Gautam Rashi, Chintala Sreenivasulu, Li Wei, Zhang Qing, Tan Jian, Novak Edward K, Di Pietro Santiago M, Dell'Angelica Esteban C, Swank Richard T
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
J Biol Chem. 2004 Mar 26;279(13):12935-42. doi: 10.1074/jbc.M311311200. Epub 2004 Jan 12.
Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous inherited disease affecting vesicle trafficking among lysosome-related organelles. The Hps3, Hps5, and Hps6 genes are mutated in the cocoa, ruby-eye-2, and ruby-eye mouse pigment mutants, respectively, and their human orthologs are mutated in HPS3, HPS5, and HPS6 patients. These three genes encode novel proteins of unknown function. The phenotypes of Hps5/Hps5,Hps6/Hps6 and Hps3/Hps3,Hps6/Hps6 double mutant mice mimic, in coat and eye colors, in melanosome ultrastructure, and in levels of platelet dense granule serotonin, the corresponding phenotypes of single mutants. These facts suggest that the proteins encoded by these genes act within the same pathway or protein complex in vivo to regulate vesicle trafficking. Further, the Hps5 protein is destabilized within tissues of Hps3 and Hps6 mutants, as is the Hps6 protein within tissues of Hps3 and Hps5 mutants. Also, proteins encoded by these genes co-immunoprecipitate and occur in a complex of 350 kDa as determined by sucrose gradient and gel filtration analyses. Together, these results indicate that the Hps3, Hps5, and Hps6 proteins regulate vesicle trafficking to lysosome-related organelles at the physiological level as components of the BLOC-2 (biogenesis of lysosome-related organelles complex-2) protein complex and suggest that the pathogenesis and future therapies of HPS3, HPS5, and HPS6 patients are likely to be similar. Interaction of the Hps5 and Hps6 proteins within BLOC-2 is abolished by the three-amino acid deletion in the Hps6(ru) mutant allele, indicating that these three amino acids are important for normal BLOC-2 complex formation.
赫尔曼斯基-普德拉克综合征（HPS）是一种遗传性异质性疾病，会影响溶酶体相关细胞器之间的囊泡运输。Hps3、Hps5和Hps6基因分别在可可色、红宝石眼-2和红宝石眼小鼠色素突变体中发生突变，它们的人类同源基因在HPS3、HPS5和HPS6患者中发生突变。这三个基因编码功能未知的新型蛋白质。Hps5/Hps5、Hps6/Hps6以及Hps3/Hps3、Hps6/Hps6双突变小鼠在毛色和眼睛颜色、黑素体超微结构以及血小板致密颗粒5-羟色胺水平方面的表型，模拟了相应单突变体的表型。这些事实表明，这些基因编码的蛋白质在体内同一途径或蛋白质复合物中发挥作用，以调节囊泡运输。此外，Hps5蛋白在Hps3和Hps6突变体的组织中不稳定，Hps6蛋白在Hps3和Hps5突变体的组织中也是如此。同样，通过蔗糖梯度和凝胶过滤分析确定，这些基因编码的蛋白质会共同免疫沉淀，并存在于一个350 kDa的复合物中。总之，这些结果表明，Hps3、Hps5和Hps6蛋白作为BLOC-2（溶酶体相关细胞器生物发生复合物-2）蛋白质复合物的组成部分，在生理水平上调节向溶酶体相关细胞器的囊泡运输，并表明HPS3、HPS5和HPS6患者的发病机制和未来治疗可能相似。Hps6(ru)突变等位基因中的三个氨基酸缺失消除了BLOC-2内Hps5和Hps6蛋白的相互作用，表明这三个氨基酸对于正常的BLOC-2复合物形成很重要。
