Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases
Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases
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DOI：
10.1038/ncb1553
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发表时间：
2007-04-01
影响因子：
21.3
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
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作者：
Qi, Mei-Ling;Tagawa, Kazuhiko;Okazawa, Hitoshi
核功能障碍是聚谷氨酰胺（polyQ）疾病病理的一个关键特征。有研究认为突变的polyQ蛋白通过在细胞核中直接与核因子相互作用而损害核因子的功能。然而，尚未对表达突变polyQ蛋白的神经元中可溶性核蛋白的定量变化进行系统分析。在这里，我们对表达huntingtin （Htt）或ataxin-1 （AT1）蛋白的神经元制备的可溶性核蛋白进行了蛋白质组学分析，结果表明突变的AT1和Htt类似地降低了可溶性高迁移率组B1/2 （HMGB1/2）蛋白的浓度。免疫沉淀和拉下实验表明，hmgb与突变体AT1和Htt相互作用。免疫组织化学表明，这些蛋白在受损神经元包涵体外的核区减少。hmgb的代偿性表达改善了原代神经元和果蝇多q模型中多q诱导的病理。此外，hmgb抑制突变Htt或转录抑制诱导的遗传毒性应激信号。因此，hmgb可能是多q疾病病理的关键调节因子，可能是治疗开发的靶点。
Nuclear dysfunction is a key feature of the pathology of polyglutamine (polyQ) diseases. It has been suggested that mutant polyQ proteins impair functions of nuclear factors by interacting with them directly in the nucleus. However, a systematic analysis of quantitative changes in soluble nuclear proteins in neurons expressing mutant polyQ proteins has not been performed. Here, we perform a proteome analysis of soluble nuclear proteins prepared from neurons expressing huntingtin (Htt) or ataxin-1 (AT1) protein, and show that mutant AT1 and Htt similarly reduce the concentration of soluble high mobility group B1/2 (HMGB1/2) proteins. Immunoprecipitation and pulldown assays indicate that HMGBs interact with mutant AT1 and Htt. Immunohistochemistry showed that these proteins were reduced in the nuclear region outside of inclusion bodies in affected neurons. Compensatory expression of HMGBs ameliorated polyQ-induced pathology in primary neurons and in Drosophila polyQ models. Furthermore, HMGBs repressed genotoxic stress signals induced by mutant Htt or transcriptional repression. Thus, HMGBs may be critical regulators of polyQ disease pathology and could be targets for therapy development.