NSP7 Molecular Degrader Attenuates Coronaviral Infection Through the β‐TrCP1/FBXO5 Axis
NSP7 (Non-Structural Protein 7) of SARS-CoV-2 is a crucial component for viral replication and transcription. In this study, it is revealed that the host E3 ubiquitin ligase FBXO5 suppresses viral replication by mediating NSP7 lysine-48-linked ubiquitination and subsequent proteasomal degradation. Interestingly, it is also determined that NSP7 expression impairs the host antiviral response by inhibiting the ISGylation of melanoma differentiation-associated protein 5 (MDA5), a key sensor for viral RNA. Through an unbiased esiRNA screen, it is identified that NSP7 ubiquitination is coregulated by β-TrCP1 and the kinase TAF1. Additionally, this study uncovers a small molecule FBXO5 stabilizer that disrupts the β-TrCP1-FBXO5 interaction, thereby markedly enhancing NSP7 degradation and effectively mitigating SARS-CoV-2 infection. Taken together, the findings reveal a novel mechanism for NSP7 regulation and suggest that small-molecule activators of the E3 ubiquitin ligase FBXO5 represent a promising new class of host-directed antiviral therapies.
Authors
- Ferhan Tuncer (ORCID: https://orcid.org/0000-0003-4225-8627)
- Toren Finkel (ORCID: https://orcid.org/0000-0002-0726-3546)
- John Evankovich (ORCID: https://orcid.org/0000-0003-2070-0883)
- Áine N. Boudreau
- Travis Lear (ORCID: https://orcid.org/0000-0001-9156-0844)
- Simon M. Barratt‐Boyes (ORCID: https://orcid.org/0000-0002-8869-4945)
- Jason R. Kennerdell
- Irene Alfaras (ORCID: https://orcid.org/0000-0002-2073-9641)
- Yun Hua (ORCID: https://orcid.org/0000-0002-0470-6671)
- Mads Larsen (ORCID: https://orcid.org/0000-0001-5361-0898)
- Michaël Chandler (ORCID: https://orcid.org/0000-0002-0292-6662)
- Bo Lin (ORCID: https://orcid.org/0000-0002-2108-2696)
- Bill B. Chen (ORCID: https://orcid.org/0000-0003-2695-5107)
- Yuan Liu (ORCID: https://orcid.org/0000-0001-5031-7514)
- Yanwen Chen (ORCID: https://orcid.org/0000-0002-3467-2871)
- Yao Tong (ORCID: https://orcid.org/0000-0001-6573-859X)
- Ricardo Pineda (ORCID: https://orcid.org/0000-0001-8768-4801)
- Daniel P. Camarco (ORCID: https://orcid.org/0000-0001-7958-0658)
- J. Villandre
Institutions
- University of Pittsburgh (US)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1002/advs.202500798
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Foundation for the National Institutes of Health
- American Heart Association
- University of Pittsburgh
- Jewish Healthcare Foundation
- National Institutes of Health