Sumoylation regulates lamin A function and is lost in lamin A mutants associated with familial cardiomyopathies.
Lamin A mutations cause many diseases, including cardiomyopathies and Progeria Syndrome. The covalent attachment of small ubiquitin-like modifier (SUMO) polypeptides regulates the function of many proteins. Until now, no examples of human disease-causing mutations that occur within a sumoylation consensus sequence and alter sumoylation were known. We show that lamin A is sumoylated at lysine 201 and that two lamin A mutants associated with familial dilated cardiomyopathy, E203G and E203K, exhibit decreased sumoylation. E203 occupies the conserved +2 position in the sumoylation consensus Psi KXE. Lamin A mutants E203G, E203K, and K201R all exhibit a similar aberrant subcellular localization and are associated with increased cell death. Fibroblasts from an individual with the E203K lamin A mutation also exhibit decreased lamin A sumoylation and increased cell death. These results suggest that SUMO modification is important for normal lamin A function and implicate an involvement for altered sumoylation in the E203G/E203K lamin A cardiomyopathies.
Zhang
Yu-Qian
YQ
Department of Molecular and Cellular Biochemistry, Chandler Medical Center, University of Kentucky, Lexington, KY 40536, USA.
Sarge
Kevin D
KD
D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism*; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D021381:Protein Transport; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*
D034904:Lamin Type A; D050505:Mutant Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D008239:Lysine