Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin

ABSTRACT Clostridium perfringens enterotoxin (CPE) contributes to several important human gastrointestinal (GI) diseases. This toxin and its derivatives are also being explored for translational applications, i.e., cancer therapy or drug delivery. Some, but not all, members of the 24-member claudin...

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Autores principales:	Archana Shrestha, Bruce A. McClane
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/67331a8532a74cda87cdf2127b7a146b
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spelling	oai:doaj.org-article:67331a8532a74cda87cdf2127b7a146b2021-11-15T15:40:21ZHuman Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin10.1128/mBio.00594-122150-7511https://doaj.org/article/67331a8532a74cda87cdf2127b7a146b2013-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00594-12https://doaj.org/toc/2150-7511ABSTRACT Clostridium perfringens enterotoxin (CPE) contributes to several important human gastrointestinal (GI) diseases. This toxin and its derivatives are also being explored for translational applications, i.e., cancer therapy or drug delivery. Some, but not all, members of the 24-member claudin (Cldn) family of mammalian tight junction proteins can serve as CPE receptors. Among the human Cldns (hCldns), hCldn-3 and -4 are known to convey CPE sensitivity when expressed by fibroblast transfectants. However, other Cldns are also reportedly expressed in the intestines, where they might contribute to natural CPE-mediated GI disease, and in other organs, where they might react with CPE-based therapeutics. Therefore, the current study assessed whether two additional hCldns beside hCldn-3 and -4 are also functional CPE receptors. Using Cldn-expressing transfectants, hCldn-8 and -14 were shown to convey CPE-mediated cytotoxicity at pathophysiologically relevant concentrations of this toxin, although ~2-to-10-fold less efficiently than hCldn-4. Site-directed mutagenesis then demonstrated that the N146 residue in hCldn-14 and the S151 residue in hCldn-8 are largely responsible for modulating the weaker CPE binding properties of hCldn-8 and -14 versus hCldn-4, which broadens understanding of Cldn:CPE binding interactions. Since Cldn-8 and -14 are reportedly expressed in mammalian intestines, the current results support the possibility that these two hCldns contribute to natural CPE-mediated gastrointestinal disease and could be CPE-based therapeutic targets for cancers overexpressing those claudins. However, these results also suggest caution during therapeutic use of CPE, which might trigger toxic side effects in normal human tissues producing hCldn-8 or -14, as well as in those producing hCldn-3 or -4. IMPORTANCE Clostridium perfringens enterotoxin (CPE) is responsible for the gastrointestinal symptoms of the second-most-common bacterial food-borne illness and is also being explored for use as a cancer therapeutic or for increasing drug delivery. Until now, the only known human CPE receptors were claudin-3 and -4. This work shows that human claudin-8 and -14 can also bind CPE and convey cytotoxicity, although slightly less efficiently than claudin-3 and -4. The claudin-8 and -14 residues responsible for this weaker CPE binding were identified, shedding new light on CPE:claudin interactions.Archana ShresthaBruce A. McClaneAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 1 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Archana Shrestha Bruce A. McClane Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
description	ABSTRACT Clostridium perfringens enterotoxin (CPE) contributes to several important human gastrointestinal (GI) diseases. This toxin and its derivatives are also being explored for translational applications, i.e., cancer therapy or drug delivery. Some, but not all, members of the 24-member claudin (Cldn) family of mammalian tight junction proteins can serve as CPE receptors. Among the human Cldns (hCldns), hCldn-3 and -4 are known to convey CPE sensitivity when expressed by fibroblast transfectants. However, other Cldns are also reportedly expressed in the intestines, where they might contribute to natural CPE-mediated GI disease, and in other organs, where they might react with CPE-based therapeutics. Therefore, the current study assessed whether two additional hCldns beside hCldn-3 and -4 are also functional CPE receptors. Using Cldn-expressing transfectants, hCldn-8 and -14 were shown to convey CPE-mediated cytotoxicity at pathophysiologically relevant concentrations of this toxin, although ~2-to-10-fold less efficiently than hCldn-4. Site-directed mutagenesis then demonstrated that the N146 residue in hCldn-14 and the S151 residue in hCldn-8 are largely responsible for modulating the weaker CPE binding properties of hCldn-8 and -14 versus hCldn-4, which broadens understanding of Cldn:CPE binding interactions. Since Cldn-8 and -14 are reportedly expressed in mammalian intestines, the current results support the possibility that these two hCldns contribute to natural CPE-mediated gastrointestinal disease and could be CPE-based therapeutic targets for cancers overexpressing those claudins. However, these results also suggest caution during therapeutic use of CPE, which might trigger toxic side effects in normal human tissues producing hCldn-8 or -14, as well as in those producing hCldn-3 or -4. IMPORTANCE Clostridium perfringens enterotoxin (CPE) is responsible for the gastrointestinal symptoms of the second-most-common bacterial food-borne illness and is also being explored for use as a cancer therapeutic or for increasing drug delivery. Until now, the only known human CPE receptors were claudin-3 and -4. This work shows that human claudin-8 and -14 can also bind CPE and convey cytotoxicity, although slightly less efficiently than claudin-3 and -4. The claudin-8 and -14 residues responsible for this weaker CPE binding were identified, shedding new light on CPE:claudin interactions.
format	article
author	Archana Shrestha Bruce A. McClane
author_facet	Archana Shrestha Bruce A. McClane
author_sort	Archana Shrestha
title	Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
title_short	Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
title_full	Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
title_fullStr	Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
title_full_unstemmed	Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin
title_sort	human claudin-8 and -14 are receptors capable of conveying the cytotoxic effects of <named-content content-type="genus-species">clostridium perfringens</named-content> enterotoxin
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/67331a8532a74cda87cdf2127b7a146b
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Human Claudin-8 and -14 Are Receptors Capable of Conveying the Cytotoxic Effects of <named-content content-type="genus-species">Clostridium perfringens</named-content> Enterotoxin

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