Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Institute for Cellular and Molecular Biology and Departments of Molecular Biosciences and Oncology, University of Texas at Austin, Austin, TX, USA.
Nat Cell Biol. 2023 Apr;25(4):592-603. doi: 10.1038/s41556-023-01118-8. Epub 2023 Apr 14.
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.
细胞通过感应代谢物水平的变化来对炎症等干扰作出反应。精氨酸尤为突出，它与炎症反应有已知的联系。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转导。在这里，我们表明在炎症期间精氨酸的耗竭会降低核定位的精氨酰-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) 相互作用并共定位，SRRM2 是剪接体和核斑点蛋白，核 ArgRS 的水平降低与 SRRM2 的类似液滴的核运输以及某些基因中的剪接位点使用的变化相关。这些剪接位点使用的变化累积导致合成不同的蛋白质同工型，改变了细胞代谢和肽向免疫细胞的呈递。我们的发现揭示了一种机制，即一种与在炎症过程中代谢控制的关键氨基酸对应的氨酰-tRNA 合成酶调节剪接机制。
