Disease relevance of Emd

• Emery-Dreifuss muscular dystrophy can be caused by mutations in the nuclear envelope proteins lamin A/C and emerin [1].
• The lipodystrophy mutation R482Q, which causes a different phenotype and is believed to act through an emerin-independent mechanism, was indistinguishable from wild-type in its localization and its ability to trap emerin at the nuclear rim [2].

High impact information on Emd

• The EDMD gene encodes a novel serine-rich protein termed emerin, which contains a 20 amino acid hydrophobic domain at the C terminus, similar to that described for many membrane proteins of the secretory pathway involved in vesicular transport [3].
• Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope [4].
• Interestingly, expression of mechanosensitive genes in response to mechanical strain was impaired in emerin-deficient cells, and prolonged mechanical stimulation increased apoptosis in emerin-deficient cells [1].
• Thus, emerin-deficient mouse embryo fibroblasts have apparently normal nuclear mechanics but impaired expression of mechanosensitive genes in response to strain, suggesting that emerin mutations may act through altered transcriptional regulation and not by increasing nuclear fragility [1].
• These include the mislocalization of emerin, an inner nuclear membrane protein, defects in which are implicated in Emery-Dreifuss muscular dystrophy (EDMD), one of the three major X-linked dystrophies [5].

Biological context of Emd

• Although several proteins undergo tyrosine phosphorylation at the nuclear envelope, we achieved, for the first time, the identification of tyrosine-phosphorylation sites of a nuclear-membrane protein, emerin, by applying two mass spectrometry-based techniques [6].
• Subtle effects on the function of the lamina-emerin complex in EDMD/CMD1A patients might be responsible for the skeletal and/or cardiac muscle phenotype [2].
• Using transfection of lamin-A/C-deficient fibroblasts, we have studied the effects of nine pathogenic mutations on the ability of lamin A to assemble normally and to localize emerin normally at the nuclear rim [2].
• The 2.9-kb mouse emerin gene was completely sequenced and found to be composed of 6 exons and encode a protein 73% identical to that of the human protein [7].
• These results show that the process of programmed cell death in muscle cells leads to emerin proteolysis, which appears to be related to caspase 6 activation and to cleavage of other nuclear envelope proteins, that share sequence homologies or functional features with emerin [8].

Anatomical context of Emd

• Identification of tyrosine-phosphorylation sites in the nuclear membrane protein emerin [6].
• Emerin-lacking mice show minimal motor and cardiac dysfunctions with nuclear-associated vacuoles [9].
• In this paper, we analyze the interaction between emerin and actin in differentiating mouse myoblasts [10].
• We demonstrate that emerin and lamin A/C are bound to actin at the late stages of myotube differentiation and in mature muscle [10].
• A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified [11].

Associations of Emd with chemical compounds

• In this study, mutant mice lacking emerin were produced by insertion of a neomycin resistance gene into exon 6 of the coding gene [9].
• In further experiments, the metabolites from Sta. chartarum or from closely related fungi (atranones B and E, satratoxin G, trichodermin, 7-alpha-hydroxytrichodermol, staplabin, and SMTP-7) and the known fungal toxins sterigmatocystin, citrinin, and ochratoxin A were each tested with Str. californicus [12].

Other interactions of Emd

• Analysis of Rb1 phosphorylation states showed prolonged hyper-phosphorylation at key developmental stages in Emd null myogenic cells, both in vivo and in vitro [13].
• Staurosporine treatment and serum starvation promote the cleavage of emerin in cultured mouse myoblasts: involvement of a caspase-dependent mechanism [8].
• In vivo specific inhibition of caspase 3 or caspase 6 activity completely abolished emerin proteolysis [8].

Analytical, diagnostic and therapeutic context of Emd

• With a multiprotease approach combined with highly specific phosphopeptide enrichment and nano liquid chromatography tandem mass spectrometry analysis, we identified three tyrosine-phosphorylation sites, Y-75, Y-95, and Y-106, in mouse emerin [6].
• Emerin-deficient mouse embryo fibroblasts have abnormal nuclear shape, but in contrast to A-type lamin-deficient cells, exhibit nuclear deformations comparable to wild-type cells in cellular strain experiments, and the integrity of emerin-deficient nuclear envelopes appeared normal in a nuclear microinjection assay [1].
• Electrocardiography showed mild prolongation of atrioventricular conduction time in emerin-lacking male mice older than 40 weeks of age [9].
• Myoblast apoptosis and emerin degradation were associated with chromatin compaction and detachment from the nuclear lamina, as detected by electron microscopy [8].
• On the basis of equivalent numbers of bacteria and spores of fungi added to cell cultures, the overall potency to stimulate the production of proinflammatory mediators decreased in the order Ps. fluorescens > Str. californicus > B. cereus > Sta. chartarum > A. versicolor > P. spinulosum [14].

References