Interaction of Hermansky-Pudlak syndrome genes in the regulation of lysosome-related organelles
Interaction of Hermansky-Pudlak syndrome genes in the regulation of lysosome-related organelles
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DOI：
10.1111/j.1600-0854.2006.00431.x
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发表时间：
2006-07-01
期刊：
影响因子：
4.5
通讯作者：
Swank, Richard T.
中科院分区：
文献类型：
--
作者：
Gautam, Rashi;Novak, Edward K.;Swank, Richard T.
Hermansky-Pudlak综合征(HPS)是一种由溶酶体相关细胞器(LRO)合成和/或运输异常引起的遗传性异质性疾病，包括黑素体、肺II型细胞板层小体和血小板致密颗粒。至少有15个基因导致小鼠的HPS，其中相当多的基因指定了被称为BLOCK(溶酶体相关细胞器复合体的生物发生)的蛋白质复合体的新亚基。为了确定BLOC复合体在体内是否具有功能相互作用，构建了各种BLOC复合体和/或AP-3接头复合体的蛋白质亚单位双缺失或三缺失突变小鼠，并对其活性和黑素小体、肺板层小体和溶酶体的异常进行了测试。所有突变体，包括那些在所有三个区块复合体中缺失的突变体，都是可行的，尽管涉及AP-3的多个突变体的育种效率严重受损。BLOCK蛋白复合体之间的相互作用以及与AP-3的相互作用对大多数LRO有明显的影响。然而，这些相互作用依赖于组织和细胞器。这些研究记录了BLOC和AP-3复合体在LRO生物合成中的新的生物相互作用，并评估了HPS蛋白质复合体在哺乳动物一般健康和生理中的作用(S)。双突变和三突变HPS小鼠在LROS的研究中提供了独特和实用的实验优势。
Hermansky-Pudlak Syndrome (HPS) is a genetically heterogeneous disease caused by abnormalities in the synthesis and/or trafficking of lysosome-related organelles (LROs) including melanosomes, lamellar bodies of lung type II cells and platelet dense granules. At least 15 genes cause HPS in mice, with a significant number specifying novel subunits of protein complexes termed BLOCs (Biogenesis of Lysosome-related Organelles Complexes). To ascertain whether BLOC complexes functionally interact in vivo, mutant mice doubly or triply deficient in protein subunits of the various BLOC complexes and/or the AP-3 adaptor complex were constructed and tested for viability and for abnormalities of melanosomes, lung lamellar bodies and lysosomes. All mutants, including those deficient in all three BLOC complexes, were viable though the breeding efficiencies of multiple mutants involving AP-3 were severely compromised. Interactions of BLOC protein complexes with each other and with AP-3 to affect most LROs were apparent. However, these interactions were tissue and organelle dependent. These studies document novel biological interactions of BLOC and AP-3 complexes in the biosynthesis of LROs and assess the role(s) of HPS protein complexes in general health and physiology in mammals. Double and triple mutant HPS mice provide unique and practical experimental advantages in the study of LROs.