von Hippel-Lindau 肿瘤抑制蛋白 (VHL) 是一种 E3 泛素连接酶，作为氧传感通路的关键调节因子，针对缺氧诱导因子。最近的证据表明，哺乳动物 VHL 可能对 NF-κB 信号通路也至关重要，尽管具体的分子机制仍不清楚。在此，探讨了鳜鱼（Siniperca chuatsi）VHL（scVHL）在NF-κB信号通路和鳜鱼蛙病毒（MRV）复制中的作用。 scVHL 的转录是由免疫刺激和 MRV 感染诱导的，表明其在先天免疫中的潜在作用。双荧光素酶报告基因检测和逆转录定量 PCR (RT-qPCR) 结果表明，scVHL 诱发并正向调节 NF-κB 信号通路。 NF-κB信号通路抑制剂治疗表明scVHL的作用可能是通过scIKKα、scIKKβ、scIκBα或scp65介导的。免疫共沉淀 (Co-IP) 分析确定 scIκBα 是 scVHL 的新靶蛋白。此外，scVHL靶向scIκBα催化K63连接的多聚泛素链的形成，从而激活NF-κB信号通路。 MRV 感染后，NF-κB 信号保持激活状态，进而促进 MRV 复制。这些发现表明，scVHL 不仅能正向调节 NF-κB，还能显着增强 MRV 复制。这项研究揭示了 scVHL 在鱼类 NF-κB 信号传导和病毒感染中的新功能。

The von Hippel-Lindau tumor suppressor protein (VHL), an E3 ubiquitin ligase, functions as a critical regulator of the oxygen-sensing pathway for targeting hypoxia-inducible factors. Recent evidence suggests that mammalian VHL may also be critical to the NF-κB signaling pathway, although the specific molecular mechanisms remain unclear. Herein, the roles of mandarin fish ( Siniperca chuatsi) VHL ( scVHL) in the NF-κB signaling pathway and mandarin fish ranavirus (MRV) replication were explored. The transcription of scVHL was induced by immune stimulation and MRV infection, indicating a potential role in innate immunity. Dual-luciferase reporter gene assays and reverse transcription quantitative PCR (RT-qPCR) results demonstrated that scVHL evoked and positively regulated the NF-κB signaling pathway. Treatment with NF-κB signaling pathway inhibitors indicated that the role of scVHL may be mediated through scIKKα, scIKKβ, scIκBα, or scp65. Co-immunoprecipitation (Co-IP) analysis identified scIκBα as a novel target protein of scVHL. Moreover, scVHL targeted scIκBα to catalyze the formation of K63-linked polyubiquitin chains to activate the NF-κB signaling pathway. Following MRV infection, NF-κB signaling remained activated, which, in turn, promoted MRV replication. These findings suggest that scVHL not only positively regulates NF-κB but also significantly enhances MRV replication. This study reveals a novel function of scVHL in NF-κB signaling and viral infection in fish.