FHL2 Inhibits SARS-CoV-2 Replication by Enhancing IFN-β Expression through Regulating IRF-3

Int J Mol Sci. 2023 Dec 26;25(1):353. doi: 10.3390/ijms25010353.

Abstract

SARS-CoV-2 triggered the global COVID-19 pandemic, posing a severe threat to public health worldwide. The innate immune response in cells infected by SARS-CoV-2 is primarily orchestrated by type I interferon (IFN), with IFN-β exhibiting a notable inhibitory impact on SARS-CoV-2 replication. FHL2, acting as a docking site, facilitates the assembly of multiprotein complexes and regulates the transcription of diverse genes. However, the association between SARS-CoV-2 and FHL2 remains unclear. In this study, we report for the first time that SARS-CoV-2 infection in Caco2 cells results in the upregulation of FHL2 expression, while the virus's N proteins can enhance FHL2 expression. Notably, the knockdown of FHL2 significantly amplifies SARS-CoV-2 replication in vitro. Conversely, the overexpression of FHL2 leads to a marked reduction in SARS-CoV-2 replication, with the antiviral property of FHL2 being independent of the cell or virus type. Subsequent experiments reveal that FHL2 supports IFN-β transcription by upregulating the expression and phosphorylation of IRF-3, thereby impeding SARS-CoV-2 replication in cells. These findings highlight FHL2 as a potential antiviral target for treating SARS-CoV-2 infections.

Keywords: FHL2; IFN-β; IRF-3; SARS-CoV-2; infection.

MeSH terms

  • Antiviral Agents / pharmacology
  • COVID-19*
  • Caco-2 Cells
  • Humans
  • Interferon-beta / metabolism
  • LIM-Homeodomain Proteins / genetics
  • Muscle Proteins / genetics
  • Pandemics
  • SARS-CoV-2*
  • Transcription Factors

Substances

  • Antiviral Agents
  • FHL2 protein, human
  • LIM-Homeodomain Proteins
  • Muscle Proteins
  • Transcription Factors
  • IRF3 protein, human
  • Interferon-beta

Grants and funding

This work was funded by the Changchun Science and Technology Development Plan Project (21ZGY30), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2020-12M-5-001). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.