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A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin

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 specif...

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Autores principales: Ernst, Katharina, Liebscher, Markus, Mathea, Sebastian, Granzhan, Anton, Schmid, Johannes, Popoff, Michel R., Ihmels, Heiko, Barth, Holger, Schiene-Fischer, Cordelia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738285/
https://www.ncbi.nlm.nih.gov/pubmed/26839186
http://dx.doi.org/10.1038/srep20301
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author Ernst, Katharina
Liebscher, Markus
Mathea, Sebastian
Granzhan, Anton
Schmid, Johannes
Popoff, Michel R.
Ihmels, Heiko
Barth, Holger
Schiene-Fischer, Cordelia
author_facet Ernst, Katharina
Liebscher, Markus
Mathea, Sebastian
Granzhan, Anton
Schmid, Johannes
Popoff, Michel R.
Ihmels, Heiko
Barth, Holger
Schiene-Fischer, Cordelia
author_sort Ernst, Katharina
collection PubMed
description 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.
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spelling pubmed-47382852016-02-09 A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin Ernst, Katharina Liebscher, Markus Mathea, Sebastian Granzhan, Anton Schmid, Johannes Popoff, Michel R. Ihmels, Heiko Barth, Holger Schiene-Fischer, Cordelia Sci Rep Article 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. Nature Publishing Group 2016-02-03 /pmc/articles/PMC4738285/ /pubmed/26839186 http://dx.doi.org/10.1038/srep20301 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ernst, Katharina
Liebscher, Markus
Mathea, Sebastian
Granzhan, Anton
Schmid, Johannes
Popoff, Michel R.
Ihmels, Heiko
Barth, Holger
Schiene-Fischer, Cordelia
A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title_full A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title_fullStr A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title_full_unstemmed A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title_short A novel Hsp70 inhibitor prevents cell intoxication with the actin ADP-ribosylating Clostridium perfringens iota toxin
title_sort novel hsp70 inhibitor prevents cell intoxication with the actin adp-ribosylating clostridium perfringens iota toxin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738285/
https://www.ncbi.nlm.nih.gov/pubmed/26839186
http://dx.doi.org/10.1038/srep20301
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