6533b820fe1ef96bd1279bce
RESEARCH PRODUCT
Autocatalytic cleavage of Clostridium difficile toxin B.
Oliver HasselmayerAndré SchrattenholzChristoph Von Eichel-streiberHansjörg SchildStefan TenzerMaja RupnikJessica ReinekeAndreas Koschinskisubject
Cell ExtractsProteasesPhytic AcidSwineVirulence Factorsmedicine.medical_treatmentBacterial ToxinsClostridium difficile toxin AVirulenceClostridium difficile toxin Bmedicine.disease_causeCatalysisMicrobiologyCell LineNitrophenolsBiological FactorsBacterial ProteinsmedicineAnimalsAspartic Acid EndopeptidasesMultidisciplinaryProteaseBinding SitesToxinChemistryClostridioides difficilePseudomembranous colitisClostridium difficileProtein TransportBiochemistryEpoxy CompoundsProtein Processing Post-TranslationalSpleendescription
Clostridium difficile, the causative agent of nosocomial antibiotic-associated diarrhoea and pseudomembranous colitis, possesses two main virulence factors: the large clostridial cytotoxins A and B. It has been proposed that toxin B is cleaved by a cytosolic factor of the eukaryotic target cell during its cellular uptake. Here we report that cleavage of not only toxin B, but also all other large clostridial cytotoxins, is an autocatalytic process dependent on host cytosolic inositolphosphate cofactors. A covalent inhibitor of aspartate proteases, 1,2-epoxy-3-(p-nitrophenoxy)propane, completely blocked toxin B function on cultured cells and was used to identify its catalytically active protease site. To our knowledge this is the first report on a bacterial toxin that uses eukaryotic signals for induced autoproteolysis to deliver its toxic domain into the cytosol of target cells. On the basis of our data, we present an integrated model for the uptake and inositolphosphate-induced activation of toxin B.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2007-03-01 | Nature |