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

Nat Commun. 2024 Aug 13;15(1):6964. doi: 10.1038/s41467-024-51192-1.

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.

MeSH terms

  • Animals
  • Autophagy / genetics
  • COVID-19* / genetics
  • COVID-19* / metabolism
  • COVID-19* / virology
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • DNA Damage
  • Down-Regulation
  • Female
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • Humans
  • Karyopherins* / genetics
  • Karyopherins* / metabolism
  • Lung / metabolism
  • Lung / pathology
  • Lung / virology
  • Male
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • RNA Splicing
  • Ribonuclease III* / genetics
  • Ribonuclease III* / metabolism
  • SARS-CoV-2* / genetics
  • Serine-Arginine Splicing Factors* / genetics
  • Serine-Arginine Splicing Factors* / metabolism

Substances

  • Serine-Arginine Splicing Factors
  • Ribonuclease III
  • SRSF3 protein, human
  • Karyopherins
  • DICER1 protein, human
  • XPO5 protein, human
  • DEAD-box RNA Helicases
  • HNRNPA3 protein, human
  • Srsf3 protein, mouse
  • MicroRNAs
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B