AXIN1 boosts antiviral response through IRF3 stabilization and induced phase separation

Axis inhibition protein 1 (AXIN1) is a scaffold protein known for its role in cell fate determination through interactions with key signaling molecules. However, its function in the antiviral innate immune response has remained unclear. In this study, we identify AXIN1 as a critical regulator of antiviral immunity against both DNA and RNA viruses.

In resting cells, AXIN1 maintains the stability of the transcription factor IRF3 by blocking its p62-mediated autophagic degradation. This is accomplished through recruitment of USP35, which removes K48-linked ubiquitination at IRF3 K366, preventing its proteasomal breakdown. Upon viral infection, phosphorylated TBK1 triggers phase separation of AXIN1, which enhances IRF3 phosphorylation and subsequently boosts type I interferon (IFN-I) production.

Furthermore, KYA1797K, a small molecule that binds to the RGS domain of AXIN1, strengthens the AXIN1–IRF3 interaction and significantly improves viral clearance across several highly pathogenic viruses. Clinically, reduced AXIN1 expression in peritumoral tissues of patients with HBV-related hepatocellular carcinoma (HCC) is associated with lower overall and disease-free survival, as well as elevated HBV titers.

Conclusion:
These findings establish AXIN1 as a key modulator of IRF3 stability and activation through phase separation, highlighting the potential of AXIN1-targeting therapeutics, such as KYA1797K, in enhancing antiviral immunity and combating viral infections.