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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的氨酰基-tRNA 合成酶 (aaRS) 是催化第一个合成酶的必需酶家族。蛋白质生物合成中的反应，即转移 RNA (tRNA) 与其同源的电荷由于蛋白质合成在大多数细胞中的重要性，因此这并不奇怪。几乎所有 aaRS 家族成员都通过双等位基因突变与人类联系在一起经常影响多个器官系统的疾病。范围广泛的非酶功能调节许多重要的生物过程。 aaRSs原理的调节功能也可能参与疾病机制。然而，挑战在于难以剖析监管职能的影响除了在发生蛋白质合成的细胞质中外， aaRS 经常在细胞外空间中检测到，例如在细胞培养基中和在然而，细胞外的生理系统意义。 tRNA 合成酶仍然未知，该项目旨在研究病理生理功能。我们专注于与特定的 aaRS 相关的一组选择性的 tRNA 合成酶。神经退行性疾病 - 腓骨肌萎缩症 (CMT) - 通过显性单在过去 10 年的 GM 的支持下，我们确定了细胞外存在甘氨酰-tRNA 合成酶（GlyRS 或 GARS；第一个也是最重要的）显着的 CMT 相关 aaRS）与该疾病相关，我们确定了特定的细胞信号传导我们未来的研究将调查引起 CMT 的 GlyRS 突变体的失调途径。所有 aaRS 相关 CMT 亚型中特定信号通路的参与并揭示 aaRS 在正常细胞信号传导过程中的细胞外作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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
通讯作者：
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