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Sarbecovirus ORF6 proteins hamper induction of interferon signaling

Izumi Kimura1, Yoriyuki Konno1, Keiya Uriu2

  • 1Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan.

Cell Reports
|March 25, 2021
PubMed

Insights

The SARS-CoV-2 ORF6 protein inhibits innate immune signaling, including interferon production. This viral protein is a more potent immune antagonist than its SARS-CoV counterpart, contributing to COVID-19 pathogenesis.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Sarbecoviruses, including SARS-CoV and SARS-CoV-2, possess a unique ORF6 gene.
  • Innate immunity, particularly interferon (IFN) responses, is crucial for controlling viral infections.
  • Dysregulation of innate immunity is implicated in severe COVID-19 outcomes.

Purpose of the Study:

  • To investigate the role of the ORF6 gene in innate immune evasion by SARS-CoV-2.
  • To compare the immune antagonistic activity of ORF6 from SARS-CoV-2 and SARS-CoV.
  • To identify key viral determinants and mechanisms underlying ORF6-mediated immune suppression.

Main Methods:

  • In vitro assays to assess IFN induction and signaling pathways.
  • Mutational analysis of SARS-CoV-2 ORF6 to identify critical residues.
  • Analysis of ORF6 C-terminal region function and IRF3 nuclear translocation.
  • Bioinformatic analysis of SARS-CoV-2 isolates for ORF6 genetic variations.

Main Results:

  • SARS-CoV-2 ORF6 significantly inhibits type I and III IFN induction and signaling.
  • SARS-CoV-2 ORF6 is a more potent inhibitor of innate immunity than SARS-CoV ORF6.
  • Specific residues (E46, Q56) and the C-terminal region of ORF6 are critical for its antagonistic activity.
  • ORF6 inhibits the nuclear translocation of IRF3, a key transcription factor for IFN production.
  • Inactivating mutations in ORF6 were found in a small percentage of SARS-CoV-2 isolates.

Conclusions:

  • The ORF6 protein is a key viral factor contributing to SARS-CoV-2's ability to evade innate immune responses.
  • Differences in ORF6 function between SARS-CoV-2 and SARS-CoV may influence viral pathogenesis.
  • Understanding ORF6's mechanism of immune suppression provides insights into COVID-19 pathogenesis and potential therapeutic targets.
Keywords:
COVID-19ORF6SARS-CoV-2interferon-stimulated genetype I interferontype III interferon

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