Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation
Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation
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DOI：
10.1074/jbc.ra120.013835
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发表时间：
2020-11-20
影响因子：
4.8
通讯作者：
Hoshino, Shin-ichi
中科院分区：
文献类型：
--
作者：
Inagaki, Hiroto;Hosoda, Nao;Hoshino, Shin-ichi
rna结合蛋白Ataxin-2结合并稳定了许多mRNA序列，包括43 kDa的反应性dna结合蛋白（TDP-43）。Ataxin-2还参与一些需要翻译的过程，如种系形成、长期习惯化和昼夜节律形成。然而，尚未明确证明Ataxin-2实际上参与激活其靶mrna的翻译。在这里，我们从多聚体分析中提供直接证据，表明Ataxin-2增强了目标mrna的翻译。我们最近建立的抑制deadenylation条件下的转录脉冲追踪分析方法显示，Ataxin-2促进靶mrna的转录后聚腺苷化。此外，Ataxin-2通过其内在无序区域（氨基酸906-1095）与聚(a)结合蛋白PABPC1和非规范聚(a)聚合酶PAPD4结合，将PAPD4招募到靶标上。Ataxin-2的转录后聚腺苷化不仅解释了它如何激活翻译，还解释了它如何稳定靶mRNA，包括TDP-43 mRNA。Ataxin-2是TDP-43蛋白病变的有效修饰剂，在2型脊髓小脑性共济失调神经退行性疾病中起致病作用，因此这些研究结果表明，Ataxin-2诱导的细胞质多腺苷化和翻译激活可能影响神经退行性疾病（即TDP-43蛋白病变），这一过程可能成为Ataxin-2相关神经退行性疾病的治疗靶点。
The RNA-binding protein Ataxin-2 binds to and stabilizes a number of mRNA sequences, including that of the transactive response DNA-binding protein of 43 kDa (TDP-43). Ataxin-2 is additionally involved in several processes requiring translation, such as germline formation, long-term habituation, and circadian rhythm formation. However, it has yet to be unambiguously demonstrated that Ataxin-2 is actually involved in activating the translation of its target mRNAs. Here we provide direct evidence from a polysome profile analysis showing that Ataxin-2 enhances translation of target mRNAs. Our recently established method for transcriptional pulse-chase analysis under conditions of suppressing deadenylation revealed that Ataxin-2 promotes post-transcriptional polyadenylation of the target mRNAs. Furthermore, Ataxin-2 binds to a poly(A)-binding protein PABPC1 and a noncanonical poly(A) polymerase PAPD4 via its intrinsically disordered region (amino acids 906-1095) to recruit PAPD4 to the targets. Post-transcriptional polyadenylation by Ataxin-2 explains not only how it activates translation but also how it stabilizes target mRNAs, including TDP-43 mRNA. Ataxin-2 is known to be a potent modifier of TDP-43 proteinopathies and to play a causative role in the neurodegenerative disease spinocerebellar ataxia type 2, so these findings suggest that Ataxin-2-induced cytoplasmic polyadenylation and activation of translation might impact neurodegeneration (i.e. TDP-43 proteinopathies), and this process could be a therapeutic target for Ataxin-2-related neurodegenerative disorders.