Publication date: Jun 27, 2025
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.
| Concepts | Keywords |
|---|---|
| Antiviral | antiviral therapies |
| Coronaviralinfection | FBXO5 |
| Host | non‐structural protein 7 |
| Molecular | TAF1 |
| Unbiased | ubiquitination |
| β‐TrCP1 |
Semantics
| Type | Source | Name |
|---|---|---|
| disease | IDO | protein |
| pathway | KEGG | Viral replication |
| disease | IDO | host |
| drug | DRUGBANK | L-Lysine |
| disease | MESH | SARS-CoV-2 infection |
| pathway | REACTOME | SARS-CoV-2 Infection |