National Centre for Biological Sciences, Bangalore, India.
Trinity College Institute of Neuroscience, School of Genetics and Microbiology, Smurfit Institute of Genetics and School of Natural Sciences, Trinity College Dublin, Dublin, Ireland.
Elife. 2021 Mar 10;10:e60326. doi: 10.7554/eLife.60326.
Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the brain and S2 cells. Atx2 interactions with AU-rich elements in 3'UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.
共济失调-2 蛋白（Atx2）是一种翻译控制分子，在脊髓小脑共济失调 2 型和肌萎缩性侧索硬化症中发生突变。虽然 Atx2 的无规则结构域（IDR）有助于 mRNP 凝聚成颗粒，但 IDR 如何与结构域一起工作以实现对靶 mRNA 的正向和负向调节仍不清楚。使用 RNA 结合蛋白靶点鉴定的编辑技术，我们在大脑和 S2 细胞中鉴定了大量的 Atx2 靶 mRNA。Atx2 与 3'UTR 中富含 AU 的元件的相互作用似乎调节了这些靶 mRNA 的很大一部分的稳定性/周转率。对 Atx2 结构域缺失的进一步基因组和细胞生物学分析表明，Atx2（1）在 mRNP 颗粒内与靶 mRNA 密切相互作用，（2）包含驱动或反对 RNP 颗粒组装的独特蛋白结构域，以及（3）在 mRNP 颗粒之外具有其他必需的作用。这些发现增加了对神经元翻译控制机制的理解，并为正在开发的基于 Atx2 的神经退行性疾病干预策略提供了信息。
