title: Proteasome-mediated degradation of integral inner nuclear membrane protein emerin in fibroblasts lacking A-type lamins.
abstract: We previously identified and characterized a homozygous LMNA nonsense mutation leading to the absence of A-type lamins in a premature neonate who died at birth. We show here that the absence of A-type lamins is due to degradation of the aberrant mRNA transcript with a premature termination codon. In cultured fibroblasts from the subject with the homozygous LMNA nonsense mutation, there was a decreased steady-state expression of the integral inner nuclear membrane proteins emerin and nesprin-1alpha associated with their mislocalization to the bulk endoplasmic reticulum and a hyperphosphorylation of emerin. To determine if decreased emerin expression occurred post-translationally, we treated cells with a selective proteasome inhibitor and observed an increase in expression. Our results show that mislocalization of integral inner nuclear membrane proteins to the endoplasmic reticulum in human cells lacking A-type lamins leads to their degradation and provides the first evidence that their degradation is mediated by the proteasome.
authors.affiliation: Departments of Medicine and Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.forename: Catherine
authors.initials: C
authors.lastname: Massart
authors.forename: Baziel G
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
mesh_terms: D002478:Cells, Cultured; D002648:Child; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000648:ultrastructure; D006720:Homozygote; D006801:Humans; D034904:Lamin Type A / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C092710:emerin; D046988:Proteasome Endopeptidase Complex