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Autocatalytic cleavage of Clostridium difficile toxin B

Author

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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)

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.

Suggested Citation

  • Jessica Reineke & Stefan Tenzer & Maja Rupnik & Andreas Koschinski & Oliver Hasselmayer & André Schrattenholz & Hansjörg Schild & Christoph von Eichel-Streiber, 2007. "Autocatalytic cleavage of Clostridium difficile toxin B," Nature, Nature, vol. 446(7134), pages 415-419, March.
    • Handle: RePEc:nat:nature:v:446:y:2007:i:7134:d:10.1038_nature05622
    DOI: 10.1038/nature05622
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    Cited by:

    1. Alexander Belyy & Philipp Heilen & Philine Hagel & Oliver Hofnagel & Stefan Raunser, 2023. "Structure and activation mechanism of the Makes caterpillars floppy 1 toxin," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Ruoyu Zhou & Liuqing He & Jiahao Zhang & Xiaofeng Zhang & Yanyan Li & Xiechao Zhan & Liang Tao, 2024. "Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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