5/10, LSBM Monday Seminar Series #7, Fanyan Wei, Modified RNA signaling and its pathophysiological implications

Presenter: Fanyan Wei (Professor, IDAC, Tohoku University, Japan)
Title: Modified RNA signaling and its pathophysiological implications
Date: May 10th (Mon.) 12PM~

Modified RNA signaling and its pathophysiological implications


RNA contains a variety of post-transcriptional modifications, which are indispensable for the functions of RNA including RNA stability, intracellular location, and translational efficiency. Dysregulation of RNA modification has been implicated in a number of human diseases including diabetes [1], mitochondrial disease [2], intellectual disability [3]. In addition to the canonical role of RNA modifications as regulator of RNA functions, our group has recently unveiled a non-canonical role of RNA modifications [4]. We found that a number of nucleosides are generated as the consequence of RNA catabolism with the modifications being stably attached to the nucleosides. These modified nucleosides are abundantly present in the extracellular space such serum, eye fluid, and urine. By applying sensitive GPCR screening strategy and physiological approaches, we found that N6-methyladenosine (m6A), one of the most abundant RNA modifications, can bind to adenosine receptor A3 with greater affinity than unmodified adenosine, thereby activating intracellular signaling transduction such as ERK phosphorylation and calcium signaling. Extracellular release of m6A was upregulated upon cytotoxic stimulation and a majority of extracellular was derived from lysosomal degradation of ribosomal RNA. At pathophysiological level, extracellular m6A exaggerated allergic reaction and immune response via adenosine A3 receptor in vivo. These results demonstrate that m6A is a novel and endogenous adenosine A3 receptor ligand that behaves as signaling molecule. Our study provides a framework for understanding the roles played by the complex pantheon of modified nucleosides.

[1] F.-Y. Wei et al. Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice. J. Clin. Invest. (2011) 121, 3598–3608.
[2] F.-Y. Wei et al. Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Cell Metab. (2015) 21, 428–442.
[3] Y. Nagayoshi et al. Loss of Ftsj1 perturbs codon-specific translation efficiency in the brain and is associated with X-linked intellectual disability. Sci. Adv. (2021). In Press.
[4] A. Ogawa et al. N6-methyladenosine (m6A) is an endogenous A3 adenosine receptor ligand. Mol Cell. (2020). 81, 659.

Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer (IDAC), Tohoku University


2000 B.S. (Biology), Tokyo Metropolitan University
2002 M.S. (Biology), Tokyo Metropolitan University
2006 Ph.D. (Medicine), Okayama University

2006-2009 Postdoctoral Fellow (HFSP Fellow), Yale University School of Medicine, USA
2009-2015 Assistant Professor, Kumamoto University, Japan
2015-2017 Lecturer, Kumamoto University, Japan
2017-2019 Associate Professor, Kumamoto University, Japan
2019-Present Professor, IDAC, Tohoku University, Japan