Link extracellular function of tRNA synthetase with pathological mechanism of disease

将tRNA合成酶的细胞外功能与疾病的病理机制联系起来

• 批准号: 10630282
• 负责人: Xiang-Lei Yang
• 金额: $ 45.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630282
• 关键词: Affect; Alleles; Amino Acids; Amino Acyl-tRNA Synthetases; Biological Process; Cell Culture Techniques; Cell Signaling Process; Cell physiology; Cells; Charcot-Marie-Tooth Disease; Circulation; Culture Media; Cytosol; Disease; Enzymes; Extracellular Space; Family; Family member; Human; Link; Mus; Mutation; Neurodegenerative Disorders; Neuropilin-1; Normal Cell; Pathologic; Physiological; Protein Biosynthesis; Reaction; Role; Signal Pathway; Signal Transduction; Tooth Diseases; Transfer RNA Aminoacylation; body system; disorder subtype; extracellular; human disease; mutant; Affect; Alleles; Amino Acids; Amino Acyl-tRNA Synthetases; Biological Process; Cell Culture Techniques; Cell Signaling Process; Cell physiology; Cells; Charcot-Marie-Tooth Disease; Circulation; Culture Media; Cytosol; Disease; Enzymes; Extracellular Space; Family; Family member; Human; Link; Mus; Mutation; Neurodegenerative Disorders; Neuropilin-1; Normal Cell; Pathologic; Physiological; Protein Biosynthesis; Reaction; Role; Signal Pathway; Signal Transduction; Tooth Diseases; Transfer RNA Aminoacylation; body system; disorder subtype; extracellular; human disease; mutant

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.

抽象的 氨基酰基-TRNA合成酶（AARSS）是催化第一个的必需酶家族 蛋白质生物合成中的反应，即转移RNA（TRNA）与同源的反应 氨基酸。由于大多数细胞中蛋白质合成的重要性，毫不奇怪 几乎所有的AARS家族成员都通过双 - 平行突变与人类联系在一起 经常影响多个器官系统的疾病。有趣的是，人类的AARS也有广泛的 范围非酶函数调节许多重要的生物学过程。因此，在 原理，AARS的调节功能也可能参与疾病机制。 但是，挑战在于难以从监管职能的影响中 酶作用。除了在发生蛋白质合成的细胞质外， 在细胞外空间中经常检测到AARS，例如在细胞培养基中和 人类和小鼠的系统循环。然而，细胞外的身体意义 tRNA合成酶仍然未知。该项目旨在研究病理生理功能 细胞外tRNA合成酶。我们专注于选择性的AARS组，这些AARS与特定 神经退行性疾病 - charcot-marie-tooth疾病（CMT） - 通过主要的单声道 等位基因突变。在过去十年的通用汽车的支持下，我们确定 糖基-TRNA合成酶的细胞外存在（Glyrs或Gars；第一个和最多 突出的CMT链接AARS）与该疾病有关，我们确定了特定的细胞信号传导 CMT引起的Glyrs突变体失调的途径。我们未来的研究将调查 在所有AARS连接的CMT亚型中，特定信号通路的参与并发现 AAR在正常细胞信号传导过程中的细胞外作用。