title: Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress.
abstract: Familial hypercholesterolemia is an autosomal dominant disease caused by mutations in the gene encoding the low density lipoprotein receptor (LDLR). More than 50% of these mutations lead to receptor proteins that are completely or partly retained in the endoplasmic reticulum (ER). The mechanisms involved in the intracellular processing and retention of mutant LDLR are poorly understood. In the present study we show that the G544V mutant LDLR associates with the chaperones Grp78, Grp94, ERp72, and calnexin in the ER of transfected Chinese hamster ovary cells. Retention of the mutant LDLR was shown to cause ER stress and activation of the unfolded protein response. We observed a marked increase in the activity of two ER stress sensors, IRE1 and PERK. These results show that retention of mutant LDLR in ER induces cellular responses, which might be important for the clinical outcome of familial hypercholesterolemia.
authors.affiliation: Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet, University Hospital, N-0027 Oslo, Norway.
authors.forename: Stine
authors.initials: S
authors.lastname: Sørensen
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.forename: Kari Solberg
authors.initials: KS
authors.lastname: Bakken
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
authors.forename: Mari Ann
authors.initials: MA
authors.lastname: Kulseth
mesh_terms: D000818:Animals; D016466:CHO Cells; D037281:Calnexin / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D016296:Mutagenesis; D017510:Protein Folding; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D037281:Calnexin; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D035941:Iron Regulatory Protein 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D011973:Receptors, LDL; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D019892:eIF-2 Kinase; C062477:endoplasmic reticulum glycoprotein p72; C053387:endoplasmin; C018551:glucose-regulated proteins