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The SARS-CoV-2 protein ORF3c is a mitochondrial modulator of innate immunity

Hazel Stewart1, Yongxu Lu1, Sarah O'Keefe2

  • 1Department of Pathology, University of Cambridge, Cambridge, UK.

Iscience
|October 20, 2023
PubMed

Insights

SARS-CoV-2 accessory protein ORF3c inhibits innate immunity by targeting MAVS in mitochondria, restricting interferon-beta production and aiding viral immune evasion.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • The SARS-CoV-2 genome encodes accessory proteins, including the predicted ORF3c.
  • ORF3c is present in SARS-CoV and SARS-CoV-2, but its function is unknown.
  • Ribosome profiling confirmed ORF3c expression during infection.

Purpose of the Study:

  • To investigate the function of the SARS-CoV-2 accessory protein ORF3c.
  • To elucidate the mechanism by which ORF3c interacts with the host immune system.

Main Methods:

  • Comparative genomics to predict ORF3c.
  • Ribosome profiling to confirm ORF3c expression.
  • Subcellular localization studies (mitochondria).
  • Immune signaling assays (IFN-β, NF-κB, JAK-STAT).
  • Co-immunoprecipitation and protein cleavage assays.

Main Results:

  • ORF3c localizes to mitochondria.
  • ORF3c restricts IFN-β production but not NF-κB or JAK-STAT signaling.
  • ORF3c inhibits pathways involving RIG-I, MDA5, and MAVS, but not TRIF, TBK1, or IRF3.
  • ORF3c co-immunoprecipitates with MAVS and PGAM5.
  • ORF3c induces MAVS cleavage by caspase-3.

Conclusions:

  • SARS-CoV-2 ORF3c is a mitochondrial protein that inhibits innate immunity.
  • ORF3c evades host defenses by cleaving the antiviral adaptor protein MAVS.
  • This mechanism contributes to SARS-CoV-2 immune evasion.
Keywords:
ImmunologyMicrobiologyMolecular biologyProteomics

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