The effect of bafilomycin A1 and protease inhibitors on the degradation and recycling of a

The effect of bafilomycin A1 and protease inhibitors on the degradation and recycling of a

Class 5-mutant LDLR

Kristian Tveten;Trine Ranheim;Knut Erik Berge;Trond P.Leren;Mari Ann Kulseth

【期刊名称】《生物化学与生物物理学报：英文版》 【年(卷),期】2009(041)003

【摘要】The low-density lipoprotein receptor (LDLR) mediates cholesterol homeostasis through endocytosis of lipoprotein particles, particularly low-density lipoproteins (LDLs). Normally, the lipoprotein particles are released in the endosomes and the receptors recycle to the cell surface. Familial hypercholesterolemia (FH) is an autoso-mal dominant disease caused by mutations in the gene encoding the LDLR. These mutations are divided into five functional classes where Class 5 mutations encode receptors that suffer from ligand-induced degradation and recycling deficiency. The aim of this study was to investigate whether it is possible to prevent the fast ligand-induced degradation of Class 5-mutant LDLR and to restore its ability to recycle to the cell surface. E387K is a naturally occurring Class 5 mutation found in FH patients, and in the present study, we used Chinese hamster ovary cells transfected with an E387K-mutant LDLR. Abrogation of endosomal acidification by adding bafilomycin Al or addition of the irreversible serine protease inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride