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Visualization of SARS-CoV-2 using Immuno RNA-Fluorescence In Situ Hybridization
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SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

Yu-Wei Luo1, Jiang-Peng Zhou1, Hongyu Ji1

  • 1Key Laboratory of Molecular Biology on Infectious Disease, Ministry of Education, Chongqing Medical University, Chongqing, PR China.

Nature Communications
|August 13, 2024
PubMed

Insights

The SARS-CoV-2 N protein degrades key RNAi and splicing factors, worsening COVID-19 pneumonia. Restoring these factors, Dicer, XPO5, SRSF3, and hnRNPA3, may treat severe disease.

Area of Science:

  • Molecular Biology
  • Virology
  • Immunology

Background:

  • The roles of RNA interference (RNAi) and RNA splicing in SARS-CoV-2 pathogenesis are not fully understood.
  • These processes are crucial for regulating gene expression and cellular homeostasis.

Purpose of the Study:

  • To investigate the involvement of RNAi and splicing factors in COVID-19 severity.
  • To elucidate the mechanism by which SARS-CoV-2 N protein affects these factors.

Main Methods:

  • Correlating expression levels of Dicer, XPO5, SRSF3, and hnRNPA3 with COVID-19 severity.
  • Investigating the effect of SARS-CoV-2 N protein on these factors using cell and animal models.
  • Assessing the impact of modulating these factors on pneumonia severity.
  • Evaluating therapeutic interventions targeting these pathways.

Main Results:

  • Decreased expression of Dicer, XPO5, SRSF3, and hnRNPA3 correlates with increased COVID-19 severity.
  • SARS-CoV-2 N protein induces autophagic degradation of these factors, impairing miRNA biogenesis and RNA splicing.
  • This degradation leads to DNA damage, proteotoxic stress, and pneumonia.
  • Knockdown of these factors exacerbates N protein-induced pneumonia, while overexpression mitigates it.
  • Older mice exhibit lower expression of these factors and more severe pneumonia.
  • PJ34 and anastrozole treatments restore factor expression and ameliorate pneumonia.

Conclusions:

  • The SARS-CoV-2 N protein disrupts RNAi and splicing machinery, contributing to COVID-19 pathogenesis.
  • Restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression presents a potential therapeutic strategy for SARS-CoV-2-associated pneumonia.

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