2. Academic Validation
  3. The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins like Clostridium difficile toxins A and B

The chaperonin TRiC/CCT is essential for the action of bacterial glycosylating protein toxins like Clostridium difficile toxins A and B

  • Proc Natl Acad Sci U S A. 2018 Sep 18;115(38):9580-9585. doi: 10.1073/pnas.1807658115.
Marcus Steinemann 1 2,  Andreas Schlosser 3,  Thomas Jank 4,  Klaus Aktories 4 5
Affiliations

Affiliations

  • 1 Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.
  • 2 Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
  • 3 Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, 97080 Würzburg, Germany.
  • 4 Institute for Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany; thomas.jank@pharmakol.uni-freiburg.de Klaus.Aktories@pharmakol.uni-freiburg.de.
  • 5 Center for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
PMID: 30181275 DOI: 10.1073/pnas.1807658115
Abstract

Various Bacterial protein toxins, including Clostridium difficile toxins A (TcdA) and B (TcdB), attack intracellular target proteins of host cells by glucosylation. After receptor binding and endocytosis, the toxins are translocated into the cytosol, where they modify target proteins (e.g., Rho proteins). Here we report that the activity of translocated glucosylating toxins depends on the chaperonin TRiC/CCT. The chaperonin subunits CCT4/5 directly interact with the toxins and enhance the refolding and restoration of the glucosyltransferase activities of toxins after heat treatment. Knockdown of CCT5 by siRNA and HSF1A, an inhibitor of TRiC/CCT, blocks the cytotoxic effects of TcdA and TcdB. In contrast, HSP90, which is involved in the translocation and uptake of ADP ribosylating toxins, is not involved in uptake of the glucosylating toxins. We show that the actions of numerous glycosylating toxins from various toxin types and different species depend on TRiC/CCT. Our data indicate that the TRiC/CCT chaperonin system is specifically involved in toxin uptake and essential for the action of various glucosylating protein toxins acting intracellularly on target proteins.

Keywords

Clostridium difficile toxins; TRiC/CCT; chaperonin; glycosyltransferase toxins; toxin uptake.

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