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Uptake and Trafficking of Protein Toxins pp 163–198Cite as

Host Cell Chaperones Hsp70/Hsp90 and Peptidyl-Prolyl Cis/Trans Isomerases Are Required for the Membrane Translocation of Bacterial ADP-Ribosylating Toxins

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Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 406))

Abstract

Bacterial ADP-ribosylating toxins are the causative agents for several severe human and animal diseases such as diphtheria, cholera, or enteric diseases. They display an AB-type structure: The enzymatically active A-domain attaches to the binding/translocation B-domain which then binds to a receptor on the cell surface. After receptor-mediated endocytosis, the B-domain facilitates the membrane translocation of the unfolded A-domain into the host cell cytosol. Here, the A-domain transfers an ADP-ribose moiety onto its specific substrate which leads to characteristic cellular effects and thus to severe clinical symptoms. Since the A-domain has to reach the cytosol to achieve a cytotoxic effect, the membrane translocation represents a crucial step during toxin uptake. Host cell chaperones including Hsp90 and protein-folding helper enzymes of the peptidyl-prolyl cis/trans isomerase (PPIase) type facilitate this membrane translocation of the unfolded A-domain for ADP-ribosylating toxins but not for toxins with a different enzyme activity. This review summarizes the uptake mechanisms of the ADP-ribosylating clostridial binary toxins, diphtheria toxin (DT) and cholera toxin (CT), with a special focus on the interaction of these toxins with the chaperones Hsp90 and Hsp70 and PPIases of the cyclophilin and FK506-binding protein families during the membrane translocation of their ADP-ribosyltransferase domains into the host cell cytosol. Moreover, the medical implications of host cell chaperones and PPIases as new drug targets for the development of novel therapeutic strategies against diseases caused by bacterial ADP-ribosylating toxins are discussed.

Katharina Ernst and Leonie Schnell contributed equally to this work

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Abbreviations

ADP-RT:

ADP-ribosyltransferase

CsA:

Cyclosporine A, inhibitor of cyclophilins

CT:

Cholera toxin

Cyp:

Cyclophilin

DT:

Diphtheria toxin

FK506:

Inhibitor of FK506-binding proteins

FKBP:

FK506-binding protein

GA:

Geldanamycin, inhibitor of Hsp90

PPIase:

Peptidyl-prolyl cis/trans isomerase

Rad:

Radicicol, inhibitor of Hsp90

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

    Katharina Ernst, Leonie Schnell & Holger Barth

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Ernst, K., Schnell, L., Barth, H. (2016). Host Cell Chaperones Hsp70/Hsp90 and Peptidyl-Prolyl Cis/Trans Isomerases Are Required for the Membrane Translocation of Bacterial ADP-Ribosylating Toxins. In: Barth, H. (eds) Uptake and Trafficking of Protein Toxins. Current Topics in Microbiology and Immunology, vol 406. Springer, Cham. https://doi.org/10.1007/82_2016_14

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