Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency
Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency
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DOI：
10.1093/hmg/ddp555
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发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Dell'Angelica, Esteban C.
中科院分区：
文献类型：
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作者：
Cheli, Veronica T.;Daniels, Richard W.;Dell'Angelica, Esteban C.
溶酶体相关细胞器复合物1（BLOC-1）是由8个不同基因的产物形成的蛋白质复合物。其中两个基因DTNBP 1和BLOC 1 S3的功能缺失突变导致Hermansky-Pudlak综合征，这是一种以溶酶体相关细胞器的生物发生缺陷为特征的人类疾病。此外，在相同的两个基因内的单倍型变异已被假定为增加患精神分裂症的风险。然而，BLOC-1的分子功能仍然未知。在这里，我们已经生成了一个BLOC-1缺陷的苍蝇模型。突变果蝇缺乏保守的EST 1亚基显示眼睛色素缺陷，由于异常的色素颗粒，这是溶酶体相关的细胞器，以及异常的神经递质传递和行为。上位性分析表明，BLOC-1在色素颗粒生物发生中的功能需要BLOC-2和一个假定的Rab鸟嘌呤核苷酸交换因子Claret的活性。眼睛色素沉着表型被修改的错误表达的蛋白质参与细胞内的蛋白质运输，特别是，表型部分改善Rab 11和强烈增强网格蛋白分解因子，fetalilin。这些观察结果验证了果蝇作为一个强大的模型，BLOC-1的功能和它与修饰基因的相互作用的研究。
Biogenesis of lysosome-related organelles complex 1 (BLOC-1) is a protein complex formed by the products of eight distinct genes. Loss-of-function mutations in two of these genes, DTNBP1 and BLOC1S3, cause Hermansky-Pudlak syndrome, a human disorder characterized by defective biogenesis of lysosome-related organelles. In addition, haplotype variants within the same two genes have been postulated to increase the risk of developing schizophrenia. However, the molecular function of BLOC-1 remains unknown. Here, we have generated a fly model of BLOC-1 deficiency. Mutant flies lacking the conserved Blos1 subunit displayed eye pigmentation defects due to abnormal pigment granules, which are lysosome-related organelles, as well as abnormal glutamatergic transmission and behavior. Epistatic analyses revealed that BLOC-1 function in pigment granule biogenesis requires the activities of BLOC-2 and a putative Rab guanine-nucleotide-exchange factor named Claret. The eye pigmentation phenotype was modified by misexpression of proteins involved in intracellular protein trafficking; in particular, the phenotype was partially ameliorated by Rab11 and strongly enhanced by the clathrin-disassembly factor, Auxilin. These observations validate Drosophila melanogaster as a powerful model for the study of BLOC-1 function and its interactions with modifier genes.