SARS-CoV-2 nucleocapsid protein interaction with YBX1 displays oncolytic properties through PKM mRNA destabilization

Mol Cancer. 2024 Nov 6;23(1):248. doi: 10.1186/s12943-024-02153-1.

Abstract

Background: SARS-CoV-2, a highly contagious coronavirus, is responsible for the global pandemic of COVID-19 in 2019. Currently, it remains uncertain whether SARS-CoV-2 possesses oncogenic or oncolytic potential in influencing tumor progression. Therefore, it is important to evaluate the clinical and functional role of SARS-CoV-2 on tumor progression.

Methods: Here, we integrated bioinformatic analysis of COVID-19 RNA-seq data from the GEO database and performed functional studies to explore the regulatory role of SARS-CoV-2 in solid tumor progression, including lung, colon, kidney and liver cancer.

Results: Our results demonstrate that infection with SARS-CoV-2 is associated with a decreased expression of genes associated with cancer proliferation and metastasis in lung tissues from patients diagnosed with COVID-19. Several cancer proliferation or metastasis related genes were frequently downregulated in SARS-CoV-2 infected intestinal organoids and human colon carcinoma cells. In vivo and in vitro studies revealed that SARS-CoV-2 nucleocapsid (N) protein inhibits colon and kidney tumor growth and metastasis through the N-terminal (NTD) and the C-terminal domain (CTD). The molecular mechanism indicates that the N protein of SARS-CoV-2 interacts with YBX1, resulting in the recruitment of PKM mRNA into stress granules mediated by G3BP1. This process ultimately destabilizes PKM expression and suppresses glycolysis.

Conclusion: Our study reveals a new function of SARS-CoV-2 nucleocapsid protein on tumor progression.

Keywords: Cancer; Glycolysis; Nucleocapsid protein; SARS-CoV-2; Stress granule.

MeSH terms

  • Animals
  • COVID-19* / genetics
  • COVID-19* / metabolism
  • COVID-19* / virology
  • Cell Line, Tumor
  • Cell Proliferation
  • Coronavirus Nucleocapsid Proteins* / genetics
  • Coronavirus Nucleocapsid Proteins* / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / metabolism
  • SARS-CoV-2* / physiology
  • Y-Box-Binding Protein 1* / genetics
  • Y-Box-Binding Protein 1* / metabolism

Substances

  • Y-Box-Binding Protein 1
  • YBX1 protein, human
  • Coronavirus Nucleocapsid Proteins
  • nucleocapsid phosphoprotein, SARS-CoV-2
  • Phosphoproteins
  • RNA, Messenger