A Novel Contact by a Novel Protein Complex Supports Cholesterol Transport to the Endoplasmic Reticulum
A Novel Contact by a Novel Protein Complex Supports Cholesterol Transport to the Endoplasmic Reticulum
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DOI：
10.1177/2515256418779685
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
A. Harada
中科院分区：
文献类型：
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作者：
A. Harada
胆固醇是膜脂的重要组成部分，也是激素合成的起始物质。胆固醇以低密度脂蛋白的形式进入细胞后，在溶酶体中被内吞和降解，释放游离胆固醇。游离胆固醇被运送到内质网（ER）并被酯化以供进一步使用。然而，将胆固醇从溶酶体转运到内质网的机制尚不清楚。我们搜索了一个小的gtp结合蛋白Rab11的结合蛋白，并鉴定了一个新的蛋白，Rab11结合蛋白含有LisH， coil coil和heat repeats （RELCH）。RELCH还与氧甾醇结合蛋白（OSBP）结合，这是一种非囊性胆固醇运输的必需蛋白。Rab11-RELCH-OSBP复合物被发现与循环内体和反式高尔基网络相连，从而介导它们之间的非囊性胆固醇运输。这一途径不同于先前发现的胆固醇转运途径。在缺乏这种复合物的情况下，胆固醇在体内和体外的溶酶体中积累，这表明这种复合物参与了与胆固醇运输相关的疾病。
Cholesterol is an essential component of membrane lipids and a starting material for hormone synthesis. After cholesterol is delivered to the cell as low-density lipoprotein, it is endocytosed and degraded in lysosomes to liberate free cholesterol. Free cholesterol is transported to the endoplasmic reticulum (ER) and esterified for further use. However, the mechanisms that transport cholesterol from lysosomes to the endoplasmic reticulum are poorly understood. We searched for binding proteins of a small GTP-binding protein, Rab11, and identified a novel protein, Rab11-binding protein containing LisH, coiled coil, and heat repeats (RELCH). RELCH also binds to oxysterol-binding protein (OSBP), an essential protein for nonvesicular cholesterol transport. The Rab11-RELCH-OSBP complex was found to tether to recycling endosomes and the trans-Golgi network, thereby mediating nonvesicular cholesterol transport between them. This pathway is distinct from the cholesterol transport pathway identified previously. In the absence of this complex, cholesterol accumulates in lysosomes in vitro and in vivo, suggesting the involvement of this complex in diseases associated with cholesterol transport.