Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress
Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress
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DOI：
10.1074/jbc.m507071200
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发表时间：
2006-01-06
影响因子：
4.8
通讯作者：
Kulseth, MA
中科院分区：
文献类型：
--
作者：
Sorensen, S;Ranheim, T;Kulseth, MA
家族性高胆固醇血症是一种常染色体显性遗传疾病，由编码低密度脂蛋白受体（LDLR）的基因突变引起。超过 50% 的突变导致受体蛋白完全或部分保留在内质网 (ER) 中。突变型 LDLR 的细胞内加工和保留机制尚不清楚。在本研究中，我们发现 G544V 突变体 LDLR 与转染的中国仓鼠卵巢细胞内质网中的伴侣蛋白 Grp78、Grp94、ERp72 和钙联蛋白相关。突变 LDLR 的保留被证明会引起 ER 应激并激活未折叠的蛋白质反应。我们观察到两个 ER 压力传感器 IRE1 和 PERK 的活性显着增加。这些结果表明，ER 中突变 LDLR 的保留会诱导细胞反应，这可能对家族性高胆固醇血症的临床结果很重要。
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.