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

  • Katharina Ernst
  • Leonie Schnell
  • Holger Barth
Chapter
Part of the Current Topics in Microbiology and Immunology book series (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.

List of Abbreviations (Optional)

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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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Institute of Pharmacology and ToxicologyUniversity of Ulm Medical CenterUlmGermany

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