The Wilson disease protein ATP7B resides in the late endosomes with rab7 and the Niemann-Pick C1 protein
The Wilson disease protein ATP7B resides in the late endosomes with rab7 and the Niemann-Pick C1 protein
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DOI：
10.1016/s0002-9440(10)62272-9
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发表时间：
2005-02-01
影响因子：
6
通讯作者：
Sata, M
中科院分区：
文献类型：
--
作者：
Harada, M;Masaru, H;Sata, M
威尔逊病是一种遗传性疾病，其特征是由于胆道铜排泄缺陷导致体内铜积聚。虽然威尔逊病基因已被克隆，但基因产物（ATP7B）的细胞定位尚未完全明确。因此，ATP7B的确切生理作用尚不清楚。我们使用抗ATP7B抗体、绿色荧光蛋白(GFP)-ATP7B （GFP-ATP7B）和ATP7B- dsred检测了ATP7B在不同培养细胞中的分布。荧光显微镜观察胞内细胞器。将ATP7B的分布与Rab7和Niemann-Pick C1 （NPC1）的分布进行了比较。诱导鼻咽癌表型的U18666A被用于调节细胞内囊泡交通。GFP-ATP7B与包括Rab7和NPC1在内的各种内核体晚期标记共定位，但与高尔基体或溶酶体标记不共定位。U18666A诱导晚期内溶酶体杂交细胞器的形成，GFP-ATP7B在这些结构中定位于NPC1。我们已经证实ATP7B是一种晚期内体相关膜蛋白。ATP7B似乎将铜从细胞质转运到后期内体管腔，从而通过染色体体参与胆道铜排泄。因此。晚期核内体中ATP7B铜atp酶活性缺陷似乎是威尔逊病的主要缺陷。
Wilson disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. Although the Wilson disease gene has been cloned, the cellular localization of the gene product (ATP7B) has not been fully clarified. Therefore, the precise physiological action of ATP7B is still unknown. We examined the distribution of ATP7B using an anti-ATP7B antibody, green fluorescent protein (GFP)-ATP7B (GFP-ATP7B) and ATP7B-DsRed in various cultured cells. Intracellular organelles were visualized by fluorescence microscopy. The distribution of ATP7B was compared with that of Rab7 and Niemann-Pick C1 (NPC1), proteins that localize in the late endosomes. U18666A, which induces the NPC phenotype, was used to modulate the intracellular vesicle traffic. GFP-ATP7B colocalized with various late endosome markers including Rab7 and NPC1 but not with Golgi or lysosome markers. U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures. We have confirmed that ATP7B is a late endosome-associated membrane protein. ATP7B appears to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via hsosomes. Thus. defective copper ATPase activity of ATP7B in the late endosomes appears to be the main defect of Wilson disease.