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SARS-CoV-2 3C-like protease antagonizes interferon-beta production by facilitating the degradation of IRF3

Wenwen Zhang1, Zhenling Ma1, Yaru Wu1

  • 1College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China.

Cytokine
|September 11, 2021
PubMed

Insights

The SARS-CoV-2 3C-like protease suppresses host innate immunity by downregulating interferon-beta (IFN-β) and inhibiting key immune signaling proteins, impacting viral replication and host defense.

Area of Science:

  • Virology and Immunology
  • Molecular Biology
  • Infectious Diseases

Background:

  • Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) poses a significant global health risk.
  • The interaction between SARS-CoV-2 and the host's innate immune system remains incompletely understood.
  • SARS-CoV-2 encodes a 3C-like protease (3CL) crucial for viral polyprotein processing during replication.

Purpose of the Study:

  • To investigate the impact of SARS-CoV-2 3CL on the host's RIG-I like receptor (RLR)-mediated innate immune response.
  • To elucidate the molecular mechanisms by which SARS-CoV-2 3CL interferes with antiviral signaling pathways.

Main Methods:

  • Transfection of 293T cells with SARS-CoV-2 3CL.
  • Infection of transfected cells with Sendai virus (SeV) to activate the RLR pathway.
  • Quantitative PCR (q-PCR), luciferase reporter assays, and Western blotting were employed for analysis.

Main Results:

  • SARS-CoV-2 3CL significantly downregulated the expression of interferon-beta (IFN-β) mRNA.
  • The viral protease inhibited the nuclear translocation of Interferon Regulatory Factor 3 (IRF3) and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 subunit upon SeV infection.
  • SARS-CoV-2 3CL promoted the degradation of IRF3, further compromising the antiviral response.

Conclusions:

  • SARS-CoV-2 3CL actively suppresses the type I interferon (IFN) production within the RLR immune pathway.
  • This viral protease interferes with critical host antiviral signaling, potentially facilitating viral replication.
  • The findings offer new avenues for understanding SARS-CoV-2 pathogenesis and developing therapeutic strategies.
Keywords:
IFNsIRF3Innate immuneRLR signalling pathwaySARS-CoV-2 3CL

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