Link extracellular function of tRNA synthetase with pathological mechanism of disease

摘要 氨基酰基-tRNA合成酶(AARs)是一类重要的酶家族，催化第一种 蛋白质生物合成中的反应，即转移RNA(TRNAs)与其同源物的荷电 氨基酸。由于蛋白质合成在大多数细胞中的重要性，并不令人惊讶 几乎所有的AARSS家族成员都通过双等位基因突变与人类 经常影响多个器官系统的疾病。有趣的是，人类的AAR也有广泛的- 调节许多重要生物过程的一系列非酶功能。因此，在 原则上，AARS的调节功能也可能参与疾病的机制。 然而，挑战在于很难剖析监管职能对 酶的作用。除了在蛋白质合成发生的细胞质中， AARs经常在细胞外空间中被检测到，例如在细胞培养液中和在 人类和小鼠的全身循环。然而，细胞外的生理意义 TRNA合成酶仍不清楚。本项目旨在研究病理生理功能。 胞外tRNA合成酶。我们专注于一组与特定AAR相关联的AAR 神经退行性疾病-Charcot-Marie-Tooth病(CMT)-通过显性单基因 等位基因突变。在通用汽车过去10年的支持下，我们确立了 细胞外存在甘氨酰-tRNA合成酶(GlyRS或GARS；第一个也是最多的 突出的CMT连锁AARs)与疾病相关，我们确定了特定的细胞信号 由CMT引起的GlyRS突变体调节失调的通路。我们未来的研究将调查 在所有AARS连锁的CMT亚型和发现中涉及特定的信号通路 AARs在正常细胞信号传递过程中的细胞外作用。

Abstract Aminoacyl-tRNA synthetases (aaRSs) are a family of essential enzymes that catalyze the first reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino acids. Due to the importance of protein synthesis in most cells, it is not surprising that almost all aaRSs family members have been linked through bi-allelic mutations to human diseases that often affect multiple organ systems. Interestingly, human aaRSs also have wide- ranging non-enzymatic functions regulating many important biological processes. Therefore, in principle, regulatory functions of aaRSs could also be involved in the disease mechanism. However, the challenge lies in the difficulties to dissect the impact of regulatory functions from that of the enzymatic roles. In addition to being in the cytosol where protein synthesis occurs, aaRSs are frequently detected in the extracellular space, such as in cell culture media and in the systemic circulations of humans and mice. Yet, the physiological significance of extracellular tRNA synthetases remains unknown. This project aims to investigate pathophysiological function of extracellular tRNA synthetases. We focus on a selective group of aaRSs linked to a specific neurodegenerative disease – Charcot-Marie-Tooth disease (CMT) – through dominant mono- allelic mutations. Under the support of GM for the last 10 years, we established that the extracellular presence of glycyl-tRNA synthetase (GlyRS or GARS; the first and the most prominent CMT-linked aaRS) is relevant to the disease and we identified specific cell signaling pathways dysregulated by CMT-causing GlyRS mutants. Our future research will investigate the involvement of a particular signaling pathway in all aaRS-linked CMT subtypes and uncover extracellular roles of aaRS in the normal cell signaling process.