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Molecular mechanism by which SARS-CoV-2 Orf9b suppresses the Tom70-Hsp90 interaction to evade innate immunity

Noah Sherer1, Abhishek Bastiray1, Xiao-Ru Chen1

  • 1Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, United States.

Science Advances
|July 31, 2026
PubMed

Insights

SARS-CoV-2 Orf9b protein inhibits interferon production by blocking the Tom70-Hsp90 interaction. This study reveals Orf9b

Area of Science:

  • Immunology
  • Virology
  • Structural Biology

Background:

  • The Tom70-Hsp90 interaction is crucial for MAVS-mediated interferon (IFN) production during RNA virus infections.
  • SARS-CoV-2 Orf9b protein antagonizes this innate immune response by disrupting the Tom70-Hsp90 interaction.

Purpose of the Study:

  • To elucidate the molecular mechanism by which SARS-CoV-2 Orf9b inhibits the Tom70-Hsp90 interaction and suppresses IFN production.

Main Methods:

  • Cryo-electron microscopy
  • 19F NMR spectroscopy
  • Structural, thermodynamic, and kinetic analyses.

Main Results:

  • Orf9b inhibits the Tom70-Hsp90 interaction via a bipartite mechanism.
  • A previously unrecognized interplay between Orf9b's rigid and disordered regions blocks Hsp90 access to Tom70.

Conclusions:

  • Provides a high-resolution mechanistic framework for Orf9b-mediated suppression of host innate immunity.
  • Highlights the role of Orf9b's structural dynamics in viral immune evasion.

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