Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells

Abstract 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-...

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Autores principales:	Katharina Ernst, Johannes Schmid, Matthias Beck, Marlen Hägele, Meike Hohwieler, Patricia Hauff, Anna Katharina Ückert, Anna Anastasia, Michael Fauler, Thomas Jank, Klaus Aktories, Michel R. Popoff, Cordelia Schiene-Fischer, Alexander Kleger, Martin Müller, Manfred Frick, Holger Barth
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2307dc2fc83143dcbe2b740f45e9f84a
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spelling	oai:doaj.org-article:2307dc2fc83143dcbe2b740f45e9f84a2021-12-02T12:30:53ZHsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells10.1038/s41598-017-02882-y2045-2322https://doaj.org/article/2307dc2fc83143dcbe2b740f45e9f84a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02882-yhttps://doaj.org/toc/2045-2322Abstract 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.Katharina ErnstJohannes SchmidMatthias BeckMarlen HägeleMeike HohwielerPatricia HauffAnna Katharina ÜckertAnna AnastasiaMichael FaulerThomas JankKlaus AktoriesMichel R. PopoffCordelia Schiene-FischerAlexander KlegerMartin MüllerManfred FrickHolger BarthNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katharina Ernst Johannes Schmid Matthias Beck Marlen Hägele Meike Hohwieler Patricia Hauff Anna Katharina Ückert Anna Anastasia Michael Fauler Thomas Jank Klaus Aktories Michel R. Popoff Cordelia Schiene-Fischer Alexander Kleger Martin Müller Manfred Frick Holger Barth Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
description	Abstract 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.
format	article
author	Katharina Ernst Johannes Schmid Matthias Beck Marlen Hägele Meike Hohwieler Patricia Hauff Anna Katharina Ückert Anna Anastasia Michael Fauler Thomas Jank Klaus Aktories Michel R. Popoff Cordelia Schiene-Fischer Alexander Kleger Martin Müller Manfred Frick Holger Barth
author_facet	Katharina Ernst Johannes Schmid Matthias Beck Marlen Hägele Meike Hohwieler Patricia Hauff Anna Katharina Ückert Anna Anastasia Michael Fauler Thomas Jank Klaus Aktories Michel R. Popoff Cordelia Schiene-Fischer Alexander Kleger Martin Müller Manfred Frick Holger Barth
author_sort	Katharina Ernst
title	Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
title_short	Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
title_full	Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
title_fullStr	Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
title_full_unstemmed	Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells
title_sort	hsp70 facilitates trans-membrane transport of bacterial adp-ribosylating toxins into the cytosol of mammalian cells
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2307dc2fc83143dcbe2b740f45e9f84a
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Hsp70 facilitates trans-membrane transport of bacterial ADP-ribosylating toxins into the cytosol of mammalian cells

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