轴抑制蛋白 1 (AXIN1) 是一种与各种关键分子相互作用的支架蛋白，在决定细胞命运方面发挥着至关重要的作用。然而，它对抗病毒先天免疫反应的影响仍然很大程度上未知。在这里，我们确定 AXIN1 是针对 DNA 和 RNA 病毒感染的抗病毒先天免疫的有效调节剂。在静息状态下，AXIN1 通过阻止 p62 介导的 IRF3 自噬降解来维持转录因子干扰素调节因子 3 (IRF3) 的稳定性。这是通过招募泛素特异性肽酶 35 (USP35) 来实现的，该肽酶可消除 IRF3 K366 处赖氨酸 (K) 48 连接的泛素化。病毒感染后，AXIN1 会发生由磷酸化 TANK 结合激酶 1 (TBK1) 触发的相分离。这导致 IRF3 磷酸化增加并增加 IFN-I 的产生。此外，KYA1797K是一种与AXIN1 RGS结构域结合的小分子，可增强AXIN1-IRF3相互作用，促进消除各种高致病性病毒。临床上，癌周组织中 AXIN1 表达降低的 HBV 相关肝细胞癌 (HCC) 患者的总体生存率和无病生存率较低，且血液中 HBV 水平较高。总体而言，我们的研究结果揭示了 AXIN1 如何调节 IRF3 信号传导和相分离介导的抗病毒免疫反应，强调了 AXIN1 激动剂 KYA1797K 作为有效抗病毒药物的潜力。© 2024。作者。

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.© 2024. The Author(s).