Retention of mutant low density lipoprotein receptor in ER leads to ER stress

doi:10.1074/jbc.M507071200

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Papers In Press, published online ahead of print October 28, 2005
J. Biol. Chem, 10.1074/jbc.M507071200
Submitted on June 29, 2005
Revised on October 28, 2005
Accepted on October 28, 2005

Retention of mutant low density lipoprotein receptor in ER leads to ER stress

Stine Sørensen, Trine Ranheim, Kari Solberg Bakken, Trond P. Leren, and Mari Ann Kulseth

Dept of Medical Genetics, University Hospital, Oslo N-0027

Corresponding Author: mari.ann.kulseth{at}rikshospitalet.no

Familial hypercholesterolemia (FH) 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 CHO cells. Retention of the mutant LDLR was shown to cause ER stress and activation of the unfolded protein response (UPR). 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 FH.

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