Impact of alanyl-tRNA synthetase editing deficiency in yeast.
Impact of alanyl-tRNA synthetase editing deficiency in yeast.
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DOI：
10.1093/nar/gkab766
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发表时间：
2021-09-27
影响因子：
14.9
通讯作者：
Ling J
中科院分区：
文献类型：
--
作者：
Zhang H;Wu J;Lyu Z;Ling J
氨酰-tRNA合成酶（aminoacyl-tRNA synthetases，aaRSs）是核糖体合成蛋白质所必需的酶。aaRS突变会导致人类各种神经系统疾病。许多aaRS利用编辑来防止翻译期间的错误传播。丙氨酰-tRNA合成酶（AlaRS）的编辑缺陷导致小鼠神经变性和心脏蛋白病，并与人类患者的小头畸形有关。真核生物中AlaRS编辑缺陷的细胞影响仍不清楚。在这里，我们使用酵母作为模式生物系统地研究AlaRS编辑的生理作用。我们的RNA测序和定量蛋白质组学结果表明，AlaRS编辑缺陷令人惊讶地激活了一般的氨基酸控制途径，并减弱了热休克反应。我们已经用报告基因和生长测定证实了这些结果。此外，AlaRS编辑缺陷下调碳代谢并减弱蛋白质合成。为酵母细胞提供额外的碳源部分地挽救了由AlaRS编辑缺陷引起的热敏感性。这些发现与其他aaRS中编辑缺陷引起的细胞效应形成鲜明对比。因此，我们的研究强调了与其他aaRS相比，AlaRS编辑的特殊作用，并为缺乏AlaRS编辑所造成的生理影响提供了一个模型。
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that provide the ribosome with aminoacyl-tRNA substrates for protein synthesis. Mutations in aaRSs lead to various neurological disorders in humans. Many aaRSs utilize editing to prevent error propagation during translation. Editing defects in alanyl-tRNA synthetase (AlaRS) cause neurodegeneration and cardioproteinopathy in mice and are associated with microcephaly in human patients. The cellular impact of AlaRS editing deficiency in eukaryotes remains unclear. Here we use yeast as a model organism to systematically investigate the physiological role of AlaRS editing. Our RNA sequencing and quantitative proteomics results reveal that AlaRS editing defects surprisingly activate the general amino acid control pathway and attenuate the heatshock response. We have confirmed these results with reporter and growth assays. In addition, AlaRS editing defects downregulate carbon metabolism and attenuate protein synthesis. Supplying yeast cells with extra carbon source partially rescues the heat sensitivity caused by AlaRS editing deficiency. These findings are in stark contrast with the cellular effects caused by editing deficiency in other aaRSs. Our study therefore highlights the idiosyncratic role of AlaRS editing compared with other aaRSs and provides a model for the physiological impact caused by the lack of AlaRS editing.
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