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A disease- and phosphorylation-related nonmechanical function for keratin 8

Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphoryla...

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Autores principales: Ku, Nam-On, Omary, M. Bishr
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064169/
https://www.ncbi.nlm.nih.gov/pubmed/16818723
http://dx.doi.org/10.1083/jcb.200602146
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author Ku, Nam-On
Omary, M. Bishr
author_facet Ku, Nam-On
Omary, M. Bishr
author_sort Ku, Nam-On
collection PubMed
description Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate “sponge” for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins.
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spelling pubmed-20641692007-11-29 A disease- and phosphorylation-related nonmechanical function for keratin 8 Ku, Nam-On Omary, M. Bishr J Cell Biol Research Articles Keratin 8 (K8) variants predispose to human liver injury via poorly understood mechanisms. We generated transgenic mice that overexpress the human disease-associated K8 Gly61-to-Cys (G61C) variant and showed that G61C predisposes to liver injury and apoptosis and dramatically inhibits K8 phosphorylation at serine 73 (S73) via stress-activated kinases. This led us to generate mice that overexpress K8 S73-to-Ala (S73A), which mimicked the susceptibility of K8 G61C mice to injury, thereby providing a molecular link between K8 phosphorylation and disease-associated mutation. Upon apoptotic stimulation, G61C and S73A hepatocytes have persistent and increased nonkeratin proapoptotic substrate phosphorylation by stress-activated kinases, compared with wild-type hepatocytes, in association with an inability to phosphorylate K8 S73. Our findings provide the first direct link between patient-related human keratin variants and liver disease predisposition. The highly abundant cytoskeletal protein K8, and possibly other keratins with the conserved S73-containing phosphoepitope, can protect tissue from injury by serving as a phosphate “sponge” for stress-activated kinases and thereby provide a novel nonmechanical function for intermediate filament proteins. The Rockefeller University Press 2006-07-03 /pmc/articles/PMC2064169/ /pubmed/16818723 http://dx.doi.org/10.1083/jcb.200602146 Text en Copyright © 2006, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Ku, Nam-On
Omary, M. Bishr
A disease- and phosphorylation-related nonmechanical function for keratin 8
title A disease- and phosphorylation-related nonmechanical function for keratin 8
title_full A disease- and phosphorylation-related nonmechanical function for keratin 8
title_fullStr A disease- and phosphorylation-related nonmechanical function for keratin 8
title_full_unstemmed A disease- and phosphorylation-related nonmechanical function for keratin 8
title_short A disease- and phosphorylation-related nonmechanical function for keratin 8
title_sort disease- and phosphorylation-related nonmechanical function for keratin 8
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064169/
https://www.ncbi.nlm.nih.gov/pubmed/16818723
http://dx.doi.org/10.1083/jcb.200602146
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