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

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.

摘要 氨酰-tRNA合成酶（aaRSs）是一个必需的酶家族，其催化第一种酶， 蛋白质生物合成中的反应，即转移RNA（tRNA）与其同源物的电荷 个氨基酸由于蛋白质合成在大多数细胞中的重要性， 几乎所有的aaRS家族成员都通过双等位基因突变与人 这些疾病通常会影响多个器官系统。有趣的是，人类aaRS也有广泛的- 调节许多重要生物过程的非酶功能。因此在 原则上，aaRSs的调节功能也可能参与疾病机制。 然而，挑战在于，很难将监管职能的影响从 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检测到，例如在细胞培养基中和细胞外基质中。 人和小鼠的全身循环。然而，细胞外的生理意义 tRNA合成酶仍然未知。本项目旨在研究病理生理功能 细胞外的tRNA合成酶。我们专注于一组选择性的aaRS链接到一个特定的 神经退行性疾病-腓骨肌萎缩症（CMT）-通过显性单- 等位基因突变在通用汽车公司过去10年的支持下， 细胞外存在甘氨酰-tRNA合成酶（GlyRS或加尔斯;第一个也是最重要的 突出的CMT连锁阿尔斯）与该疾病相关，并且我们鉴定了特定的细胞信号传导 导致CMT的GlyRS突变体失调的途径。我们未来的研究将调查 在所有aaRS连锁CMT亚型中涉及特定信号传导途径， 阿尔斯在正常细胞信号传导过程中的细胞外作用。

项目成果

The binding mode of orphan glycyl-tRNA synthetase with tRNA supports the synthetase classification and reveals large domain movements.

• DOI: 10.1126/sciadv.adf1027
• 发表时间: 2023-02-10
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Han, Lu;Luo, Zhiteng;Ju, Yingchen;Chen, Bingyi;Zou, Taotao;Wang, Junjian;Xu, Jun;Gu, Qiong;Yang, Xiang-Lei;Schimmel, Paul;Zhou, Huihao
• 通讯作者: Zhou, Huihao

Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice.

• DOI: 10.1172/jci.insight.157191
• 发表时间: 2023-05-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Sleigh, James N.;Villarroel-Campos, David;Surana, Sunaina;Wickenden, Tahmina;Tong, Yao;Simkin, Rebecca L.;Vargas, Jose Norberto S.;Rhymes, Elena R.;Tosolini, Andrew P.;West, Steven J.;Zhang, Qian;Yang, Xiang-Lei;Schiavo, Giampietro
• 通讯作者: Schiavo, Giampietro

Neuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability.

• DOI: 10.1038/s41467-022-31904-1
• 发表时间: 2022-07-20
• 期刊: Nature communications
• 影响因子: 16.6

Mechanistic perspectives on anti-aminoacyl-tRNA synthetase syndrome.

• DOI: 10.1016/j.tibs.2022.09.011
• 发表时间: 2022-10
• 期刊: Trends in biochemical sciences
• 影响因子: 13.8
• 作者: S. Kanaji;Wenqian Chen;Y. Morodomi;Ryan Shapiro;T. Kanaji;Xiang-Lei Yang

Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase.

• DOI: 10.1093/nar/gkad696
• 发表时间: 2023-10-13
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: de Potter, Bastiaan;Vallee, Ingrid;Camacho, Noelia;Povoas, Luis Filipe Costa;Bonsembiante, Aureliano;Pons i Pons, Alba;Eckhard, Ulrich;Gomis-Ruth, Francesc-Xavier;Yang, Xiang-Lei;Schimmel, Paul;Kuhle, Bernhard;Ribas de Pouplana, Lluis
• 通讯作者: Ribas de Pouplana, Lluis