Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex
Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex
复制标题
DOI：
10.7554/elife.51401
复制
发表时间：
2019-11-14
期刊：
影响因子：
7.7
通讯作者：
Saheki, Yasunori
中科院分区：
文献类型：
--
作者：
Naito, Tomoki;Ercan, Bilge;Saheki, Yasunori
胆固醇是质膜（PM）的主要结构成分。大多数PM胆固醇与其他PM脂质形成复合物，使其无法进行细胞内转运。PM胆固醇在可接近和不可接近的池之间的转换维持细胞内稳态，但细胞如何监测PM胆固醇的可接近性仍不清楚。我们发现，内质网（ER）锚定的脂质转运蛋白，GRAMD 1，感测和运输可访问PM胆固醇的ER。GRAMD 1相互结合，并通过它们的β结构域感测PM胆固醇可及池的瞬时扩增来填充ER-PM接触。然后，它们通过其StART样结构域促进这种胆固醇的运输。缺乏所有三种GRAMD 1的细胞表现出PM胆固醇的可及池的显著扩增，这是由于可及胆固醇的PM至ER转运效率较低。因此，GRAMD 1促进可接近的PM胆固醇移动到ER，以抵消PM胆固醇的急剧增加，从而激活非囊泡胆固醇转运。
Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor the accessibility of PM cholesterol remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind to one another and populate ER-PM contacts by sensing a transient expansion of the accessible pool of PM cholesterol via their GRAM domains. They then facilitate the transport of this cholesterol via their StART-like domains. Cells that lack all three GRAMD1s exhibit striking expansion of the accessible pool of PM cholesterol as a result of less efficient PM to ER transport of accessible cholesterol. Thus, GRAMD1s facilitate the movement of accessible PM cholesterol to the ER in order to counteract an acute increase of PM cholesterol, thereby activating non-vesicular cholesterol transport.