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SARS-CoV-2 ORF6 disrupts nucleocytoplasmic trafficking to advance viral replication

Yoichi Miyamoto1, Yumi Itoh2, Tatsuya Suzuki2

  • 1Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan. ymiyamoto@nibiohn.go.jp.

Communications Biology
|May 19, 2022
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 protein directly binds STAT1, preventing its nuclear entry. This mechanism enhances viral replication and disease progression by disrupting antiviral signaling.

Area of Science:

  • Virology
  • Molecular Biology
  • Immunology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 protein antagonizes interferon-mediated antiviral signaling by blocking STAT1 nuclear localization.
  • The precise mechanism by which ORF6 inhibits STAT1 nuclear trafficking is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism of SARS-CoV-2 ORF6 in preventing STAT1 nuclear translocation.
  • To investigate the interaction between ORF6, STAT1, and importin α subtypes.
  • To evaluate the role of ORF6 in viral pathogenesis.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate direct binding of ORF6 and STAT1.
  • Analysis of importin α subtype recognition by ORF6.
  • Assessment of ORF6's impact on nuclear transport of other proteins.
  • Utilizing a SARS-CoV-2 replicon system and a hamster model.

Main Results:

  • ORF6 directly binds STAT1, independent of interferon stimulation, causing STAT1 nuclear exclusion.
  • ORF6 exhibits differential binding affinities to importin α subtypes, with high affinity for importin α1.
  • While ORF6 can interfere with general nuclear transport, its effect on STAT1 is more pronounced due to specific binding.
  • ORF6 acts as a virulence factor by regulating nucleocytoplasmic trafficking, promoting viral replication and disease progression.

Conclusions:

  • SARS-CoV-2 ORF6 employs a distinct strategy, directly binding STAT1 via the importin α1 pathway, to achieve nuclear exclusion.
  • ORF6's regulation of nucleocytoplasmic trafficking is crucial for viral virulence and disease progression.

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