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Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3

Author

Listed:
  • Xing Liu

    (Chinese Academy of Sciences
    Hubei Hongshan Laboratory
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Jinhua Tang

    (Chinese Academy of Sciences
    Women and Children’s Hospital of Chongqing Medical University)

  • Zixuan Wang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chunchun Zhu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Hongyan Deng

    (Chinese Academy of Sciences)

  • Xueyi Sun

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Guangqing Yu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Fangjing Rong

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xiaoyun Chen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Qian Liao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shuke Jia

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wen Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Huangyuan Zha

    (Chinese Academy of Sciences)

  • Sijia Fan

    (Chinese Academy of Sciences)

  • Xiaolian Cai

    (Chinese Academy of Sciences)

  • Jian-Fang Gui

    (Chinese Academy of Sciences
    Hubei Hongshan Laboratory
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Wuhan Xiao

    (Chinese Academy of Sciences
    Hubei Hongshan Laboratory
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

Abstract

Oxygen is essential for aerobic organisms, but little is known about its role in antiviral immunity. Here, we report that during responses to viral infection, hypoxic conditions repress antiviral-responsive genes independently of HIF signaling. EGLN1 is identified as a key mediator of the oxygen enhancement of antiviral innate immune responses. Under sufficient oxygen conditions, EGLN1 retains its prolyl hydroxylase activity to catalyze the hydroxylation of IRF3 at proline 10. This modification enhances IRF3 phosphorylation, dimerization and nuclear translocation, leading to subsequent IRF3 activation. Furthermore, mice and zebrafish with Egln1 deletion, treatment with the EGLN inhibitor FG4592, or mice carrying an Irf3 P10A mutation are more susceptible to viral infections. These findings not only reveal a direct link between oxygen and antiviral responses, but also provide insight into the mechanisms by which oxygen regulates innate immunity.

Suggested Citation

  • Xing Liu & Jinhua Tang & Zixuan Wang & Chunchun Zhu & Hongyan Deng & Xueyi Sun & Guangqing Yu & Fangjing Rong & Xiaoyun Chen & Qian Liao & Shuke Jia & Wen Liu & Huangyuan Zha & Sijia Fan & Xiaolian Ca, 2024. "Oxygen enhances antiviral innate immunity through maintenance of EGLN1-catalyzed proline hydroxylation of IRF3," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47814-3
    DOI: 10.1038/s41467-024-47814-3
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    References listed on IDEAS

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    1. Patrick H. Maxwell & Michael S. Wiesener & Gin-Wen Chang & Steven C. Clifford & Emma C. Vaux & Matthew E. Cockman & Charles C. Wykoff & Christopher W. Pugh & Eamonn R. Maher & Peter J. Ratcliffe, 1999. "The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis," Nature, Nature, vol. 399(6733), pages 271-275, May.
    2. Yukiji Takeda & Sandra Costa & Estelle Delamarre & Carmen Roncal & Rodrigo Leite de Oliveira & Mario Leonardo Squadrito & Veronica Finisguerra & Sofie Deschoemaeker & Françoise Bruyère & Mathias Wenes, 2011. "Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis," Nature, Nature, vol. 479(7371), pages 122-126, November.
    3. Shijun Ma & Yue Zhao & Wee Chyan Lee & Li-Teng Ong & Puay Leng Lee & Zemin Jiang & Gokce Oguz & Zhitong Niu & Min Liu & Jian Yuan Goh & Wenyu Wang & Matias A. Bustos & Sidse Ehmsen & Adaikalavan Ramas, 2022. "Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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