ATXN2 is a target of N-terminal proteolysis.
ATXN2 is a target of N-terminal proteolysis.
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DOI：
10.1371/journal.pone.0296085
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
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脊髓小脑性共济失调2(SCA2)是由Aaxin-2多聚谷氨酰胺(PolyQ)区扩张引起的一种神经退行性疾病。其他含有多Q的蛋白，如ATXN7和Huntingtin，当其N-末端多Q结构域扩展时，与神经退行性疾病的发生有关。此外，它们还经历蛋白降解处理事件，产生N-末端片段，其中包括多聚Q伸展，这与发病机制有关。有趣的是，在一名SCA2患者的脑提取液中报告了N-末端ATXN2片段，但目前尚不清楚扩展的多Q结构域是否有助于ATXN2蛋白分解的易感性。在这里，我们使用HEK293细胞中的瞬时表达来确定ATXN2是否是特定N端蛋白降解的靶点。我们发现，具有正常或扩展的多Q伸展的ATXN2蛋白会发生蛋白水解性切割，释放出一个含有多Q的N末端片段。我们在PolyQ结构域下游发现了一个短的氨基酸序列，它是全长ATXN2的N端切割所必需的，并且足以诱导异源蛋白的蛋白分解。然而，该序列不是切割由编码多Q结构域的CAG重复序列上游的替代起始密码子产生的短ATXN2异构体所必需的。我们的研究扩展了我们对ATXN2翻译后调控的理解，揭示了该蛋白可以成为特定的蛋白水解性切割事件的靶点，释放由ATXN2的N-末端结构域调节的含有多Q的产物。扩展的多Q结构域的N-末端ATXN2蛋白分解可能与SCA2病理有关，正如观察到的由多Q结构域扩展引起的其他神经退行性疾病一样。
Spinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder caused by the expansion of the poly-glutamine (polyQ) tract of Ataxin-2 (ATXN2). Other polyQ-containing proteins such as ATXN7 and huntingtin are associated with the development of neurodegenerative diseases when their N-terminal polyQ domains are expanded. Furthermore, they undergo proteolytic processing events that produce N-terminal fragments that include the polyQ stretch, which are implicated in pathogenesis. Interestingly, N-terminal ATXN2 fragments were reported in a brain extract from a SCA2 patient, but it is currently unknown whether an expanded polyQ domain contributes to ATXN2 proteolytic susceptibility. Here, we used transient expression in HEK293 cells to determine whether ATXN2 is a target for specific N-terminal proteolysis. We found that ATXN2 proteins with either normal or expanded polyQ stretches undergo proteolytic cleavage releasing an N-terminal polyQ-containing fragment. We identified a short amino acid sequence downstream of the polyQ domain that is necessary for N-terminal cleavage of full-length ATXN2 and sufficient to induce proteolysis of a heterologous protein. However, this sequence is not required for cleavage of a short ATXN2 isoform produced from an alternative start codon located just upstream of the CAG repeats encoding the polyQ domain. Our study extends our understanding of ATXN2 posttranslational regulation by revealing that this protein can be the target of specific proteolytic cleavage events releasing polyQ-containing products that are modulated by the N-terminal domain of ATXN2. N-terminal ATXN2 proteolysis of expanded polyQ domains might contribute to SCA2 pathology, as observed in other neurodegenerative disorders caused by polyQ domain expansion.
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