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Role of Peptidyl-Prolyl cis/trans Isomerases in Cellular Uptake of Bacterial Protein Toxins

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Moonlighting Cell Stress Proteins in Microbial Infections

Part of the book series: Heat Shock Proteins ((HESP,volume 7))

Abstract

Binary actin ADP-ribosylating toxins consist of two proteins which are produced and secreted by pathogenic clostridia. The enzyme components ADP-­ribosylate actin in the cytosol of mammalian cells which leads to destruction of the actin cytoskeleton. The separate transport components are heptameric ring-shaped molecules which bind to receptors on the surface of target cells, assemble with the enzyme components and trigger the subsequent receptor-mediated endocytosis of the toxin complexes. The enzyme components then translocate from acidified endosomal vesicles into the host cell cytosol. This step is also mediated by the transport components which change their conformation and form pores in the endosomal membranes due to the acidic conditions in the endosomes. The enzyme components translocate as unfolded proteins through these pores across endosomal membranes and their translocation and/or refolding is facilitated by cytosolic host cell factors including the chaperone Hsp90. We discovered that PPIases such as cyclophilin A and FK506-binding proteins 51/52 are also involved in membrane translocation of these toxins. The PPIases interacted with the enzyme components in vitro and in living cells and their pharmacological inhibition by cyclosporin A or FK506 inhibited the translocation of the enzyme components to the cytosol and thus protected living cells from intoxication with binary actin-ADP-ribosylating toxins. In conclusion, we have identified a novel Hsp90/PPIase-dependent translocation mechanism which might be selective for ADP-ribosylating toxins. The pharmacological inhibition of toxin translocation could lead to novel therapeutic strategies against diseases associated with such bacterial toxins.

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Acknowledgments

The research underlying this book chapter was supported by the Deutsche Forschungsgemeinschaft (BA 2087/1, BA 2087/2) and the Medical Faculty of the University of Ulm.

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  1. Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Holger Barth

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Correspondence to Holger Barth .

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  1. Eastman Dental Institute, Div. Microbial Diseases, University College, London, Gray's Inn Road 256, London, WC1X 8LD, United Kingdom

    Brian Henderson

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Barth, H. (2013). Role of Peptidyl-Prolyl cis/trans Isomerases in Cellular Uptake of Bacterial Protein Toxins. In: Henderson, B. (eds) Moonlighting Cell Stress Proteins in Microbial Infections. Heat Shock Proteins, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6787-4_16

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