Volume 9 Issue 11, Nov 2024:
Article
AXIN1 boosts antiviral response through IRF3 stabilization and induced phase separation
Dan-Ling Dai,Chu Xie
ORCID: orcid.org/0000-0003-1206-3124,Lan-Yi Zhong,Shang-Xin Liu,Le-Le Zhang,Hua Zhang,Xing-Ping Wu,Zhou-Ming Wu,Kexin Kang,Yan Li,Ya-Meng Sun,Tian-Liang Xia
ORCID: orcid.org/0009-0002-3369-8612,Chen-Song Zhang,Ao Zhang,Ming Shi,Cong Sun
ORCID: orcid.org/0000-0003-1786-7420,Mei-Ling Chen,Ge-Xin Zhao,Guo-Long Bu,Yuan-Tao Liu
ORCID: orcid.org/0000-0002-5071-9780,Kui-Yuan Huang,Zheng Zhao,Shu-Xin Li,Xiao-Yong Zhang
ORCID: orcid.org/0000-0002-6930-9423,Yun-Fei Yuan,Shi-Jun Wen
ORCID: orcid.org/0000-0002-9347-8243,Lingqiang Zhang
ORCID: orcid.org/0000-0002-9795-2141,Bin-Kui Li,Qian Zhong &…Mu-Sheng Zeng
ORCID: orcid.org/0000-0003-3509-5591
Axis inhibition protein 1 (AXIN1), a scaffold protein interacting with various critical molecules, plays a vital role in determining cell fate. However, its impact on the antiviral innate immune response remains largely unknown. Here, we identify that AXIN1 acts as an effective regulator of antiviral innate immunity against both DNA and RNA virus infections. In the resting state, AXIN1 maintains the stability of the transcription factor interferon regulatory factor 3 (IRF3) by preventing p62-mediated autophagic degradation of IRF3. This is achieved by recruiting ubiquitin-specific peptidase 35 (USP35), which removes lysine (K) 48-linked ubiquitination at IRF3 K366. Upon virus infection, AXIN1 undergoes a phase separation triggered by phosphorylated TANK-binding kinase 1 (TBK1). This leads to increased phosphorylation of IRF3 and a boost in IFN-I production. Moreover, KYA1797K, a small molecule that binds to the AXIN1 RGS domain, enhances the AXIN1-IRF3 interaction and promotes the elimination of various highly pathogenic viruses. Clinically, patients with HBV-associated hepatocellular carcinoma (HCC) who show reduced AXIN1 expression in pericarcinoma tissues have low overall and disease-free survival rates, as well as higher HBV levels in their blood. Overall, our findings reveal how AXIN1 regulates IRF3 signaling and phase separation-mediated antiviral immune responses, underscoring the potential of the AXIN1 agonist KYA1797K as an effective antiviral agent.
