The impact of Coronavirus Nsp1 on host mRNA degradation is independent of its role in translation inhibition.

Summary

Using cell-free systems, the study shows that ribosome binding by SARS-CoV-2 Nsp1 is sufficient to induce host mRNA decay independently of translation, unlike MERS-CoV Nsp1 which inhibits translation without decay. Viral mRNAs appear co-evolved to evade Nsp1-mediated degradation, illuminating therapeutic opportunities to disrupt host shutoff.

Key Findings

• SARS-CoV-2 Nsp1 triggers host mRNA degradation via ribosome binding, independently of translation or ribosome collisions.
• MERS-CoV Nsp1 inhibits translation but does not induce mRNA degradation, indicating mechanistic divergence.
• Viral mRNAs co-evolve to evade Nsp1-mediated degradation across SARS-CoV-2, MERS-CoV, and Bat-Hp viruses.

Clinical Implications

Therapeutics that block Nsp1–ribosome interactions could protect host mRNA from degradation without impairing viral antigen translation needed for immune recognition, potentially reducing disease severity.

Limitations

• Lacks in vivo infection models and clinical correlation
• Specific structural determinants of ribosome binding–induced decay were not fully resolved

Future Directions

Define structural interfaces enabling Nsp1-driven decay and develop small-molecule or biologic inhibitors; test host-protective strategies in animal models of coronavirus infection.