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SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

Author

Listed:
  • Yu-Wei Luo

    (Chongqing Medical University)

  • Jiang-Peng Zhou

    (Chongqing Medical University)

  • Hongyu Ji

    (Chongqing Medical University)

  • Doudou Xu

    (National Center of Technology Innovation for animal model, CAMS & PUMC)

  • Anqi Zheng

    (The First Affiliated Hospital of Wenzhou Medical University)

  • Xin Wang

    (Chongqing Medical University)

  • Zhizheng Dai

    (Chongqing Medical University)

  • Zhicheng Luo

    (Chongqing Medical University
    The First Affiliated Hospital of Wenzhou Medical University)

  • Fang Cao

    (Chongqing Medical University)

  • Xing-Yue Wang

    (The First Affiliated Hospital of Wenzhou Medical University)

  • Yunfang Bai

    (Chongqing Medical University)

  • Di Chen

    (Chongqing Medical University)

  • Yueming Chen

    (The First Affiliated Hospital of Wenzhou Medical University)

  • Qi Wang

    (Chongqing Medical University)

  • Yaying Yang

    (Chongqing Medical University)

  • Xinghai Zhang

    (Chinese Academy of Sciences)

  • Sandra Chiu

    (University of Science and Technology of China
    Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases)

  • Xiaozhong Peng

    (National Center of Technology Innovation for animal model, CAMS & PUMC
    School of Basic Medicine Peking Union Medical College)

  • Ai-Long Huang

    (Chongqing Medical University)

  • Kai-Fu Tang

    (Chongqing Medical University)

Abstract

Though RNAi and RNA-splicing machineries are involved in regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, their precise roles in coronavirus disease 2019 (COVID-19) pathogenesis remain unclear. Herein, we show that decreased RNAi component (Dicer and XPO5) and splicing factor (SRSF3 and hnRNPA3) expression correlate with increased COVID-19 severity. SARS-CoV-2 N protein induces the autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, inhibiting miRNA biogenesis and RNA splicing and triggering DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 knockdown increases, while their overexpression decreases, N protein-induced pneumonia’s severity. Older mice show lower expression of Dicer, XPO5, SRSF3, and hnRNPA3 in their lung tissues and exhibit more severe N protein-induced pneumonia than younger mice. PJ34, a poly(ADP-ribose) polymerase inhibitor, or anastrozole, an aromatase inhibitor, ameliorates N protein- or SARS-CoV-2-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.

Suggested Citation

  • Yu-Wei Luo & Jiang-Peng Zhou & Hongyu Ji & Doudou Xu & Anqi Zheng & Xin Wang & Zhizheng Dai & Zhicheng Luo & Fang Cao & Xing-Yue Wang & Yunfang Bai & Di Chen & Yueming Chen & Qi Wang & Yaying Yang & X, 2024. "SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51192-1
    DOI: 10.1038/s41467-024-51192-1
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