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
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DOI：
10.1073/pnas.1807658115
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Marcus Steinemann;A. Schlosser;T. Jank;K. Aktories
中科院分区：
文献类型：
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作者：
Marcus Steinemann;A. Schlosser;T. Jank;K. Aktories
Significance Glucosylation of host proteins is a common pathogenicity mechanism of bacterial protein toxins. Prominent examples are Clostridium difficile toxins A and B, which inactivate Rho proteins by glucosylation and cause diarrhea and pseudomembranous colitis in C. difficile infections. So far, host factors involved in uptake and/or intracellular stabilization of the toxins are not known. Here we show that TRiC/CCT chaperonins interact with glycosylating toxins and play an essential role in the intoxication process. Knockdown of chaperonins or inhibition of TRiC/CCT functions by compound HSF1A prevents the cytotoxic effects of glucosylating toxins. In contrast, HSP90, which is essential for ADP-ribosylating toxins, does not affect the uptake of glucosylating toxins. Our data provide insight into the cellular actions of glucosylating toxins. 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.
