Nucleocytoplasmic Shuttling of Dysbindin-1, a Schizophrenia-related Protein, Regulates Synapsin I Expression
Nucleocytoplasmic Shuttling of Dysbindin-1, a Schizophrenia-related Protein, Regulates Synapsin I Expression
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精神分裂症相关蛋白 Dysbindin-1 的核质穿梭调节突触蛋白 I 表达
DOI：
10.1074/jbc.m110.107912
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发表时间：
2010-12-03
影响因子：
4.8
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
--
作者：
Fei, Erkang;Ma, Xiaochuan;Wang, Guanghui
Dysbindin-1 是一种 50 kDa 的含有卷曲螺旋的蛋白质，由基因 DTNBP1（dystrobrevin 结合蛋白 1）编码，是精神分裂症的候选遗传因子。该基因的遗传变异通过减少 Dysbindin-1 的表达而导致对精神分裂症的易感性。据报道，dysbindin-1 调节突触前蛋白的表达和神经递质的释放。然而，dysbindin-1 的确切功能很大程度上未知。在这里，我们证明了dysbindin-1是一种新型的核细胞质穿梭蛋白，在用leptomycin B（一种exportin-1/CRM1介导的核输出抑制剂）处理后易位到细胞核。 Dysbindin-1 具有核输出所需的功能性核输出信号，并且 Dysbindin-1 的核质穿梭影响其对突触蛋白 I 表达的调节。在沙鼠（一种 Dysbindin-1 缺失菌株，表现出与精神分裂症相关的异常行为）的大脑中，突触蛋白 I 的蛋白质和 mRNA 水平降低。这些发现表明，dysbindin-1 的核质穿梭调节突触蛋白 I 的表达，因此可能参与精神分裂症的发病机制。
Dysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia.