA binding partners. Moreover, pharmacological inhibition of the chaperone activity of Hsp90 and Hsp70 and of the peptidyl-prolyl <jats:italic>cis\/trans<\/jats:italic> isomerase (PPIase) activity of Cyps and FKBPs protected cells from intoxication with diphtheria toxin and inhibited the pH-dependent trans-membrane transport of DTA into the cytosol. In conclusion, these host cell factors facilitate toxin uptake into human cells, which might lead to development of novel therapeutic strategies against diphtheria.<\/jats:p>","DOI":"10.1038\/s41598-017-00780-x","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T10:12:39Z","timestamp":1490782359000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The Hsp90 machinery facilitates the transport of diphtheria toxin into human cells"],"prefix":"10.1038","volume":"7","author":[{"given":"Manuel","family":"Schuster","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Schnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Feigl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Birkhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Mohr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice","family":"Roeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Carle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Tippel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Buchner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunter","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Hausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4763-1104","authenticated-orcid":false,"given":"Manfred","family":"Frick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Schwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Aktories","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cordelia","family":"Schiene-Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Barth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,4]]},"reference":[{"key":"780_CR1","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3390\/toxins3030294","volume":"3","author":"JR Murphy","year":"2011","unstructured":"Murphy, J. 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Science \n                           164, 1179\u20131181, doi:10.1126\/science.164.3884.1179 (1969).","journal-title":"Science"},{"key":"780_CR4","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1146\/annurev.bi.46.070177.000441","volume":"46","author":"AM Pappenheimer Jr.","year":"1977","unstructured":"Pappenheimer, A. M. Jr. Diphtheria toxin. Annu. Rev. Biochem. \n                           46, 69\u201394, doi:10.1146\/annurev.bi.46.070177.000441 (1977).","journal-title":"Annu. Rev. Biochem."},{"key":"780_CR5","doi-asserted-by":"publisher","first-page":"3344","DOI":"10.1128\/IAI.01937-06","volume":"75","author":"B Blumenthal","year":"2007","unstructured":"Blumenthal, B., Hoffmann, C., Aktories, K., Backert, S. & Schmidt, G. The cytotoxic necrotizing factors from Yersinia pseudotuberculosis and from Escherichia coli bind to different cellular receptors but take the same route to the cytosol. Infect. Immun. \n                           75, 3344\u20133353, doi:10.1128\/IAI.01937-06 (2007).","journal-title":"Infect. Immun."},{"key":"780_CR6","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.toxicon.2015.04.012","volume":"116","author":"L Schnell","year":"2016","unstructured":"Schnell, L., Dmochewitz-K\u00fcck, L., Feigl, P., Montecucco, C. & Barth, H. Thioredoxin reductase inhibitor auranofin prevents membrane transport of diphtheria toxin into the cytosol and protects human cells from intoxication. Toxicon \n                           116, 23\u201328, doi:10.1016\/j.toxicon.2015.04.012 (2016).","journal-title":"Toxicon"},{"key":"780_CR7","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1016\/S0021-9258(19)77001-X","volume":"246","author":"R Drazin","year":"1971","unstructured":"Drazin, R., Kandel, J. & Collier, R. J. Structure and activity of diphtheria toxin. II. Attack by trypsin at a specific site within the intact toxin molecule. J. Biol. 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EMBO J. \n                           7, 3353\u20133359 (1988).","journal-title":"EMBO J."},{"key":"780_CR18","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1111\/j.1365-2958.1997.tb02669.x","volume":"23","author":"E Lemichez","year":"1997","unstructured":"Lemichez, E. et al. Membrane translocation of diphtheria toxin fragment A exploits early to late endosome trafficking machinery. Mol. Microbiol. \n                           23, 445\u2013457, doi:10.1111\/j.1365-2958.1997.tb02669.x (1997).","journal-title":"Mol. Microbiol."},{"key":"780_CR19","doi-asserted-by":"crossref","first-page":"12352","DOI":"10.1016\/S0021-9258(18)37762-7","volume":"263","author":"K Sandvig","year":"1988","unstructured":"Sandvig, K. & Olsnes, S. Diphtheria toxin-induced channels in Vero cells selective for monovalent cations. J. Biol. Chem. \n                           263, 12352\u201312359 (1988).","journal-title":"J. Biol. 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