title: A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin.
abstract: Hsp70 family proteins are folding helper proteins involved in a wide variety of cellular pathways. Members of this family interact with key factors in signal transduction, transcription, cell-cycle control, and stress response. Here, we developed the first Hsp70 low molecular weight inhibitor specifically targeting the peptide binding site of human Hsp70. After demonstrating that the inhibitor modulates the Hsp70 function in the cell, we used the inhibitor to show for the first time that the stress-inducible chaperone Hsp70 functions as molecular component for entry of a bacterial protein toxin into mammalian cells. Pharmacological inhibition of Hsp70 protected cells from intoxication with the binary actin ADP-ribosylating iota toxin from Clostridium perfringens, the prototype of a family of enterotoxins from pathogenic Clostridia and inhibited translocation of its enzyme component across cell membranes into the cytosol. This finding offers a starting point for novel therapeutic strategies against certain bacterial toxins.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ernst
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding Halle, Halle (Saale), Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Liebscher
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding Halle, Halle (Saale), Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mathea
authors.affiliation: Department of Chemistry and Biology, University of Siegen, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Granzhan
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmid
authors.affiliation: Department of Anaerobic Bacteria, Pasteur Institute, Paris, France.
authors.forename: Michel R
authors.initials: MR
authors.lastname: Popoff
authors.affiliation: Department of Anaerobic Bacteria, Pasteur Institute, Paris, France.
authors.forename: Heiko
authors.initials: H
authors.lastname: Ihmels
authors.affiliation: Institute of Pharmacology and Toxicology, University of Ulm Medical Center, Ulm, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Barth
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding Halle, Halle (Saale), Germany.
authors.forename: Cordelia
authors.initials: C
authors.lastname: Schiene-Fischer
mesh_terms: D036002:ADP Ribose Transferases / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D001427:Bacterial Toxins / Q000633:toxicity*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D001427:Bacterial Toxins; D018840:HSP70 Heat-Shock Proteins; D054852:Small Molecule Libraries; C050737:iota toxin, Clostridium perfringens; D036002:ADP Ribose Transferases
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