SARS-CoV-2 ORF3a suppresses host antiviral interferon responses by promoting STUB1-mediated PTEN proteasomal degradation.

Summary

The study identifies PTEN as a broad antiviral factor against multiple HCoVs and shows that SARS-CoV-2 ORF3a drives STUB1-dependent PTEN K6 ubiquitination and proteasomal degradation, blunting type I interferon signaling. Oroxin B, a PTEN agonist, enhanced antiviral responses in mice, suggesting a host-directed antiviral avenue.

Key Findings

• PTEN inhibited replication of SARS-CoV-2, HCoV-229E, and HCoV-OC43.
• SARS-CoV-2 induced PTEN K6 ubiquitination and proteasomal degradation.
• STUB1 was identified as the E3 ligase mediating PTEN degradation; ORF3a promoted this process.
• Oroxin B upregulated PTEN and significantly enhanced antiviral responses in mice.

Clinical Implications

Supports exploration of PTEN agonists or inhibitors of ORF3a–STUB1 interaction as host-directed antivirals, potentially mitigating severe COVID-19 pneumonia and ARDS by restoring interferon responses.

Limitations

• Preclinical mechanistic work; human clinical validation lacking
• Potential off-target effects and pharmacokinetics of Oroxin B not addressed

Future Directions

Define structural interfaces of ORF3a–STUB1–PTEN, test PTEN-agonists in rigorous animal models of severe pneumonia/ARDS, and evaluate safety and antiviral efficacy in early-phase clinical trials.