AXIN1 boosts antiviral response through IRF3 stabilization and induced phase separation

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Axis inhibition protein 1 (AXIN1) is a key scaffold protein involved in cell fate determination.
• The role of AXIN1 in antiviral innate immunity is largely unexplored.
• Interferon regulatory factor 3 (IRF3) is a critical transcription factor in the innate immune response to viral infections.

Purpose of the Study:

• To investigate the function of AXIN1 in antiviral innate immunity.
• To elucidate the mechanism by which AXIN1 regulates IRF3.
• To evaluate the therapeutic potential of AXIN1 modulation against viral infections.

Main Methods:

• Western blotting and immunoprecipitation to assess protein stability and interactions.
• Autophagy assays to determine the role of degradation pathways.
• Virus infection models (DNA and RNA viruses) to evaluate antiviral responses.
• Phase separation assays to study protein complex formation.
• Analysis of clinical data from HBV-associated hepatocellular carcinoma (HCC) patients.

Main Results:

• AXIN1 stabilizes IRF3 by preventing its autophagic degradation via USP35 recruitment, deubiquitinating IRF3 at K366.
• Virus infection induces AXIN1 phase separation, enhancing IRF3 phosphorylation and type I interferon (IFN-I) production.
• The small molecule KYA1797K, an AXIN1 agonist, strengthens the AXIN1-IRF3 interaction and promotes viral clearance.
• Reduced AXIN1 expression in HCC patients correlates with poor prognosis and higher HBV levels.

Conclusions:

• AXIN1 is a crucial regulator of antiviral innate immunity, controlling IRF3 stability and signaling through phase separation.
• AXIN1 modulation, particularly with agonists like KYA1797K, represents a promising therapeutic strategy against viral infections.
• AXIN1 dysfunction is linked to poor outcomes in viral-associated cancers, highlighting its clinical significance.