Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.
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酪蛋白-TRNA合成酶在肌动蛋白捆绑中具有非规范功能。
DOI：
10.1038/s41467-023-35908-3
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发表时间：
2023-03-08
影响因子：
16.6
通讯作者：
Jordanova, Albena
中科院分区：
文献类型：
--
作者：
Ermanoska, Biljana;Asselbergh, Bob;Morant, Laura;Petrovic-Erfurth, Maria-Luise;Hosseinibarkooie, Seyyedmohsen;Leitao-Goncalves, Ricardo;Almeida-Souza, Leonardo;Bervoets, Sven;Sun, Litao;Lee, LaTasha;Atkinson, Derek;Khanghahi, Akram;Tournev, Ivaylo;Callaerts, Patrick;Verstreken, Patrik;Yang, Xiang-Lei;Wirth, Brunhilde;Rodal, Avital A.;Timmerman, Vincent;Goode, Bruce L.;Godenschwege, Tanja A.;Jordanova, Albena
酪氨酰-tRNA合成酶（YARS 1）和其他六种tRNA连接酶的显性突变会导致Charcot-Marie-Tooth周围神经病变（CMT）。其致病性不需要氨酰化的丧失，这表明了功能获得性疾病机制。通过果蝇无偏见的遗传筛选，我们将YARS 1功能障碍与肌动蛋白细胞骨架组织联系起来。生物化学研究揭示了YARS 1的未知肌动蛋白捆绑特性通过CMT突变增强，导致果蝇神经系统，人类SH-SY 5 Y神经母细胞瘤细胞和患者来源的成纤维细胞中的肌动蛋白解体。F-actin组织的遗传调节改善了表达CMT引起的YARS 1突变的果蝇神经元的标志性电生理和形态学特征。在表达引起神经病的甘氨酰-tRNA合成酶的果蝇中观察到类似的有益效果。因此，在这项工作中，我们表明，YARS 1是一个进化保守的F-肌动蛋白的组织者，连接肌动蛋白细胞骨架的tRNA合成酶诱导的神经退行性变。tRNA连接酶是翻译机制的重要组成部分，其突变与腓骨肌萎缩性侧索硬化周围神经病变相关，但其机制细节尚不清楚。作者报告说，酪氨酰-tRNA合成酶是一种进化上保守的F-肌动蛋白组织者，这种功能的失调与这种疾病有关。
Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen in Drosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in the Drosophila nervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration. Mutations in tRNA ligases, essential components of the translational machinery, are associated with Charcot-Marie-Tooth peripheral neuropathy, but the mechanistic details are not known. The authors report that the tyrosyl-tRNA synthetase is an evolutionary-conserved F-actin organizer, and dysregulation of this function is associated with the disorder.
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影响因子：
7.8
作者：
DANG, CV;YANG, DCH;POLLARD, TD
通讯作者：
POLLARD, TD
影响因子：
64.8
作者：
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Yang, Xiang-Lei
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Arganda-Carreras, Ignacio;Kaynig, Verena;Seung, H. Sebastian
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