Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305-5307.
J Biol Chem. 2019 Feb 1;294(5):1706-1709. doi: 10.1074/jbc.TM118.004165.
Low-density lipoprotein particles are taken up by cells and delivered to the lysosome where their cholesterol esters are cleaved off by acid lipase. The released, free cholesterol is then exported from lysosomes for cellular needs or storage. This article summarizes recent advances in our understanding of the molecular basis of cholesterol export from lysosomes. Cholesterol export requires NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, genetic mutations of which can cause Niemann-Pick type C disease, a disorder characterized by massive lysosomal accumulation of cholesterol and glycosphingolipids. Analysis of the NPC1 and NPC2 structures and biochemical properties, together with new structures of the related Patched (PTCH) protein, provides new clues to the mechanisms by which NPC proteins may function.
低密度脂蛋白颗粒被细胞摄取，并被运送到溶酶体，在那里它们的胆固醇酯被酸性脂肪酶分解。释放的游离胆固醇随后从溶酶体中输出，以满足细胞的需要或储存。本文总结了我们对胆固醇从溶酶体输出的分子基础的最新理解。胆固醇的输出需要 NPC 细胞内胆固醇转运蛋白 1（NPC1）和 NPC2，其基因突变可导致尼曼-皮克 C 型病，这是一种以溶酶体中胆固醇和糖脂大量积累为特征的疾病。对 NPC1 和 NPC2 结构和生化特性的分析，以及相关 patched（PTCH）蛋白的新结构，为 NPC 蛋白可能的作用机制提供了新的线索。
