Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1.
Quantitative proteomic and genetic analyses of the schizophrenia susceptibility factor dysbindin identify novel roles of the biogenesis of lysosome-related organelles complex 1.
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DOI：
10.1523/jneurosci.5640-11.2012
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发表时间：
2012-03-14
期刊：
影响因子：
--
通讯作者：
Faundez V
中科院分区：
文献类型：
--
作者：
Gokhale A;Larimore J;Werner E;So L;Moreno-De-Luca A;Lese-Martin C;Lupashin VV;Smith Y;Faundez V
溶酶体相关细胞器复合物1（BLOC-1）是一种蛋白质复合物，含有精神分裂症易感因子dysbindin，由基因DTNBP 1编码。然而，dysbindin定义精神分裂症易感性途径的机制尚未定量阐明。在这里，我们发现了BLOC-1复合物在神经元细胞中的普遍和新的细胞作用，通过进行大规模的稳定同位素标记细胞培养定量蛋白质组学（SILAC）结合基因分析，在dysbindin-null小鼠（小家鼠）和精神分裂症患者的基因组。我们鉴定了24种与BLOC-1复合物相关的蛋白质，其中许多蛋白质在BLOC-1缺陷的细胞或组织中的含量/分布发生了改变。新的发现包括BLOC-1与COG复合物、高尔基体系链和抗氧化酶过氧化物酶1-2的相互作用。重要的是，编码24种蛋白质中的8种的基因座受到精神分裂症患者基因组拷贝数变异的影响。因此，我们的定量蛋白质组学研究扩展了BLOC-1复合物的功能库，并提供了对精神分裂症易感性的假定分子途径的深入了解。
The Biogenesis of Lysosome-Related Organelles Complex 1 (BLOC-1) is a protein complex containing the schizophrenia susceptibility factor dysbindin, which is encoded by the gene DTNBP1. However, mechanisms engaged by dysbindin defining schizophrenia susceptibility pathways have not been quantitatively elucidated. Here, we discovered prevalent and novel cellular roles of the BLOC-1 complex in neuronal cells by performing large-scale Stable Isotopic Labeling of Cells in Culture quantitative proteomics (SILAC) combined with genetic analyses in dysbindin-null mice (Mus musculus) and the genome of schizophrenia patients. We identified 24 proteins that associate with the BLOC-1 complex many of which were altered in content/distribution in cells or tissues deficient in BLOC-1. New findings include BLOC-1 interactions with the COG complex, a Golgi apparatus tether, and antioxidant enzymes peroxiredoxins 1-2. Importantly, loci encoding eight of the 24 proteins are affected by genomic copy number variation in schizophrenia patients. Thus, our quantitative proteomic studies expand the functional repertoire of the BLOC-1 complex and provide insight into putative molecular pathways of schizophrenia susceptibility.