A Novel Hsp70 Inhibitor Prevents Cell Intoxication with the Actin ADP-ribosylating Clostridium Perfringens Iota Toxin

Overview

Journal Sci Rep

Specialty Science

Date 2016 Feb 4

PMID 26839186

Citations 19

Authors

Katharina Ernst

Markus Liebscher

Sebastian Mathea

Anton Granzhan

Johannes Schmid

Michel R Popoff

Heiko Ihmels

Holger Barth

Cordelia Schiene-Fischer

Affiliations

Soon will be listed here.

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.

Citing Articles

Structural and Functional Insights into the Delivery Systems of and Clostridial Binary Toxins.

Sevdalis S, Varney K, Cook M, Gillespie J, Pozharski E, Weber D Toxins (Basel). 2024; 16(8).

PMID: 39195740 PMC: 11359772. DOI: 10.3390/toxins16080330.

Cellular Uptake and Cytotoxicity of Iota-Toxin.

Nagahama M, Takehara M, Seike S, Sakaguchi Y Toxins (Basel). 2023; 15(12).

PMID: 38133199 PMC: 10747272. DOI: 10.3390/toxins15120695.

Domperidone Inhibits C2 Toxin and Toxin.

Jia J, Braune-Yan M, Lietz S, Wahba M, Pulliainen A, Barth H Toxins (Basel). 2023; 15(7).

PMID: 37505681 PMC: 10467066. DOI: 10.3390/toxins15070412.

Domperidone Protects Cells from Intoxication with Toxins by Inhibiting Hsp70-Assisted Membrane Translocation.

Braune-Yan M, Jia J, Wahba M, Schmid J, Papatheodorou P, Barth H Toxins (Basel). 2023; 15(6).

PMID: 37368685 PMC: 10305128. DOI: 10.3390/toxins15060384.

HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances.

Zhao K, Zhou G, Liu Y, Zhang J, Chen Y, Liu L Biomolecules. 2023; 13(4).

PMID: 37189349 PMC: 10136146. DOI: 10.3390/biom13040601.

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