Open AccessHsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
Author(s) -
Katharina Ernst,
Johannes A. Schmid,
Matthias Beck,
Marlen Hägele,
Meike Hohwieler,
Patricia Hauff,
Anna Katharina Ückert,
Anna Anastasia,
Michael Fauler,
Thomas Jank,
Klaus Aktories,
Michel R. Popoff,
Cordelia SchieneFischer,
Alexander Kleger,
Martin C. Müller,
Manfred Frick,
Holger Barth
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-02882-y
Subject(s) - cytosol , endosome , microbiology and biotechnology , endocytic cycle , anthrax toxin , chemistry , clostridium perfringens , transport protein , intracellular , toxin , cell , biochemistry , enzyme , biology , endocytosis , fusion protein , bacteria , recombinant dna , genetics , gene
Binary enterotoxins Clostridium ( C .) botulinum C2 toxin, C. perfringens iota toxin and C. difficile toxin CDT are composed of a transport (B) and a separate non-linked enzyme (A) component. Their B-components mediate endocytic uptake into mammalian cells and subsequently transport of the A-components from acidic endosomes into the cytosol, where the latter ADP-ribosylate G-actin resulting in cell rounding and cell death causing clinical symptoms. Protein folding enzymes, including Hsp90 and peptidyl-prolyl cis/trans isomerases facilitate transport of the A-components across endosomal membranes. Here, we identified Hsp70 as a novel host cell factor specifically interacting with A-components of C2, iota and CDT toxins to facilitate their transport into the cell cytosol. Pharmacological Hsp70-inhibition specifically prevented pH-dependent trans-membrane transport of A-components into the cytosol thereby protecting living cells and stem cell-derived human miniguts from intoxication. Thus, Hsp70-inhibition might lead to development of novel therapeutic strategies to treat diseases associated with bacterial ADP-ribosylating toxins.