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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.

Original publication




Journal article



Publication Date





415 - 419


Animals, Aspartic Acid Endopeptidases, Bacterial Proteins, Bacterial Toxins, Binding Sites, Biological Factors, Catalysis, Cell Extracts, Cell Line, Clostridium difficile, Epoxy Compounds, Nitrophenols, Phytic Acid, Protein Processing, Post-Translational, Protein Transport, Spleen, Swine, Virulence Factors