As a core kinase of antiviral immunity, the activity and stability of TANK-binding kinase 1 (TBK1) is tightly controlled by multiple post-translational modifications. Although it has been demonstrated that TBK1 stability can be regulated by ubiquitin-dependent proteasome pathway, it is unclear whether another important protein degradation pathway, autophagosome pathway, can specifically affect TBK1 degradation by cargo receptors. Here we report that E3 ubiquitin ligase NEDD4 functions as a negative regulator of type I interferon (IFN) signaling by targeting TBK1 for degradation at the late stage of viral infection, to prevent the host from excessive immune response. Mechanically NEDD4 catalyzes the K27-linked poly-ubiquitination of TBK1 at K344, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, our study reveals the regulatory role of NEDD4 in balancing TBK1-centered type I IFN activation and provides insights into the crosstalk between selective autophagy and antiviral signaling.

作为抗病毒免疫的核心激酶，TANK 结合激酶 1 (TBK1) 的活性和稳定性受到多种翻译后修饰的严格控制。虽然已经证明 TBK1 稳定性可以通过泛素依赖性蛋白酶体途径进行调节，但尚不清楚另一种重要的蛋白质降解途径，即自噬体途径，是否可以特异性影响货物受体对 TBK1 的降解。在这里，我们报告 E3 泛素连接酶 NEDD4 通过靶向 TBK1 在病毒感染后期降解，作为 I 型干扰素 (IFN) 信号的负调节剂，以防止宿主过度免疫反应。NEDD4 机械催化 TBK1 在 K344 处的 K27 连接多泛素化，作为货物受体 NDP52 介导的选择性自噬降解的识别信号。