@article{332d7caa8bcd46d69fb5d641c50c3bb1,
title = "N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand",
abstract = "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 G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.",
keywords = "N6-methyladenosine, RNA catabolism, RNA modification, adenosine, adenosine A3 receptor, extracellular modified nucleosides, signaling molecule",
author = "Akiko Ogawa and Chisae Nagiri and Wataru Shihoya and Asuka Inoue and Kouki Kawakami and Suzune Hiratsuka and Junken Aoki and Yasuhiro Ito and Takeo Suzuki and Tsutomu Suzuki and Toshihiro Inoue and Osamu Nureki and Hidenobu Tanihara and Kazuhito Tomizawa and Wei, {Fan Yan}",
note = "Funding Information: We are grateful for suggestions and technical support from T. Chujo and all other members of the Department of Molecular Physiology, Kumamoto University. We thank N. Maeda, H. Masumoto, Y. Takahata, Y. Tashiro, A. Yoshinaga, and T. Matsunaga for technical assistance. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 18H02599, 18K19521, and 20H05309 (to F.-Y.W.); 18H02865, 17905074, and 18959602 (to K.T.); 20K18371 (to A.O.); and 17K08264 (to A.I.). This work was also supported by Japan Science and Technology Agency (JST) SAKIGAKE JPMJPR1532 (to F.-Y.W.) and Exploratory Research for Advanced Technology (JST ERATO) JPMJER2002 (to F.-Y.W. and T.S.); Japan Agency for Medical Research and Development (AMED) J200001951 (to K.T. and F.-Y.W.), 17935694 (to K.T.), PRIME JP18gm5910013 (to A.I.), and LEAP JP18gm0010004 (to A.I. and J.A.); the Takeda Science Foundation (to K.T. and F.-Y.W.); the Uehara Memorial Foundation (to F.-Y.W.); the Astellas Foundation for Research on Metabolic Disorders (to A.O. and F.-Y.W.); start-up research funding of the TUMUG support project conducted by Tohoku University (A.O.); and the Japan Medical Women's Association Foundation (to A.O.). A.O. and F.-Y.W. contributed to the overall conceptualization, design, and management of the study. C.N. and W.S. performed and analyzed modeling of m6A bound to A3R. S.H. K.K. and A.I. performed and analyzed internalization and β-arrestin recruitment of m6A. Y.I. T.I. and H.T. prepared samples. K.T. O.N. and J.A. supervised the study. A.O. C.N. W.S. A.I. and F.-Y.W. wrote the paper. The authors declare no competing interests. Funding Information: We are grateful for suggestions and technical support from T. Chujo and all other members of the Department of Molecular Physiology, Kumamoto University. We thank N. Maeda, H. Masumoto, Y. Takahata, Y. Tashiro, A. Yoshinaga, and T. Matsunaga for technical assistance. This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 18H02599 , 18K19521 , and 20H05309 (to F.-Y.W.); 18H02865 , 17905074 , and 18959602 (to K.T.); 20K18371 (to A.O.); and 17K08264 (to A.I.). This work was also supported by Japan Science and Technology Agency (JST) SAKIGAKE JPMJPR1532 (to F.-Y.W.) and Exploratory Research for Advanced Technology (JST ERATO) JPMJER2002 (to F.-Y.W. and T.S.); Japan Agency for Medical Research and Development (AMED) J200001951 (to K.T. and F.-Y.W.), 17935694 (to K.T.), PRIME JP18gm5910013 (to A.I.), and LEAP JP18gm0010004 (to A.I. and J.A.); the Takeda Science Foundation (to K.T. and F.-Y.W.); the Uehara Memorial Foundation (to F.-Y.W.); the Astellas Foundation for Research on Metabolic Disorders (to A.O. and F.-Y.W.); start-up research funding of the TUMUG support project conducted by Tohoku University (A.O.); and the Japan Medical Women{\textquoteright}s Association Foundation (to A.O.). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = feb,
day = "18",
doi = "10.1016/j.molcel.2020.12.038",
language = "English",
volume = "81",
pages = "659--674.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}