Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state
Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state
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DOI：
10.1038/ncb1478
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发表时间：
2006-10-01
影响因子：
21.3
通讯作者：
Nagata, Kazuhiro
中科院分区：
文献类型：
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作者：
Kitamura, Akira;Kubota, Hiroshi;Nagata, Kazuhiro
多聚谷氨酰胺（polyQ）-扩增蛋白引起神经退行性疾病，包括亨廷顿病、肯尼迪病和各种共济失调。这些蛋白质的细胞毒性与聚集体或其他构象毒性物质的形成有关。在这里，我们表明，胞质伴侣蛋白CCT（也称为TRiC）可以改变哺乳动物细胞中亨廷顿蛋白（Htt）- polyQ蛋白的聚集和细胞毒性的过程。通过RNA介导的敲低破坏CCT复合物增强了Htt-polyQ聚集体形成和细胞毒性。通过荧光相关光谱法分析Htt-polyQ蛋白的聚集状态揭示了CCT耗尽导致可溶性Htt-polyQ聚集体的出现。同样，CCT的所有八个亚基的过表达抑制Htt聚集和神经元细胞死亡。这些结果表明，CCT通过影响聚集过程在保护polyQ蛋白免受细胞毒性方面具有重要作用。
Polyglutamine (polyQ)-expansion proteins cause neurodegenerative disorders including Huntington's disease, Kennedy's disease and various ataxias. The cytotoxicity of these proteins is associated with the formation of aggregates or other conformationally toxic species. Here, we show that the cytosolic chaperonin CCT (also known as TRiC) can alter the course of aggregation and cytotoxicity of huntingtin (Htt) - polyQ proteins in mammalian cells. Disruption of the CCT complex by RNA-imediated knockdown enhanced Htt - polyQ aggregate formation and cellular toxicity. Analysis of the aggregation states of the Htt - polyQ proteins by fluorescence correlation spectroscopy revealed that CCT depletion results in the appearance of soluble Htt - polyQ aggregates. Similarly, overexpression of all eight subunits of CCT suppressed Htt aggregation and neuronal cell death. These results indicate that CCT has an essential role in protecting against the cytotoxicity of polyQ proteins by affecting the course of aggregation.