Yao Peng, Poruri Kiran, Martinis Susan A, Fox Paul L
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Top Curr Chem. 2014;344:167-87. doi: 10.1007/128_2013_422.
Aminoacyl-tRNA synthetases (AARSs) are a group of essential and ubiquitous "house-keeping" enzymes responsible for charging corresponding amino acids to their cognate transfer RNAs (tRNAs) and providing the correct substrates for high-fidelity protein synthesis. During the last three decades, wide-ranging biochemical and genetic studies have revealed non-catalytic regulatory functions of multiple AARSs in biological processes including gene transcription, mRNA translation, and mitochondrial RNA splicing, and in diverse species from bacteria through yeasts to vertebrates. Remarkably, ongoing exploration of non-canonical functions of AARSs has shown that they contribute importantly to control of inflammation, angiogenesis, immune response, and tumorigenesis, among other critical physiopathological processes. In this chapter we consider the non-canonical functions of AARSs in regulating gene expression by mechanisms not directly related to their enzymatic activities, namely, at the levels of mRNA production, processing, and translation. The scope of AARS-mediated gene regulation ranges from negative autoregulation of single AARS genes to gene-selective control, and ultimately to global gene regulation. Clearly, AARSs have evolved these auxiliary regulatory functions that optimize the survival and well-being of the organism, possibly with more complex regulatory mechanisms associated with more complex organisms. In the first section on transcriptional control, we introduce the roles of autoregulation by Escherichia coli AlaRS, transcriptional activation by human LysRS, and transcriptional inhibition by vertebrate SerRS. In the second section on translational control, we recapitulate the roles of GluProRS in translation repression at the initiation step, auto-inhibition of E. coli thrS mRNA translation by ThrRS, and global translational arrest by phosphorylated human MetRS. Finally, in the third section, we describe the RNA splicing activities of mitochondrial TyrRS and LeuRS in Neurospora and yeasts, respectively.
氨酰 - tRNA合成酶（AARSs）是一组必不可少且普遍存在的“管家”酶，负责将相应的氨基酸加载到其同源转运RNA（tRNA）上，并为高保真蛋白质合成提供正确的底物。在过去三十年中，广泛的生化和遗传学研究揭示了多种AARSs在包括基因转录、mRNA翻译和线粒体RNA剪接在内的生物过程中，以及在从细菌到酵母再到脊椎动物的各种物种中的非催化调节功能。值得注意的是，对AARSs非经典功能的持续探索表明，它们在控制炎症、血管生成、免疫反应和肿瘤发生等其他关键生理病理过程中发挥着重要作用。在本章中，我们将探讨AARSs通过与其酶活性不直接相关的机制调节基因表达的非经典功能，即在mRNA产生、加工和翻译水平上的功能。AARS介导的基因调控范围从单个AARS基因的负自调控到基因选择性控制，最终到全局基因调控。显然，AARSs已经进化出这些辅助调节功能，以优化生物体的生存和健康，可能与更复杂生物体相关的更复杂调节机制有关。在关于转录控制的第一部分中，我们介绍了大肠杆菌丙氨酸 - tRNA合成酶（AlaRS）的自调控作用、人赖氨酸 - tRNA合成酶（LysRS）的转录激活作用以及脊椎动物丝氨酸 - tRNA合成酶（SerRS）的转录抑制作用。在关于翻译控制的第二部分中，我们概述了谷氨酰胺 - 脯氨酸 - tRNA合成酶（GluProRS）在起始步骤的翻译抑制作用、苏氨酸 - tRNA合成酶（ThrRS）对大肠杆菌苏氨酸 - tRNA合成酶（thrS）mRNA翻译的自抑制作用以及磷酸化的人甲硫氨酸 - tRNA合成酶（MetRS）引起的全局翻译停滞。最后，在第三部分中，我们分别描述了粗糙脉孢菌和酵母中线粒体酪氨酸 - tRNA合成酶（TyrRS）和亮氨酸 - tRNA合成酶（LeuRS）的RNA剪接活性。
