Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export
Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export
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DOI：
10.7554/elife.21635
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发表时间：
2016-09-24
期刊：
影响因子：
7.7
通讯作者：
Pfeffer, Suzanne R.
中科院分区：
文献类型：
--
作者：
Li, Jian;Pfeffer, Suzanne R.
LAMP1和LAMP2蛋白是高度丰富、普遍存在的哺乳动物蛋白，排列在溶酶体限制膜上，保护其免受溶酶体水解酶的作用。LAMP2缺乏会导致达农病，这是一种X连锁的肥厚型心肌病。LAMP2是伴侣介导的自噬所必需的，它的表达改善了衰老模型中的组织功能。我们在这里表明，人类LAMP1和LAMP2以一种埋葬胆固醇313-羟基的方式与胆固醇结合；它们也与从溶酶体输出胆固醇的NPC1和NPC2蛋白紧密结合。对细胞LAMP2和NPC1蛋白水平的定量检测表明，LAMP蛋白代表溶酶体限制膜上一个重要的胆固醇结合部位，可能是胆固醇可获得性的信号。功能挽救实验表明，人类LAMP2促进胆固醇从溶酶体输出的能力依赖于它直接结合胆固醇的能力。
LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X-linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone-mediated autophagy, and its expression improves tissue function in models of aging. We show here that human LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 313-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.