Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy
Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy
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DOI：
10.1038/s41467-019-12909-9
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发表时间：
2019-11-06
影响因子：
16.6
通讯作者：
Yang, Xiang-Lei
中科院分区：
文献类型：
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作者：
Bervoets, Sven;Wei, Na;Yang, Xiang-Lei
腓骨肌萎缩症（CMT）是一种长度依赖性周围神经病变。氨酰-tRNA合成酶是CMT中最大的蛋白质家族。氨酰-tRNA合成酶主要存在于细胞质中，但也存在于细胞核中。在这里，我们表明，核功能的酪氨酰-tRNA合成酶（TyrRS）牵连在果蝇模型的CMT。TyrRS中引起CMT的突变诱导独特的构象变化，其赋予与细胞核中的转录调控因子异常相互作用的能力，导致转录因子E2 F1超活化。使用神经元组织，我们揭示了一个广泛的转录调控网络与野生型TyrRS的表达，这是一个CMT突变体表达时被扰乱。Embelin对TyrRS核进入的药理学抑制减少，而突变体TyrRS的遗传核排斥防止了果蝇模型中CMT的标志表型。这些数据突出表明，这种翻译因子可能有助于神经元中的转录调控，并提出了CMT的治疗策略。
Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.