Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5
Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5
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DOI：
10.1038/sj.jid.5700737
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发表时间：
2007-06-01
影响因子：
6.5
通讯作者：
Gahl, William A.
中科院分区：
文献类型：
--
作者：
Helip-Wooley, Amanda;Westbroek, Wendy;Gahl, William A.
Hermansky-Pudlak综合征（HPS）是一种溶酶体相关的细胞器生物发生障碍，导致黑素小体功能障碍和血小板致密体缺失。HPS患者有眼皮肤白化病、瘀伤和出血。HPS-5由HPS 5蛋白的缺乏引起，HPS 5蛋白是溶酶体相关细胞器复合物-2（BLOC-2）的生物发生的组分。HPS 5具有未知的功能，并且与已知蛋白质缺乏同源性。我们对HPS-5黑素细胞进行了超微结构研究，发现主要是早期黑素体，在整个细胞体和树突中有许多小的3，4（OH）（2）-苯丙氨酸阳性囊泡。这些发现类似于HPS-3黑素细胞的独特超微结构特征; HPS 3也是BLOC-2组分。免疫荧光和免疫电镜研究表明，减少TYRP 1标记的树突HPS-5黑素细胞，和TYRP 1的总体丰度降低。在HPS-5黑素细胞中未观察到Pmel 17的分布或丰度的实质性差异。在正常黑素细胞中，内源性酪氨酸酶与Pmel 17和TYRP 1共定位于核周区域和树突尖端;这在HPS-5黑素细胞中大大减少，特别是在尖端。我们的结论是，早期黑素小体的形成和Pmel 17贩运保存在HPS 5缺陷细胞。然而，酪氨酸酶和TYRP 1被错误地激活，并且不能有效地递送到HPS-5黑素细胞的黑素体。
Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis resulting in melanosome dysfunction and absent platelet dense bodies. HPS patients have oculocutaneous albinism, bruising, and bleeding. HPS-5 results from deficiency of the HPS5 protein, a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). HPS5 has an unknown function and lacks homology to known proteins. We performed ultrastructural studies of HPS-5 melanocytes revealing predominantly early-stage melanosomes with many small 3,4(OH)(2)-phenylalanine-positive vesicles throughout the cell body and dendrites. These findings resemble the distinct ultrastructural features of HPS-3 melanocytes; HPS3 is also a BLOC-2 component. Immunofluorescence and immunoEM studies showed decreased TYRP1 labeling in the dendrites of HPS-5 melanocytes, and the overall abundance of TYRP1 was reduced. No substantial differences were observed in the distribution or abundance of Pmel17 in HPS-5 melanocytes. In normal melanocytes, endogenous tyrosinase colocalized with Pmel17 and TYRP1 in the perinuclear area and dendritic tips; this was much reduced in HPS-5 melanocytes, particularly in the tips. We conclude that early stage melanosome formation and Pmel17 trafficking are preserved in HPS5-deficient cells. Tyrosinase and TYRP1 are mistrafficked, however, and fail to be efficiently delivered to melanosomes of HPS-5 melanocytes.