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dc.contributor.authorBeer, Lara-Antonia
dc.contributor.authorTatge, Helma
dc.contributor.authorReich, Nicole
dc.contributor.authorTenspolde, Michel
dc.contributor.authorOlling, Alexandra
dc.contributor.authorGoy, Sebastian
dc.contributor.authorRottner, Klemens
dc.contributor.authorAlekov, Alexi Kirilov
dc.contributor.authorGerhard, Ralf
dc.date.accessioned2018-08-29T08:52:33Z
dc.date.available2018-08-29T08:52:33Z
dc.date.issued2018-06-14
dc.identifier.issn1462-5822
dc.identifier.pmid29904993
dc.identifier.doi10.1111/cmi.12865
dc.identifier.urihttp://hdl.handle.net/10033/621459
dc.description.abstractToxin A and Toxin B (TcdA/TcdB) are large glucosyltransferases produced by Clostridium difficile. TcdB but not TcdA induces reactive oxygen species-mediated early cell death (ECD) when applied at high concentrations. We found that nonglucosylated Rac1 is essential for induction of ECD since inhibition of Rac1 impedes this effect. ECD only occurs when TcdB is rapidly endocytosed. This was shown by generation of chimeras using the trunk of TcdB from a hypervirulent strain. TcdB from hypervirulent strain has been described to translocate from endosomes at higher pH values and thus, meaning faster than reference type TcdB. Accordingly, intracellular delivery of the glucosyltransferase domain of reference TcdB by the trunk of TcdB from hypervirulent strain increased ECD. Furthermore, proton transporters such as sodium/proton exchanger (NHE) or the ClC-5 anion/proton exchanger, both of which contribute to endosomal acidification, also affected cytotoxic potency of TcdB: Specific inhibition of NHE reduced cytotoxicity, whereas transfection of cells with the endosomal anion/proton exchanger ClC-5 increased cytotoxicity of TcdB. Our data suggest that both the uptake rate of TcdB into the cytosol and the status of nonglucosylated Rac1 are key determinants that are decisive for whether ECD or delayed apoptosis is triggered.en_US
dc.rightsAttribution-NonCommercial-ShareAlike 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/us/*
dc.subjectcell deathen_US
dc.subjectcellular uptakeen_US
dc.subjectclostridium difficileen_US
dc.subjectreactive oxygen speciesen_US
dc.subjecttoxinsen_US
dc.titleEarly cell death induced by Clostridium difficile TcdB: Uptake and Rac1-glucosylation kinetics are decisive for cell fate.en_US
dc.typeArticleen_US
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.en_US
dc.source.journaltitleCellular microbiology


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