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E6-AP促进错误折叠的多聚谷氨酰胺蛋白进行蛋白酶体降解,并抑制多聚谷氨酰胺蛋白的聚集和毒性。

E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity.

作者信息

Mishra Amit, Dikshit Priyanka, Purkayastha Sudarshana, Sharma Jaiprakash, Nukina Nobuyuki, Jana Nihar Ranjan

机构信息

Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon-122 050.

出版信息

J Biol Chem. 2008 Mar 21;283(12):7648-56. doi: 10.1074/jbc.M706620200. Epub 2008 Jan 17.

Abstract

The accumulation of intracellular protein deposits as inclusion bodies is the common pathological hallmark of most age-related neurodegenerative disorders including polyglutamine diseases. Appearance of aggregates of the misfolded mutant disease proteins suggest that cells are unable to efficiently degrade them, and failure of clearance leads to the severe disturbances of the cellular quality control system. Recently, the quality control ubiquitin ligase CHIP has been shown to suppress the polyglutamine protein aggregation and toxicity. Here we have identified another ubiquitin ligase, called E6-AP, which is able to promote the proteasomal degradation of misfolded polyglutamine proteins and suppress the polyglutamine protein aggregation and polyglutamine protein-induced cell death. E6-AP interacts with the soluble misfolded polyglutamine protein and associates with their aggregates in both cellular and transgenic mouse models. Partial knockdown of E6-AP enhances the rate of aggregate formation and cell death mediated by the polyglutamine protein. Finally, we have demonstrated the up-regulation of E6-AP in the expanded polyglutamine protein-expressing cells as well as cells exposed to proteasomal stress. These findings suggest that E6-AP is a critical mediator of the neuronal response to misfolded polyglutamine proteins and represents a potential therapeutic target in the polyglutamine diseases.

摘要

细胞内蛋白质沉积物以包涵体形式积累是包括多聚谷氨酰胺疾病在内的大多数与年龄相关的神经退行性疾病常见的病理特征。错误折叠的突变疾病蛋白聚集体的出现表明细胞无法有效降解它们,而清除失败会导致细胞质量控制系统的严重紊乱。最近,质量控制泛素连接酶CHIP已被证明可抑制多聚谷氨酰胺蛋白聚集和毒性。在此,我们鉴定出另一种泛素连接酶,称为E6-AP,它能够促进错误折叠的多聚谷氨酰胺蛋白的蛋白酶体降解,并抑制多聚谷氨酰胺蛋白聚集和多聚谷氨酰胺蛋白诱导的细胞死亡。在细胞和转基因小鼠模型中,E6-AP与可溶性错误折叠的多聚谷氨酰胺蛋白相互作用并与其聚集体相关联。E6-AP的部分敲低会提高多聚谷氨酰胺蛋白介导的聚集体形成率和细胞死亡率。最后,我们证明了在表达扩展多聚谷氨酰胺蛋白的细胞以及暴露于蛋白酶体应激的细胞中E6-AP的上调。这些发现表明,E6-AP是神经元对错误折叠的多聚谷氨酰胺蛋白反应的关键介质,并且是多聚谷氨酰胺疾病的潜在治疗靶点。

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