N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA

Weinan Qiu, Qingyang Zhang, Rui Zhang, Yangxu Lu, Xin Wang, Huabin Tian, Ying Yang, Zijuan Gu, Yanan Gao, Xin Yang, Guanshen Cui, Baofa Sun, Yanan Peng, Hongyu Deng, Hua Peng, Angang Yang, Yun-Gui Yang () and Pengyuan Yang ()
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Weinan Qiu: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Qingyang Zhang: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Rui Zhang: Fourth Military Medical University
Yangxu Lu: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xin Wang: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Huabin Tian: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Ying Yang: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Zijuan Gu: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yanan Gao: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xin Yang: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Guanshen Cui: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Baofa Sun: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Yanan Peng: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hongyu Deng: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Hua Peng: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Angang Yang: Fourth Military Medical University
Yun-Gui Yang: Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
Pengyuan Yang: Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N6-methyladenosine (m6A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m6A methyltransferase METTL3 translocates into the cytoplasm to increase m6A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m6A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity.

Date: 2021
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DOI: 10.1038/s41467-021-21904-y

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