BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles
BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles
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DOI：
10.1091/mbc.e06-12-1066
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发表时间：
2007-03-01
影响因子：
3.3
通讯作者：
Marks, Michael S.
中科院分区：
文献类型：
--
作者：
Setty, Subba Rao Gangi;Tenza, Daniele;Marks, Michael S.
Hermansky-Pudlak综合征（HPS）是一种以溶酶体相关细胞器（如黑素体）的形成和功能缺陷为特征的遗传性疾病。人类或小鼠的HPS是由15个基因中的任何一个突变引起的，其中5个基因编码溶酶体相关细胞器复合物(BLOC)-1的生物发生亚基，这是一种未知功能的蛋白质复合物。在这里，我们发现block -1在从早期核内体到黑素体的选择性货物出口中起作用。缺乏block -1的黑素细胞在内体空泡和细胞表面积累黑素体蛋白酪氨酸酶相关蛋白-1 (Tyrp1)，而不是其他黑素体蛋白，这是由于早期内体到黑素体的生物合成转运失败，导致内吞通量增加。通过恢复缺失的block -1亚基来纠正缺陷。来自HPS模型小鼠的黑色素细胞缺乏不同的蛋白复合物block -2，在不同的下游内体中间体中积累Tyrp1，这表明block -1和block -2在相同的途径中顺序起作用。相比之下，细胞内Tyrp1可以正确靶向缺乏另一种hps相关蛋白复合物的黑素细胞中的黑素小体，即接头蛋白(AP)-3。结果表明，黑素小体的成熟至少需要两条直接从早期内体到黑素小体的货物运输途径，一条是由AP-3介导的，另一条是由block -1和block -2介导的，这两条途径在几种形式的HPS中是缺乏的。
Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defects in the formation and function of lysosome-related organelles such as melanosomes. HPS in humans or mice is caused by mutations in any of 15 genes, five of which encode subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, a protein complex with no known function. Here, we show that BLOC-1 functions in selective cargo exit from early endosomes toward melanosomes. BLOC-1-deficient melanocytes accumulate the melanosomal protein tyrosinase-related protein-1 (Tyrp1), but not other melanosomal proteins, in endosomal vacuoles and the cell surface due to failed biosynthetic transit from early endosomes to melanosomes and consequent increased endocytic flux. The defects are corrected by restoration of the missing BLOC-1 subunit. Melanocytes from HPS model mice lacking a different protein complex, BLOC-2, accumulate Tyrp1 in distinct downstream endosomal intermediates, suggesting that BLOC-1 and BLOC-2 act sequentially in the same pathway. By contrast, intracellular Tyrp1 is correctly targeted to melanosomes in melanocytes lacking another HPS-associated protein complex, adaptor protein (AP)-3. The results indicate that melanosome maturation requires at least two cargo transport pathways directly from early endosomes to melanosomes, one pathway mediated by AP-3 and one pathway mediated by BLOC-1 and BLOC-2, that are deficient in several forms of HPS.