Paramyxovirus matrix protein redirects METTL3 for dual regulation of viral replication and immune evasion.

Summary

Paramyxoviruses co-opt the host methyltransferase METTL3 by M protein–mediated nuclear export to the cytoplasm, boosting m6A marks on viral N mRNA and dampening m6A on host IFN-β mRNA. This conserved mechanism enhances viral replication and suppresses interferon responses across multiple paramyxoviruses, revealing a druggable epitranscriptomic pathway.

Key Findings

• Paramyxovirus M protein binds nuclear METTL3 and drives its exportin-1–dependent cytoplasmic translocation, conserved across HPIV3, Sendai, Nipah, and measles viruses.
• Cytoplasmic METTL3 increases m6A at defined sites in viral N mRNA, enhancing mRNA stability/protein expression; m6A-site mutant viruses show attenuated replication that is partially rescued by exogenous N.
• Nuclear METTL3 depletion reduces m6A on host IFN-β mRNA, lowering IFN-β expression; preventing METTL3 export restores IFN-β m6A and elevates IFN-β responses.

Clinical Implications

Although preclinical, inhibiting M-driven METTL3 relocalization or selective m6A deposition could yield broad antivirals against human parainfluenza and other paramyxoviruses that cause lower respiratory infections.

Limitations

• Predominantly in vitro mechanistic work; in vivo validation of pathogenesis and therapeutic targeting is needed.
• Potential off-target or global effects of METTL3 manipulation on host transcriptome require safety assessment.

Future Directions

Develop small molecules or peptides to block METTL3–M interaction or exportin-1–mediated trafficking and test efficacy/safety in animal models of paramyxovirus disease.