Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress

Stine Sørensen; Trine Ranheim; Kari Solberg Bakken; Trond P Leren; Mari Ann Kulseth

doi:10.1074/jbc.M507071200

Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress

J Biol Chem. 2006 Jan 6;281(1):468-76. doi: 10.1074/jbc.M507071200. Epub 2005 Oct 28.

Authors

Stine Sørensen¹, Trine Ranheim, Kari Solberg Bakken, Trond P Leren, Mari Ann Kulseth

Affiliation

¹ Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet, University Hospital, N-0027 Oslo, Norway.

PMID: 16257961
DOI: 10.1074/jbc.M507071200

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.

MeSH terms

Animals
CHO Cells
Calnexin / metabolism
Cricetinae
DNA-Binding Proteins / genetics
Endoplasmic Reticulum / metabolism*
Endoplasmic Reticulum Chaperone BiP
HSP70 Heat-Shock Proteins / genetics
HSP70 Heat-Shock Proteins / metabolism
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism
Iron Regulatory Protein 1 / metabolism
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Molecular Chaperones / genetics
Molecular Chaperones / metabolism*
Mutagenesis
Protein Folding
RNA, Messenger / analysis
Receptors, LDL / chemistry*
Receptors, LDL / genetics*
Regulatory Factor X Transcription Factors
Transcription Factors / genetics
Transfection
eIF-2 Kinase / metabolism

Substances

DNA-Binding Proteins
Endoplasmic Reticulum Chaperone BiP
HSP70 Heat-Shock Proteins
Heat-Shock Proteins
Membrane Glycoproteins
Membrane Proteins
Molecular Chaperones
RNA, Messenger
Receptors, LDL
Regulatory Factor X Transcription Factors
Transcription Factors
endoplasmic reticulum glycoprotein p72
endoplasmin
glucose-regulated proteins
Calnexin
PERK kinase
eIF-2 Kinase
Iron Regulatory Protein 1