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Abstract
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.
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1 Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
2 Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, Shenzhen Key Laboratory of Systems Medicine for inflammatory diseases, School of Medicine, Guangdong, P. R. China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X)
3 Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
4 School of Life Sciences, Tsinghua University, The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, Beijing, P. R. China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
5 Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Department of Pathology, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
6 School of Life Sciences, Xiamen University, Xiamen, State Key Laboratory of Cellular Stress Biology, Fujian, P. R. China (GRID:grid.12955.3a) (ISNI:0000 0001 2264 7233)
7 Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Department of Liver Surgery, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
8 Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Department of Nuclear medicine, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
9 Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, P. R. China (GRID:grid.284723.8) (ISNI:0000 0000 8877 7471)
10 Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Medicinal Synthetic Chemistry Center, Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangzhou, P. R. China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
11 National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, State Key Laboratory of Medical Proteomics, Beijing, P. R. China (GRID:grid.488530.2)