Fudan Research Team Successfully Reveals Sensing and Signal Transduction System of Amino Acid

There is yet no full understanding concerning the issue of how nutrition metabolites are sensed intracellularly. Recent studies have shed some light on the fact that cells through sensing certain metabolite substances such as 1,6 fructose diphosphate, glutamine and arginine, are able to control the significant cellular signal networks, i.e., AMPK and mTORC1. Discovery as such, further stresses the importance of metabolite sensing. However, little is known concerning how cells systematically sense a specific metabolite and their signal transduction. The research team at Fudan which is made up of Professor Zhao Shimin, research associate Xu Wei and Professor Xu Yanhui has been working on this tricky scientific issue for five years, and has recently discovered that not only can tRNA synthetases recognize amino acids and activate tRNA’s role in protein synthesis, but they also bear the function of modifying lysine aminoacylation. This breakthrough helps reveal the systematic and functional amino acid sensing and signal transduction network. Furthermore, it makes possible in the future to explain how different amino acids control and modify specific signal networks, how the mutation of various tRNA synthetases leads to different human disease mechanisms, and what kind of strategies we should develop to intervene those mechanisms. On November 30 (U.S. time), the result of the team’s research was published on Cell Metabolism. Interested readers may refer to the following link for the details of their work: http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30629-0.

As one of the most important intracellular metabolites, amino acid is known as the participant of protein synthesis and the regulator of cellular signaling. For instance, leucine can activate the mTORC1 signal network, and glutamine can suppress the relevant signal network of apoptosis. However, there remains some confusing phenomenon that cannot be explained by the disturbance of protein synthesis. For example, the leucine-tRNA synthetase and the glutamine-tRNA synthetase as participants of protein synthesis can respectively activate the mTORC1 signal network and suppress the relevant signal network of apotosis; some pathogenic mutation of tRNA synthetases such as that of the glycine-tRNA synthetase will not influence their sensing and activating of amino acid, but can lead to neurological diseases such as Charcot-Marie-Tooth. And for a long time, the problems of how amino acids are sensed and how tRNA synthetases participate in the sensing and signal transduction network remain unsolved.

The research team of Fudan has revealed the function of tRNA sythetases in modifying protein lysine. They discover that when the concentration of intracellular amino acid reaches a certain level, the amino acid concerned together with its corresponding tRNA synthetase would produce reactive intermediate aminoacyl AMP. And the amino acid thereafter would promote the conjugation of aminoacyl-tRNA synthetase with specific intracellular protein, and modifies itself onto the substrate protein of lysine by virtue of reactive intermediate aminoacyl AMP.

The property of protein changes after the modification of amino acid, and it transduces the information of the latter to the cellular signal network. The research team also discovers that the amino acid that is modified onto the substrate protein can be removed by de-modification enzymes such as deacetylase, which indicates that the regulation of amino acid is actually a dynamically reversible post-proteinaceous-translation regulation.

The completion of the research owes much thanks to Obstetrics and Gynecology Hospital of Fudan University, School of Life Science of Fudan University, State Key Laboratory of Genetic Engineering of Fudan University and Institutes of Biomedical Sciences of Fudan University for their equal support and help. Dr. He Xiadi, the nominee of 2017 “Bo Xin Project”, is the first author of the paper. Professor Zhao Shimin, the leading scientist of the State Key Laboratory of Genetic Engineering Fudan University and resident professor at Obstetrics and Gynecology Hospital of Fudan University, is the principal investigator of the research. Xu Wei, research associate at the Institute of Biomedical Research, and Professor Xu Yanhui of the Oncology Hospital Fudan University / School of Life and Science of Fudan University, are co-authors of the paper, both of whom have made a major contribution in terms of the discovery of amino acid modification and in functional study and structural biology analysis. The research has also received help from the project team of Professor Wang Enduo of Chinese Academy of Sciences, and that of Professor Tang Huiru of School of Life and Sciences at Fudan University. Finally, the research project is financially supported by the National Natural Science Foundation of China, the Major Research Program of Ministry of Science and Technology, and Shanghai Basic Research Foundation.

The research team led by Professor Zhao Shimin has long been devoted to the study of molecular mechanism of pathogenic effect of nutritional metabolites disorder, and has reaped a series of original findings in this field. Also, Professor Zhao Shimin himself has published many of his scientific achievements on various world-acknowledged journals such as Science, Cancer Cell, Cell Metabolism, Molecular Cell, etc.