Characterization of novel nucleoside signaling

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02599
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Tohoku University (2019-2020); Kumamoto University (2018)
• Principal Investigator: Wei Fanyan 東北大学, 加齢医学研究所, 教授 (90555773)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: RNA修飾 / 液性因子 / GPCR

Outline of Final Research Achievements

About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating GPCRs and triggering pathophysiological responses, a previously unreported property of RNA modifications.

Free Research Field

生理学

Academic Significance and Societal Importance of the Research Achievements

今回、RNA修飾の代謝産物の一つであるm6Aが、生体内で受容体を強力に活性化して生理作用・病的作用を起こすことを明らかにした。アデノシンの生理作用が発見されて以来約90年振りに、内在性に存在しアデノシンよりも強力なヌクレオシドを見出し、生命科学研究において非常に意義が高い。本研究成果により、従来の概念に存在しない新しい液性因子として、RNA由来の修飾ヌクレオシドが生体機能に関わる可能性が示され、修飾ヌクレオシドのさらなる研究によって、全く新しい核酸医薬開発への基盤研究となることが期待される。