Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor
Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the β3A subunit of the AP-3 adaptor
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DOI：
10.1016/s1097-2765(00)80170-7
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发表时间：
1999-01-01
期刊：
影响因子：
16
通讯作者：
Bonifacino, JS
中科院分区：
文献类型：
--
作者：
Dell'Angelica, EC;Shotelersuk, V;Bonifacino, JS
Hermansky-Pudlak综合征（HPS）是一种以溶酶体相关细胞器缺陷为特征的遗传性疾病。在这里，我们报告了两个HPS患者的异源四聚体AP-3复合物的P3 A亚基突变的鉴定。由于突变型β 3A的降解增强，患者的成纤维细胞表现出AP-3水平的急剧降低。AP-3缺陷导致溶酶体膜蛋白CD 63、lamp-1和lamp-2的表面表达增加，但非溶酶体蛋白的表面表达不增加。这些差异效应与AP-3 mu 3A亚基与参与溶酶体靶向的基于酪氨酸的信号的优先相互作用一致。我们的研究结果表明，AP-3的功能在蛋白质分选溶酶体，并提供了一个例子，人类疾病中，改变运输的完整的膜蛋白是由于突变的一个组成部分的分选机器。
Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. Here, we report the identification of two HPS patients with mutations in the P3A subunit of the heterotetrameric AP-3 complex. The patients' fibroblasts exhibit drastically reduced levels of AP-3 due to enhanced degradation of mutant beta 3A. The AP-3 deficiency results in increased surface expression of the lysosomal membrane proteins CD63, lamp-1, and lamp-2, but not of nonlysosomal proteins. These differential effects are consistent with the preferential interaction of the AP-3 mu 3A subunit with tyrosine-based signals involved in lysosomal targeting. Our results suggest that AP-3 functions in protein sorting to lysosomes and provide an example of a human disease in which altered trafficking of integral membrane proteins is due to mutations in a component of the sorting machinery.