APOBEC-1 cofactors regulate APOBEC3-induced mutations in hepatitis B virus.

Summary

Using HBV replication as a model, the authors show that APOBEC-1 cofactors and associated hnRNPs physically associate with APOBEC3 proteins to enhance their mutational activity. Disrupting A3–hnRNP interactions via mutagenesis or siRNA knockdown markedly reduces A3 activity, and A1 cofactors increase A3C access to HBV (−)DNA, generating kataegis-like hypermutation.

Key Findings

• APOBEC-1 cofactors and hnRNPs strongly interact with APOBEC3 proteins and enhance A3 mutational activity in HBV replication systems.
• siRNA knockdown of cofactors reduces A3 activity, while mutagenesis disrupting A3–hnRNP interactions nearly abolishes mutagenesis.
• A1 cofactors increase A3C accessibility to HBV (−)DNA and promote kataegis-like hypermutation genome-wide.

Clinical Implications

Targeting APOBEC-1 cofactors/hnRNP interactions may offer strategies to limit APOBEC-driven tumor mutagenesis or to enhance antiviral restriction. It also informs biomarker development for A3 activity in HBV infection and possibly cancers.

Limitations

• Findings are based on cellular replication models; in vivo physiological relevance remains to be confirmed
• Focuses primarily on HBV and selected APOBEC3 family members; generalizability across viruses and tissues is uncertain

Future Directions

Validate cofactor-dependent A3 regulation in vivo, map interaction interfaces structurally, and develop small molecules to modulate A3–hnRNP interactions in antiviral or anticancer settings.