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Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells

Clostridium perfringens enterotoxin (CPE) contributes to diarrhea and an often-lethal enterotoxemia. CPE action starts when it binds to claudin receptors, forming a small complex (90 kDa). Six small complexes then oligomerize to create prepores, followed by insertion of beta-hairpins from CPE to for...

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Autores principales: Mehdizadeh Gohari, Iman, Li, Jihong, Navarro, Mauricio, Uzal, Francisco, McClane, Bruce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832201/
https://www.ncbi.nlm.nih.gov/pubmed/31601044
http://dx.doi.org/10.3390/toxins11100582
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author Mehdizadeh Gohari, Iman
Li, Jihong
Navarro, Mauricio
Uzal, Francisco
McClane, Bruce
author_facet Mehdizadeh Gohari, Iman
Li, Jihong
Navarro, Mauricio
Uzal, Francisco
McClane, Bruce
author_sort Mehdizadeh Gohari, Iman
collection PubMed
description Clostridium perfringens enterotoxin (CPE) contributes to diarrhea and an often-lethal enterotoxemia. CPE action starts when it binds to claudin receptors, forming a small complex (90 kDa). Six small complexes then oligomerize to create prepores, followed by insertion of beta-hairpins from CPE to form beta-barrel pores named CH-1 or CH-2. Of the ~27 members of the human claudin protein family, only some bind CPE. However, both receptor claudins and the nonreceptor claudin-1 (CLDN-1) are associated with the small and CH-1/CH-2 CPE complexes. Therefore, this study evaluated whether claudin-1 affects CPE action by generating a CLDN-1 null mutant in Caco-2 cells using CRISPR-Cas9. Compared to wild-type Caco-2 cells, paracellular permeability of the CLDN-1 mutant was significantly enhanced, suggesting that claudin-1 may reduce CPE absorption during enterotoxemia. The CLDN-1 mutant was also markedly more sensitive than wild-type Caco-2 cells to apically-applied CPE. The mechanism behind this increased sensitivity involved higher CPE binding by the CLDN-1 mutant vs. wild-type Caco-2 cells, which led to more CH-1/CH-2 complex formation. However, the CH-1/CH-2 complexes formed by the CLDN-1 mutant were less stable or trypsin resistant than those of wild-type cells. These results indicate that, although a nonreceptor, CLDN-1 positively and negatively influences CPE action.
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spelling pubmed-68322012019-11-20 Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells Mehdizadeh Gohari, Iman Li, Jihong Navarro, Mauricio Uzal, Francisco McClane, Bruce Toxins (Basel) Article Clostridium perfringens enterotoxin (CPE) contributes to diarrhea and an often-lethal enterotoxemia. CPE action starts when it binds to claudin receptors, forming a small complex (90 kDa). Six small complexes then oligomerize to create prepores, followed by insertion of beta-hairpins from CPE to form beta-barrel pores named CH-1 or CH-2. Of the ~27 members of the human claudin protein family, only some bind CPE. However, both receptor claudins and the nonreceptor claudin-1 (CLDN-1) are associated with the small and CH-1/CH-2 CPE complexes. Therefore, this study evaluated whether claudin-1 affects CPE action by generating a CLDN-1 null mutant in Caco-2 cells using CRISPR-Cas9. Compared to wild-type Caco-2 cells, paracellular permeability of the CLDN-1 mutant was significantly enhanced, suggesting that claudin-1 may reduce CPE absorption during enterotoxemia. The CLDN-1 mutant was also markedly more sensitive than wild-type Caco-2 cells to apically-applied CPE. The mechanism behind this increased sensitivity involved higher CPE binding by the CLDN-1 mutant vs. wild-type Caco-2 cells, which led to more CH-1/CH-2 complex formation. However, the CH-1/CH-2 complexes formed by the CLDN-1 mutant were less stable or trypsin resistant than those of wild-type cells. These results indicate that, although a nonreceptor, CLDN-1 positively and negatively influences CPE action. MDPI 2019-10-09 /pmc/articles/PMC6832201/ /pubmed/31601044 http://dx.doi.org/10.3390/toxins11100582 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mehdizadeh Gohari, Iman
Li, Jihong
Navarro, Mauricio
Uzal, Francisco
McClane, Bruce
Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title_full Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title_fullStr Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title_full_unstemmed Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title_short Effects of Claudin-1 on the Action of Clostridium perfringens Enterotoxin in Caco-2 Cells
title_sort effects of claudin-1 on the action of clostridium perfringens enterotoxin in caco-2 cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832201/
https://www.ncbi.nlm.nih.gov/pubmed/31601044
http://dx.doi.org/10.3390/toxins11100582
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