BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2.
BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2.
复制标题
溶酶体胆固醇通过 NPC2 排出需要 BORC-ARL8-HOPS 组合。
DOI：
10.1091/mbc.e21-11-0595-t
复制
发表时间：
2022-08-01
影响因子：
3.3
通讯作者：
Pu, Jing
中科院分区：
文献类型：
--
作者：
Anderson, Jacob;Walker, Gerard;Pu, Jing
溶酶体接受细胞外和细胞内胆固醇并将其重新分配到整个细胞。胆固醇从溶酶体排出对于胆固醇稳态是至关重要的，并且其失败是遗传性疾病如尼曼-匹克C（NPC）病的发病机制的基础。在这里，我们报告说，BLOC 1相关的复合物（BORC）-ARL 8-同型融合和蛋白分选（HOPS）合奏所需的游离胆固醇从溶酶体的出口和脂滴中的酯化胆固醇的存储。BORC、ARL 8或HOPS的耗竭不会改变溶酶体跨膜胆固醇转运蛋白NPC 1在降解区室的定位，但会减少管腔转运蛋白NPC 2的结合并增加NPC 2的分泌。BORC-ARL 8-HOPS消耗还增加阳离子非依赖性（Cl）-甘露糖6-磷酸（M6 P）受体（MPR）的溶酶体降解，其通常将NPC 2分类到内体-溶酶体系统，然后再循环到高尔基体网络。这些缺陷可能是由于内体-溶酶体细胞器的HOPS依赖性融合受损和HOPS在CI-MPR再循环中的未表征功能所致。我们的研究表明，BORC-ARL 8-HOPS系综是胆固醇从溶酶体中排出所必需的，通过使NPC 2能够依赖于CI-MPR运输到内体-溶酶体系统。
Lysosomes receive extracellular and intracellular cholesterol and redistribute it throughout the cell. Cholesterol egress from lysosomes is critical for cholesterol homeostasis, and its failure underlies the pathogenesis of genetic disorders such as Niemann-Pick C (NPC) disease. Here we report that the BLOC one-related complex (BORC)-ARL8-homotypic fusion and protein sorting (HOPS) ensemble is required for egress of free cholesterol from lysosomes and for storage of esterified cholesterol in lipid droplets. Depletion of BORC, ARL8, or HOPS does not alter the localization of the lysosomal transmembrane cholesterol transporter NPC1 to degradative compartments but decreases the association of the luminal transporter NPC2 and increases NPC2 secretion. BORC-ARL8-HOPS depletion also increases lysosomal degradation of cation-independent (CI)-mannose 6-phosphate (M6P) receptor (MPR), which normally sorts NPC2 to the endosomal-lysosomal system and then is recycled to the trans-Golgi network. These defects likely result from impaired HOPS-dependent fusion of endosomal-lysosomal organelles and an uncharacterized function of HOPS in CI-MPR recycling. Our study demonstrates that the BORC-ARL8-HOPS ensemble is required for cholesterol egress from lysosomes by enabling CI–MPR-dependent trafficking of NPC2 to the endosomal-lysosomal system.