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EKV mutant connexin 31 associated cell death is mediated by ER stress

The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies revea...

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Autores principales: Tattersall, Daniel, Scott, Claire A., Gray, Colin, Zicha, Daniel, Kelsell, David P.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778370/
https://www.ncbi.nlm.nih.gov/pubmed/19755382
http://dx.doi.org/10.1093/hmg/ddp436
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author Tattersall, Daniel
Scott, Claire A.
Gray, Colin
Zicha, Daniel
Kelsell, David P.
author_facet Tattersall, Daniel
Scott, Claire A.
Gray, Colin
Zicha, Daniel
Kelsell, David P.
author_sort Tattersall, Daniel
collection PubMed
description The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations. The Cx31 mutants (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 are associated with EKV and the mutant (66delD)Cx31 with peripheral neuropathy and hearing loss, however the mechanisms of pathogenesis remain to be elucidated. Expression of (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 in vitro, but not (WT)Cx31 or (66delD)Cx31, cause elevated levels of cell-type specific cell death. Previous studies suggest that Cx-associated cell death may be related to abnormal ‘leaky’ hemichannels but we produced direct evidence against that being the major mechanism. Additionally, our immunocytochemistry showed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not (WT)Cx31 or (66delD)Cx31. We conclude that the endoplasmic reticulum (ER) stress leading to the UPR is the main mechanism of mutant Cx31-associated cell death. These results indicate that, in vivo, ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin.
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spelling pubmed-27783702009-11-18 EKV mutant connexin 31 associated cell death is mediated by ER stress Tattersall, Daniel Scott, Claire A. Gray, Colin Zicha, Daniel Kelsell, David P. Hum Mol Genet Articles The epidermis expresses a number of connexin (Cx) proteins that are implicated in gap junction-mediated cell communication. Distinct dominantly inherited mutations in Cx31 cause the skin disease erythrokeratoderma variabilis (EKV) and hearing loss with or without neuropathy. Functional studies reveal tissue-specific effects of these Cx31 disease-associated mutations. The Cx31 mutants (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 are associated with EKV and the mutant (66delD)Cx31 with peripheral neuropathy and hearing loss, however the mechanisms of pathogenesis remain to be elucidated. Expression of (R42P)Cx31, (C86S)Cx31 and (G12D)Cx31 in vitro, but not (WT)Cx31 or (66delD)Cx31, cause elevated levels of cell-type specific cell death. Previous studies suggest that Cx-associated cell death may be related to abnormal ‘leaky’ hemichannels but we produced direct evidence against that being the major mechanism. Additionally, our immunocytochemistry showed upregulation of components of the unfolded protein response (UPR) in cells expressing the EKV-associated Cx31 mutants but not (WT)Cx31 or (66delD)Cx31. We conclude that the endoplasmic reticulum (ER) stress leading to the UPR is the main mechanism of mutant Cx31-associated cell death. These results indicate that, in vivo, ER stress may lead to abnormal keratinocyte differentiation and hyperproliferation in EKV patient skin. Oxford University Press 2009-12-15 2009-09-14 /pmc/articles/PMC2778370/ /pubmed/19755382 http://dx.doi.org/10.1093/hmg/ddp436 Text en © The Author 2009. Published by Oxford University Press http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Tattersall, Daniel
Scott, Claire A.
Gray, Colin
Zicha, Daniel
Kelsell, David P.
EKV mutant connexin 31 associated cell death is mediated by ER stress
title EKV mutant connexin 31 associated cell death is mediated by ER stress
title_full EKV mutant connexin 31 associated cell death is mediated by ER stress
title_fullStr EKV mutant connexin 31 associated cell death is mediated by ER stress
title_full_unstemmed EKV mutant connexin 31 associated cell death is mediated by ER stress
title_short EKV mutant connexin 31 associated cell death is mediated by ER stress
title_sort ekv mutant connexin 31 associated cell death is mediated by er stress
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778370/
https://www.ncbi.nlm.nih.gov/pubmed/19755382
http://dx.doi.org/10.1093/hmg/ddp436
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