Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.
Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
J Neurosci Res. 2020 Oct;98(10):2096-2108. doi: 10.1002/jnr.24684. Epub 2020 Jul 9.
Ataxin-3 is a deubiquitinase and polyglutamine disease protein whose cellular properties and functions are not entirely understood. Mutations in ataxin-3 cause spinocerebellar ataxia type 3 (SCA3), a neurodegenerative disorder that is a member of the polyglutamine family of diseases. Two major isoforms arise from alternative splicing of ATXN3 and are differently toxic in vivo as a result of faster proteasomal degradation of one isoform compared to the other. The isoforms vary only at their C-termini, suggesting that the hydrophobic C-terminus of the more quickly degraded form of ataxin-3 (here referred to as isoform 2) functions as a degron-that is, a peptide sequence that expedites the degradation of its host protein. We explored this notion in this study and present evidence that: (a) the C-terminus of ataxin-3 isoform 2 signals its degradation in a proteasome-dependent manner, (b) this effect from the C-terminus of isoform 2 does not require the ubiquitination of ataxin-3, and (c) the isolated C-terminus of isoform 2 can enhance the degradation of an unrelated protein. According to our data, the C-terminus of ataxin-3 isoform 2 is a degron, increasing overall understanding of the cellular properties of the SCA3 protein.
Ataxin-3 是一种去泛素化酶和多聚谷氨酰胺疾病蛋白，其细胞特性和功能尚未完全了解。Ataxin-3 的突变导致脊髓小脑共济失调 3 型（SCA3），这是一种多聚谷氨酰胺疾病家族的神经退行性疾病。两种主要的异构体通过 ATXN3 的选择性剪接产生，由于一种异构体比另一种异构体更快地被蛋白酶体降解，因此在体内具有不同的毒性。异构体仅在其 C 末端有所不同，这表明更快速降解形式的 Ataxin-3 的疏水性 C 末端（在此称为异构体 2）作为一种降解信号，即促进其宿主蛋白降解的肽序列。在这项研究中，我们探讨了这一概念，并提出了以下证据：（a）Ataxin-3 异构体 2 的 C 末端以依赖蛋白酶体的方式信号其降解，（b）这种来自异构体 2 的 C 末端的效应不需要 Ataxin-3 的泛素化，以及（c）异构体 2 的分离 C 末端可以增强与无关蛋白的降解。根据我们的数据，Ataxin-3 异构体 2 的 C 末端是一种降解信号，这增加了对 SCA3 蛋白细胞特性的整体理解。
