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

Author

Listed:
  • 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
    Institute of Stem Cell and Regeneration, 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
    Institute of Stem Cell and Regeneration, 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
    Institute of Stem Cell and Regeneration, Chinese Academy of Sciences)

  • Guanshen Cui

    (Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    Institute of Stem Cell and Regeneration, Chinese Academy of Sciences)

  • Baofa Sun

    (Beijing Institute of Genomics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    Institute of Stem Cell and Regeneration, 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
    Institute of Stem Cell and Regeneration, Chinese Academy of Sciences)

  • Pengyuan Yang

    (Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences
    Chongqing International Institute for Immunology)

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.

Suggested Citation

  • 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 Ya, 2021. "N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21904-y
    DOI: 10.1038/s41467-021-21904-y
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