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Oligoadenylate synthetase 1 displays dual antiviral mechanisms in driving translational shutdown and protecting

Munesh K Harioudh1, Joseph Perez1, Zhenlu Chong2

  • 1Cancer Virology Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA; Department of Microbiology and Molecular Genetics, Pittsburgh, PA, USA.

Immunity
|February 29, 2024
PubMed

Insights

Oligoadenylate synthetase 1 (OAS1) has dual antiviral roles. It inhibits SARS-CoV-2 via RNase L but protects interferon expression from shutdown for other viruses.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Cellular responses to viral infection involve balancing translational control and antiviral component induction, such as interferons (IFNs).
  • The specific roles of distinct oligoadenylate synthetase 1 (OAS1) isoforms in antiviral defense are not fully understood.
  • Understanding these mechanisms is crucial for developing broad-spectrum antiviral strategies.

Purpose of the Study:

  • To investigate the distinct antiviral mechanisms of human and mouse OAS1 against different viruses.
  • To elucidate the role of OAS1 isoforms in regulating viral replication and interferon production.
  • To identify the molecular interactions of OAS1 with viral components and host cell machinery.

Main Methods:

  • Comparative analysis of OAS1 function in human and mouse cells infected with SARS-CoV-2 and West Nile virus.
  • Enzyme activity assays to assess canonical RNase L activation by OAS1.
  • RNA immunoprecipitation and mRNA stability assays to study OAS1 binding to AU-rich elements (AREs) and IFNβ mRNA localization.

Main Results:

  • Human OAS1 inhibits SARS-CoV-2 replication through canonical RNase L activity, while mouse OAS1 does not.
  • Both human and mouse OAS1 protect against West Nile virus via a non-canonical mechanism independent of RNase L.
  • OAS1 binds to AU-rich elements (AREs) on IFNβ mRNA, sequestering it to endomembranes, prolonging its half-life and translation.

Conclusions:

  • OAS1 exhibits dual antiviral functions: inhibiting viral replication and promoting interferon expression.
  • The canonical RNase L-dependent pathway is specific to human OAS1 against SARS-CoV-2.
  • OAS1 acts as an ARE-binding protein, providing a non-canonical antiviral mechanism by stabilizing IFNβ mRNA against translational shutdown.
Keywords:
SARS-CoV-2West Nile virusantiviral mechanisminterferoninterferon-stimulated genesoligoadenylate synthetase

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