Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex*
Aggregation of Polyglutamine-expanded Ataxin 7 Protein Specifically Sequesters Ubiquitin-specific Protease 22 and Deteriorates Its Deubiquitinating Function in the Spt-Ada-Gcn5-Acetyltransferase (SAGA) Complex*
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DOI：
10.1074/jbc.m114.631663
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Hui Yang;Shuai Liu;Wen-tian He;Jian Zhao;Leilei Jiang;Hong-Yu Hu
中科院分区：
文献类型：
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作者：
Hui Yang;Shuai Liu;Wen-tian He;Jian Zhao;Leilei Jiang;Hong-Yu Hu
背景：共济失调蛋白7中polyQ束的扩张是SCA 7的主要病理。结果：polyQ-扩增的共济失调蛋白7形成的聚集体通过特异性相互作用螯合USP 22。结论：USP 22在佐贺复合物中的螯合作用损害了其去泛素化功能。意义：这为劫持模型提供了证据，在该模型中，特异性隔离导致细胞毒性和神经变性。人共济失调蛋白7（Atx 7）是Spt-Ada-Gcn 5-乙酰转移酶（佐贺）复合物中用于转录调节的去泛素化模块（DUBm）的组分，其多聚谷氨酰胺（polyQ）束的扩展导致脊髓小脑共济失调7型。然而，Atx 7的polyQ扩增如何影响DUBm功能仍然难以捉摸。我们研究了polyQ扩增的Atx 7对泛素特异性蛋白酶（USP 22）的影响，该蛋白酶是Atx 7在组蛋白H2 B去泛素化中发挥作用的相互作用伴侣。结果表明，由polyQ扩增的Atx 7形成的包含体或聚集体通过Atx 7的N-末端锌指结构域介导的相互作用特异性地螯合USP 22。Atx 7中锌指结构域的突变破坏了其与USP 22的相互作用，从而显著消除了USP 22的螯合。此外，Atx 7的polyQ扩增降低了USP 22的去泛素化活性，因此增加了单泛素化H2 B的水平。因此，我们提出polyQ-扩展的Atx 7形成不溶性聚集体，将USP 22隔离成催化失活状态，然后受损的DUBm失去去泛素化单泛素化组蛋白H2 B或H2 A的功能。这可能导致佐贺复合物功能障碍和脊髓小脑共济失调7型疾病的转录失调。
Background: Expansion of the polyQ tract in ataxin 7 is the main pathology of SCA7. Results: The aggregates formed by polyQ-expanded ataxin 7 sequester USP22 through specific interactions. Conclusion: Sequestration of USP22 impairs its deubiquitinating function in the SAGA complex. Significance: This provides evidence for the hijacking model in which specific sequestration leads to cytotoxicity and neurodegeneration. Human ataxin 7 (Atx7) is a component of the deubiquitination module (DUBm) in the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex for transcriptional regulation, and expansion of its polyglutamine (polyQ) tract leads to spinocerebellar ataxia type 7. However, how polyQ expansion of Atx7 affects DUBm function remains elusive. We investigated the effects of polyQ-expanded Atx7 on ubiquitin-specific protease (USP22), an interacting partner of Atx7 functioning in deubiquitination of histone H2B. The results showed that the inclusions or aggregates formed by polyQ-expanded Atx7 specifically sequester USP22 through their interactions mediated by the N-terminal zinc finger domain of Atx7. The mutation of the zinc finger domain in Atx7 that disrupts its interaction with USP22 dramatically abolishes sequestration of USP22. Moreover, polyQ expansion of Atx7 decreases the deubiquitinating activity of USP22 and, consequently, increases the level of monoubiquitinated H2B. Therefore, we propose that polyQ-expanded Atx7 forms insoluble aggregates that sequester USP22 into a catalytically inactive state, and then the impaired DUBm loses the function to deubiquitinate monoubiquitinated histone H2B or H2A. This may result in dysfunction of the SAGA complex and transcriptional dysregulation in spinocerebellar ataxia type 7 disease.