Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 9 min ago
Peer-reviewedCC BY-NCScience Advances

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

  • Noah Sherer1,2
  • Abhishek Bastiray1,2
  • Xiaoru Chen1,2
  • Trivikram R. Molugu1,2
  • Gaya Prasad Yadav1,2
  • Tatyana I. Igumenova1,2
  • Jaehyun Cho1,2
  1. 1Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, United States
  2. 2Texas A & M University
Open at sourceDOICite

Abstract

The Tom70-Hsp90 interaction is critical for activating MAVS-mediated interferon (IFN) production. Upon RNA virus infection, cytosolic Hsp90 recruits key innate immune signaling proteins to MAVS on mitochondria through its interaction with Tom70. To evade this innate immune response, the SARS-CoV-2 protein Orf9b binds to Tom70, thereby disrupting the Tom70-Hsp90 interaction and suppressing IFN production. Despite its importance, the molecular mechanism underlying Orf9b-mediated inhibition of IFN signaling remains unclear. Here, using an integrative approach combining cryo-electron microscopy, 19 F NMR spectroscopy, and isothermal titration calorimetry (ITC), we show that Orf9b inhibits Hsp90 binding to Tom70 through a bipartite mechanism. The helix and intrinsically disordered tail of Orf9b sterically block the access of two distinct structural units of Hsp90 to Tom70. We also find that Orf9b-mediated allosteric conformational changes in Tom70 do not contribute to the inhibition of the Hsp90 binding. Comprehensive structural, thermodynamic, and kinetic analyses further reveal that Orf9b primarily slows the association kinetics between Hsp90 and Tom70. Collectively, our results provide a high-resolution mechanistic framework for understanding Orf9b-mediated suppression of the host innate immune response.

Related

  1. Coordinated regulation of nuclear integrity and STING trafficking by miR-30d suppresses innate immunity in breast cancer
    Serena Torrini, Suvarna Chatterjee, Alessandra Rustighi +17
    Nature CommunicationsPeer-reviewedCC BY-NC-ND 4.0Full textImmunologyCrossref
  2. A dynamic molecular glue targets a plastic MDA5 filament interface to stimulate innate immunity
    S. Hur, L. Yan, Z. Ye +9
    bioRxivPreprintCC BYFull textImmunologybioRxiv
  3. Food-Associated Xenobiotics and Innate Immunity: Molecular and Cellular Effects of Imazalil, TBHQ (Tert-Butylhydroquinone), Carrageenans, and Monosodium Glutamate
    Fatemeh Sayareh, Grzegorz Zwierzchowski, Roman Wójcik
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0ImmunologyCrossref
  4. HERC5-mediated co-translational ISGylation in innate immunity: molecular mechanisms, context-dependent regulation, and therapeutic potential
    Xiaomei Huang, Fengdie Huang, Dongrong Luo +5
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0ImmunologyFrontiersCrossref
  5. The mitochondrial RNA extrusion-induced innate immunity is regulated by N6-methyladenosine machinery
    Q. Hu, Y. Zhang, S. Wang +6
    bioRxivPreprintAll rights reservedFull textImmunologybioRxiv

Cite

BibTeXRIS
BibTeX
@article{sherer2026molecular,
  title = {{Molecular mechanism by which SARS-CoV-2 Orf9b suppresses the Tom70-Hsp90 interaction to evade innate immunity}},
  author = {Noah Sherer and Abhishek Bastiray and Xiaoru Chen and Trivikram R. Molugu and Gaya Prasad Yadav and Tatyana I. Igumenova and Jaehyun Cho},
  journal = {Science Advances},
  year = {2026},
  month = jul,
  doi = {10.1126/sciadv.aee5276},
  url = {https://doi.org/10.1126/sciadv.aee5276},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Molecular mechanism by which SARS-CoV-2 Orf9b suppresses the Tom70-Hsp90 interaction to evade innate immunity
AU  - Noah Sherer
AU  - Abhishek Bastiray
AU  - Xiaoru Chen
AU  - Trivikram R. Molugu
AU  - Gaya Prasad Yadav
AU  - Tatyana I. Igumenova
AU  - Jaehyun Cho
PY  - 2026
DA  - 2026/07/31
JO  - Science Advances
DO  - 10.1126/sciadv.aee5276
UR  - https://doi.org/10.1126/sciadv.aee5276
AB  - The Tom70-Hsp90 interaction is critical for activating MAVS-mediated interferon (IFN) production. Upon RNA virus infection, cytosolic Hsp90 recruits key innate immune signaling proteins to MAVS on mitochondria through its interaction with Tom70. To evade this innate immune response, the SARS-CoV-2 protein Orf9b binds to Tom70, thereby disrupting the Tom70-Hsp90 interaction and suppressing IFN production. Despite its importance, the molecular mechanism underlying Orf9b-mediated inhibition of IFN signaling remains unclear. Here, using an integrative approach combining cryo-electron microscopy, 19 F NMR spectroscopy, and isothermal titration calorimetry (ITC), we show that Orf9b inhibits Hsp90 binding to Tom70 through a bipartite mechanism. The helix and intrinsically disordered tail of Orf9b sterically block the access of two distinct structural units of Hsp90 to Tom70. We also find that Orf9b-mediated allosteric conformational changes in Tom70 do not contribute to the inhibition of the Hsp90 binding. Comprehensive structural, thermodynamic, and kinetic analyses further reveal that Orf9b primarily slows the association kinetics between Hsp90 and Tom70. Collectively, our results provide a high-resolution mechanistic framework for understanding Orf9b-mediated suppression of the host innate immune response.
SN  - 2375-2548
ER  -