A research for novel hormone: physiological functions of nucleosides derived from modified tRNAs

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02865
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kazuhito Tomizawa 熊本大学, 大学院生命科学研究部(医), 教授 (40274287)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ヌクレオシド / 修飾ヌクレオシド / オーファン受容体 / 免疫

Outline of Final Research Achievements

About 150 post-transcriptional RNA modifications are present throughout all kingdoms of life. During RNA catabolism, unlike unmodified nucleosides that are subject to further degradation or salvage pathway in cells, most modified nucleosides are resistant to degradation and are released into extracellular space4-6. However, the physiological role of these extracellular modified nucleosides remains unexplored. In this study, we found that N6-methyladenosine (m6A), widely known as an epigenetic mark in RNA, is released into extracellular space as the result of RNA breakdown and acts as a novel ligand for the adenosine A3 receptor with an 10-fold greater affinity than unmodified adenosine. Furthermore, m6A was dynamically released in response to cytotoxic stimuli both in vitro and in vivo, and facilitated type I allergy through the A3 receptor. Our findings shed new light on m6A as a signaling molecule with the ability to activate GPCRs.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

ヒトゲノム中に内在性リガントが不明の「オーファン」な非嗅覚Gタンパク質共役受容体（GPCR）が少なくとも120種類ある。この内の49種類がヌクレオシド等の低分子リガンドが結合するクラスAである。オーファンGPCRの生理的リガンド探索研究については、ヒトゲノムが解明された2003年頃に世界中で精力的に研究が行われて、多くの新規リガンドが発見された。しかし、近年新規リガンドの報告が激減している。GPCRのリガンドとして修飾ヌクレオシドを同定したという本研究成果は、GPCR研究の促進に繋がることが期待される。