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Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2
Nature Cell Biology ( IF 17.3 ) Pub Date : 2023-04-14 , DOI: 10.1038/s41556-023-01118-8
Haissi Cui 1 , Jolene K Diedrich 1 , Douglas C Wu 2 , Justin J Lim 3, 4 , Ryan M Nottingham 2 , James J Moresco 1, 5 , John R Yates 1 , Benjamin J Blencowe 3, 4 , Alan M Lambowitz 2 , Paul Schimmel 1
Affiliation  

Cells respond to perturbations such as inflammation by sensing changes in metabolite levels. Especially prominent is arginine, which has known connections to the inflammatory response. Aminoacyl-tRNA synthetases, enzymes that catalyse the first step of protein synthesis, can also mediate cell signalling. Here we show that depletion of arginine during inflammation decreased levels of nuclear-localized arginyl-tRNA synthetase (ArgRS). Surprisingly, we found that nuclear ArgRS interacts and co-localizes with serine/arginine repetitive matrix protein 2 (SRRM2), a spliceosomal and nuclear speckle protein, and that decreased levels of nuclear ArgRS correlated with changes in condensate-like nuclear trafficking of SRRM2 and splice-site usage in certain genes. These splice-site usage changes cumulated in the synthesis of different protein isoforms that altered cellular metabolism and peptide presentation to immune cells. Our findings uncover a mechanism whereby an aminoacyl-tRNA synthetase cognate to a key amino acid that is metabolically controlled during inflammation modulates the splicing machinery.



中文翻译:


Arg-tRNA 合成酶通过 SRRM2 将炎症代谢与 RNA 剪接和核运输联系起来



细胞通过感知代谢物水平的变化来应对炎症等扰动。尤其突出的是精氨酸,已知它与炎症反应有关。氨酰-tRNA 合成酶是催化蛋白质合成第一步的酶,也可以介导细胞信号传导。在这里,我们发现炎症过程中精氨酸的消耗降低了核定位的精氨酰-tRNA 合成酶 (ArgRS) 的水平。令人惊讶的是,我们发现核 ArgRS 与丝氨酸/精氨酸重复基质蛋白 2 (SRRM2)(一种剪接体和核斑点蛋白)相互作用并共定位,并且核 ArgRS 水平的降低与 SRRM2 和凝析样核运输的变化相关。某些基因中剪接位点的使用。这些剪接位点使用的变化累积在不同蛋白质亚型的合成中,改变了细胞代谢和肽向免疫细胞的呈递。我们的研究结果揭示了一种机制,氨酰-tRNA 合成酶与炎症期间代谢控制的关键氨基酸同源,从而调节剪接机制。

更新日期:2023-04-15
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