Autocatalytic cleavage of Clostridium difficile toxin B

Jessica Reineke, Stefan Tenzer, Maja Rupnik, Andreas Koschinski, Oliver Hasselmayer, André Schrattenholz, Hansjörg Schild () and Christoph von Eichel-Streiber ()
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Jessica Reineke: Johannes-Gutenberg Universität Mainz, Institut für medizinische Mikrobiologie and Hygiene, Hochhaus am Augustusplatz, 55131 Mainz, Germany
Stefan Tenzer: Johannes-Gutenberg Universität Mainz, Institut für Immunologie, Hochhaus am Augustusplatz, 55131 Mainz, Germany
Maja Rupnik: University of Maribor, Faculty of Medicine, Slomskov trg 15 and Institute of Public Health Maribor, Prvomajska 1, 2000 Maribor, Slovenia
Andreas Koschinski: Justus-Liebig Universität Giessen, Rudolf-Buchheim-Institut für Pharmakologie, Frankfurter Strasse 107, 35392 Giessen, Germany
Oliver Hasselmayer: Johannes-Gutenberg Universität Mainz, Institut für medizinische Mikrobiologie and Hygiene, Hochhaus am Augustusplatz, 55131 Mainz, Germany
André Schrattenholz: ProteoSys AG, Carl-Zeiss-Strasse 51, 55129 Mainz, Germany
Hansjörg Schild: Johannes-Gutenberg Universität Mainz, Institut für Immunologie, Hochhaus am Augustusplatz, 55131 Mainz, Germany
Christoph von Eichel-Streiber: Johannes-Gutenberg Universität Mainz, Institut für medizinische Mikrobiologie and Hygiene, Hochhaus am Augustusplatz, 55131 Mainz, Germany

Nature, 2007, vol. 446, issue 7134, 415-419

Abstract: Abstract 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.

Date: 2007
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DOI: 10.1038/nature05622

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