SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7
SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7
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DOI：
10.1093/hmg/ddp478
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Sittler, Annie
中科院分区：
文献类型：
--
作者：
Janer, Alexandre;Werner, Andreas;Sittler, Annie
SUMO（small ubiquitin-like modifier，小泛素样修饰物）的翻译后修饰被提出来调节几种神经退行性疾病的发病机制。脊髓小脑性共济失调7型（SCA 7）是一种神经退行性疾病，其病理学是由蛋白共济失调蛋白7（ATXN 7）中的多聚谷氨酰胺伸展的扩展引起的。在这里，我们确定ATXN 7作为体外和体内SUMO化的新靶点。主要的SUMO受体位点定位于赖氨酸257，这是进化上保守的共有SUMO化基序的一部分。SUMO化不影响ATXN 7的亚细胞定位，也不影响其与TFTC/STAGA复合物组分的相互作用。多聚谷氨酰胺延伸的扩展不损害ATXN 7的SUMO化。此外，SUMO 1和SUMO 2与ATXN 7共定位在SCA 7患者和SCA 7敲入小鼠脑中的神经元核内包涵体的子集中。在SCA 7的COS-7细胞模型中，除了弥漫性核质染色外，我们还鉴定了两种核内含物群体：均质或非均质。非均匀包涵体与SUMO 1和SUMO 2的共定位显着减少，但高度富集Hsp 70，19 S蛋白酶体和泛素。有趣的是，他们的特点是增加染色的凋亡标志物caspase-3和破坏PML核小体。重要的是，通过突变SUMO位点来防止扩增的ATXN 7的SUMO化增加了SDS不溶性聚集体和半胱天冬酶-3阳性非均质内含物的量，这对细胞是有毒的。我们的研究结果表明SUMO化对ATXN 7多步聚集过程的影响，并暗示ATXN 7 SUMO化在SCA 7发病机制中的作用。
Post-translational modification by SUMO (small ubiquitin-like modifier) was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder, whose pathology is caused by an expansion of a polyglutamine stretch in the protein ataxin-7 (ATXN7). Here, we identified ATXN7 as new target for SUMOylation in vitro and in vivo. The major SUMO acceptor site was mapped to lysine 257, which is part of an evolutionarily conserved consensus SUMOylation motif. SUMOylation did not influence the subcellular localization of ATXN7 nor its interaction with components of the TFTC/STAGA complex. Expansion of the polyglutamine stretch did not impair the SUMOylation of ATXN7. Furthermore, SUMO1 and SUMO2 colocalized with ATXN7 in a subset of neuronal intranuclear inclusions in the brain of SCA7 patients and SCA7 knock-in mice. In a COS-7 cellular model of SCA7, in addition to diffuse nucleoplasmic staining we identified two populations of nuclear inclusions: homogenous or non-homogenous. Non-homogenous inclusions showed significantly reduced colocalization with SUMO1 and SUMO2, but were highly enriched in Hsp70, 19S proteasome and ubiquitin. Interestingly, they were characterized by increased staining with the apoptotic marker caspase-3 and by disruption of PML nuclear bodies. Importantly, preventing the SUMOylation of expanded ATXN7 by mutating the SUMO site increased both the amount of SDS-insoluble aggregates and of caspase-3 positive non-homogenous inclusions, which act toxic to the cells. Our results demonstrate an influence of SUMOylation on the multistep aggregation process of ATXN7 and implicate a role for ATXN7 SUMOylation in SCA7 pathogenesis.