Identification of an emerin-beta-catenin complex in the heart important for intercalated disc architecture and beta-catenin localisation.
How mutations in the protein emerin lead to the cardiomyopathy associated with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is unclear. We identified emerin at the adherens junction of the intercalated disc, where it co-localised with the catenin family of proteins. Emerin bound to wild type beta-catenin both in vivo and in vitro. Mutating the GSK3beta phosphorylation sites on beta-catenin abolished this binding. Wild type but not mutant forms of emerin associated with X-EDMD were able to reduce beta-catenin protein levels. Cardiomyocytes from emerin-null mice hearts exhibited erroneous beta-catenin distribution and intercalated disc architecture. Treatment of wild type cardiomyocytes with phenylephrine, which inactivates GSK3beta, redistributed emerin and beta-catenin. Emerin was identified as a direct target of GSK3beta activity since exogenous expression of GSK3beta reduced emerin levels at the nuclear envelope. We propose that perturbation to or total loss of the emerin-beta-catenin complex compromises both intercalated disc function and beta-catenin signalling in cardiomyocytes.
Wheeler
Matthew A
MA
The Randall Division of Cell and Molecular Biophysics, King's College London, New Hunts House, Guy's Campus, London, SE1 1UL, UK. matthew.a.wheeler@kcl.ac.uk
Warley
Alice
A
Roberts
Roland G
RG
Ehler
Elisabeth
E
Ellis
Juliet A
JA
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin; C092710:emerin