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Open AccessArticle

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

1
Sorbonne Université, INSERM UMR_S974, Center for Research in Myology, 75013 Paris, France
2
Laboratory of Structural Biology and Radiobiology, Institute for Integrative Biology of the Cell (CEA, CNRS, University Paris South), University Paris-Saclay, 91190 Gif-sur-Yvette, France
3
Inovarion, 251 Rue St Jacques, 75005 Paris, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(6), 570; https://doi.org/10.3390/cells8060570
Received: 14 May 2019 / Revised: 4 June 2019 / Accepted: 5 June 2019 / Published: 10 June 2019
(This article belongs to the Special Issue Nucleolar Organization and Functions in Health and Disease)
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. View Full-Text
Keywords: emerin; atrial cardiac defects; BAF; actin; mechano-transduction emerin; atrial cardiac defects; BAF; actin; mechano-transduction
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Essawy, N.; Samson, C.; Petitalot, A.; Moog, S.; Bigot, A.; Herrada, I.; Marcelot, A.; Arteni, A.-A.; Coirault, C.; Zinn-Justin, S. An Emerin LEM-Domain Mutation Impairs Cell Response to Mechanical Stress. Cells 2019, 8, 570.

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