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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.

摘要

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