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An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress

Emerin is a nuclear envelope protein that contributes to genome organization and cell mechanics. Through its N-terminal LAP2-emerin-MAN1 (LEM)-domain, emerin interacts with the DNA-binding protein barrier-to-autointegration (BAF). Emerin also binds to members of the linker of the nucleoskeleton and...

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Autores principales: Essawy, Nada, Samson, Camille, Petitalot, Ambre, Moog, Sophie, Bigot, Anne, Herrada, Isaline, Marcelot, Agathe, Arteni, Ana-Andreea, Coirault, Catherine, Zinn-Justin, Sophie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628311/
https://www.ncbi.nlm.nih.gov/pubmed/31185657
http://dx.doi.org/10.3390/cells8060570
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author Essawy, Nada
Samson, Camille
Petitalot, Ambre
Moog, Sophie
Bigot, Anne
Herrada, Isaline
Marcelot, Agathe
Arteni, Ana-Andreea
Coirault, Catherine
Zinn-Justin, Sophie
author_facet Essawy, Nada
Samson, Camille
Petitalot, Ambre
Moog, Sophie
Bigot, Anne
Herrada, Isaline
Marcelot, Agathe
Arteni, Ana-Andreea
Coirault, Catherine
Zinn-Justin, Sophie
author_sort Essawy, Nada
collection PubMed
description Emerin is a nuclear envelope protein that contributes to genome organization and cell mechanics. Through its N-terminal LAP2-emerin-MAN1 (LEM)-domain, emerin interacts with the DNA-binding protein barrier-to-autointegration (BAF). Emerin also binds to members of the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Mutations in the gene encoding emerin are responsible for the majority of cases of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). Most of these mutations lead to an absence of emerin. A few missense and short deletion mutations in the disordered region of emerin are also associated with X-EDMD. More recently, missense and short deletion mutations P22L, ∆K37 and T43I were discovered in emerin LEM-domain, associated with isolated atrial cardiac defects (ACD). Here we reveal which defects, at both the molecular and cellular levels, are elicited by these LEM-domain mutations. Whereas ΔK37 mutation impaired the correct folding of the LEM-domain, P22L and T43I had no impact on the 3D structure of emerin. Surprisingly, all three mutants bound to BAF, albeit with a weaker affinity in the case of ΔK37. In human myofibroblasts derived from a patient’s fibroblasts, emerin ∆K37 was correctly localized at the inner nuclear membrane, but was present at a significantly lower level, indicating that this mutant is abnormally degraded. Moreover, SUN2 was reduced, and these cells were defective in producing actin stress fibers when grown on a stiff substrate and after cyclic stretches. Altogether, our data suggest that the main effect of mutation ΔK37 is to perturb emerin function within the LINC complex in response to mechanical stress.
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spelling pubmed-66283112019-07-23 An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress Essawy, Nada Samson, Camille Petitalot, Ambre Moog, Sophie Bigot, Anne Herrada, Isaline Marcelot, Agathe Arteni, Ana-Andreea Coirault, Catherine Zinn-Justin, Sophie Cells Article Emerin is a nuclear envelope protein that contributes to genome organization and cell mechanics. Through its N-terminal LAP2-emerin-MAN1 (LEM)-domain, emerin interacts with the DNA-binding protein barrier-to-autointegration (BAF). Emerin also binds to members of the linker of the nucleoskeleton and cytoskeleton (LINC) complex. Mutations in the gene encoding emerin are responsible for the majority of cases of X-linked Emery-Dreifuss muscular dystrophy (X-EDMD). Most of these mutations lead to an absence of emerin. A few missense and short deletion mutations in the disordered region of emerin are also associated with X-EDMD. More recently, missense and short deletion mutations P22L, ∆K37 and T43I were discovered in emerin LEM-domain, associated with isolated atrial cardiac defects (ACD). Here we reveal which defects, at both the molecular and cellular levels, are elicited by these LEM-domain mutations. Whereas ΔK37 mutation impaired the correct folding of the LEM-domain, P22L and T43I had no impact on the 3D structure of emerin. Surprisingly, all three mutants bound to BAF, albeit with a weaker affinity in the case of ΔK37. In human myofibroblasts derived from a patient’s fibroblasts, emerin ∆K37 was correctly localized at the inner nuclear membrane, but was present at a significantly lower level, indicating that this mutant is abnormally degraded. Moreover, SUN2 was reduced, and these cells were defective in producing actin stress fibers when grown on a stiff substrate and after cyclic stretches. Altogether, our data suggest that the main effect of mutation ΔK37 is to perturb emerin function within the LINC complex in response to mechanical stress. MDPI 2019-06-10 /pmc/articles/PMC6628311/ /pubmed/31185657 http://dx.doi.org/10.3390/cells8060570 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
Essawy, Nada
Samson, Camille
Petitalot, Ambre
Moog, Sophie
Bigot, Anne
Herrada, Isaline
Marcelot, Agathe
Arteni, Ana-Andreea
Coirault, Catherine
Zinn-Justin, Sophie
An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title_full An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title_fullStr An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title_full_unstemmed An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title_short An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress
title_sort emerin lem-domain mutation impairs cell response to mechanical stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628311/
https://www.ncbi.nlm.nih.gov/pubmed/31185657
http://dx.doi.org/10.3390/cells8060570
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