1. Mandarin fish von Hippel-Lindau protein regulates the NF-κB signaling pathway via interaction with IκB to promote fish ranavirus replication.
- Author
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Li ZM, Qin XW, Zhang Q, He J, Liang MC, Li CR, Yu Y, Liu WH, Weng SP, He JG, and Guo CJ
- Subjects
- Animals, Von Hippel-Lindau Tumor Suppressor Protein metabolism, Von Hippel-Lindau Tumor Suppressor Protein genetics, DNA Virus Infections veterinary, DNA Virus Infections virology, Fish Proteins metabolism, Fish Proteins genetics, I-kappa B Proteins metabolism, I-kappa B Proteins genetics, Gene Expression Regulation, NF-kappa B metabolism, NF-kappa B genetics, Signal Transduction, Virus Replication physiology, Fish Diseases virology, Ranavirus physiology
- Abstract
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 ( sc VHL) in the NF-κB signaling pathway and mandarin fish ranavirus (MRV) replication were explored. The transcription of sc VHL 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 sc VHL evoked and positively regulated the NF-κB signaling pathway. Treatment with NF-κB signaling pathway inhibitors indicated that the role of sc VHL may be mediated through sc IKKα, sc IKKβ, sc IκBα, or sc p65. Co-immunoprecipitation (Co-IP) analysis identified sc IκBα as a novel target protein of sc VHL. Moreover, sc VHL targeted sc IκBα 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 sc VHL not only positively regulates NF-κB but also significantly enhances MRV replication. This study reveals a novel function of sc VHL in NF-κB signaling and viral infection in fish.
- Published
- 2024
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