Department of Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9111, USA.
Traffic. 2012 Dec;13(12):1680-92. doi: 10.1111/tra.12005. Epub 2012 Sep 20.
Chediak-Higashi syndrome (CHS) is a lethal disease caused by mutations that inactivate the lysosomal trafficking regulator protein (LYST). Patients suffer from diverse symptoms including oculocutaneous albinism, recurrent infections, neutropenia and progressive neurodegeneration. These defects have been traced back to over-sized lysosomes and lysosome-related organelles (LROs) in different cell types. Here, we explore mutants in the Drosophila mauve gene as a new model system for CHS. The mauve gene (CG42863) encodes a large BEACH domain protein of 3535 amino acids similar to LYST. This reflects a functional homology between these proteins as mauve mutants also display enlarged LROs, such as pigment granules. This Drosophila model also replicates the enhanced susceptibility to infections and we show a defect in the cellular immune response. Early stages of phagocytosis proceed normally in mauve mutant hemocytes but, unlike in wild type, late phagosomes fuse and generate large vacuoles containing many bacteria. Autophagy is similarly affected in mauve fat bodies as starvation-induced autophagosomes grow beyond their normal size. Together these data suggest a model in which Mauve functions to restrict homotypic fusion of different pre-lysosomal organelles and LROs.
Chediak-Higashi 综合征（CHS）是一种致命疾病，由使溶酶体运输调节剂蛋白（LYST）失活的突变引起。患者患有多种症状，包括眼皮肤白化病、反复感染、中性粒细胞减少和进行性神经退行性变。这些缺陷可追溯到不同细胞类型中过大的溶酶体和溶酶体相关细胞器（LRO）。在这里，我们探索果蝇 mauve 基因中的突变体作为 CHS 的新模型系统。mauve 基因（CG42863）编码一个由 3535 个氨基酸组成的大型 BEACH 结构域蛋白，与 LYST 相似。这反映了这些蛋白质之间的功能同源性，因为 mauve 突变体也显示出扩大的 LRO，如色素颗粒。这种果蝇模型还复制了对感染的易感性增加，并且我们显示出细胞免疫反应的缺陷。在 mauve 突变体血细胞中，吞噬作用的早期阶段正常进行，但与野生型不同的是，晚期吞噬体融合并产生含有许多细菌的大空泡。自噬在 mauve 脂肪体中也受到类似的影响，因为饥饿诱导的自噬体生长超过其正常大小。这些数据共同表明，Mauve 的功能是限制不同的前溶酶体细胞器和 LRO 的同源融合。
