The binary C2 toxin from Clostridium botulinum consists of two separate proteins: the transport component C2IIa delivers the enzyme component C2I into the cytosol of eukaryotic host cells. In the cytosol, C2I mono-ADPribosylates actin, thereby inducing depolymerization of actin filaments resulting in delayed caspase-dependent cell death. The sophisticated cellular uptake mechanism of C2 toxin, in particular our new results regarding the role of host cell chaperones and protein-folding helper enzymes during intracellular membrane translocation of C2I, are focused upon in this minireview.
We discovered earlier that translocation of C2I across endosomal membranes in mammalian cells depends on the chaperone activity of the heat shock protein Hsp90. Recently we have demonstrated that cyclosporin A (CsA), an inhibitor of peptidyl-prolyl cis/trans isomerase (PPIase) activity of cyclophilins, inhibited intoxication of various mammalian cell lines with C2 toxin. The underlying reason for this effect was the prevented uptake of C2I into the host cell cytosol. CsA, as well as a specific antibody against cyclophilin A, blocked the pH-dependent translocation of C2I-ADPribosyltransferase activity across membranes of intact cells and of partially-purified early endosomes in vitro. In conclusion, our results imply that the activities of Hsp90 and cyclophilin A are crucial for translocation of the C2I ADPribosyltransferase from early endosomes into the cytosol of mammalian cells. This is the first observation that a host cell PPIase, in concert with a heat shock protein, facilitates intracellular membrane translocation of a bacterial protein toxin.
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