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. 2024 Sep 18;45(5):990-1000.
doi: 10.24272/j.issn.2095-8137.2023.392.

Mandarin fish von Hippel-Lindau protein regulates the NF-κB signaling pathway via interaction with IκB to promote fish ranavirus replication

Zhi-Min Li  1 , Xiao-Wei Qin  1 , Qi Zhang  1 , Jian He  1 , Min-Cong Liang  1 , Chuan-Rui Li  1 , Yang Yu  1 , Weng-Hui Liu  1 , Shao-Ping Weng  1 , Jian-Guo He  2 , Chang-Jun Guo  1   3
Affiliations

Mandarin fish von Hippel-Lindau protein regulates the NF-κB signaling pathway via interaction with IκB to promote fish ranavirus replication

Zhi-Min Li et al. Zool Res. .

Abstract
in English, Chinese

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.

肿瘤抑制蛋白VHL是一种E3泛素连接酶，在缺氧诱导因子的氧敏感通路中起关键调节作用。近期研究表明，哺乳动物VHL在NF-κB信号通路中发挥重要作用，但其具体的分子调控机制尚不清楚。在此，该文开展了鳜鱼VHL（ scVHL）在NF-κB信号通路和鳜蛙病毒（MRV）复制中的作用研究。研究结果显示，免疫刺激和MRV感染均可诱导 scVHL的转录，提示 scVHL可能在先天免疫中发挥重要作用。双荧光素酶报告基因实验和实时荧光定量PCR结果显示， scVHL可诱导并激活NF-κB信号通路。利用NF-κB信号通路抑制剂处理结果显示， scVHL在NF-κB信号通路中的调控作用可能靶向 scIKKα、 scIKKβ、 scIκBα或 scp65。通过免疫共沉淀进一步分析，发现 scIκBα是 scVHL的一个新的靶标蛋白，且 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。在MRV感染后，NF-κB信号通路处于激活状态，NF-κB的激活可促进MRV的复制。上述结果表明， scVHL可正向调控NF-κB，显著促进MRV复制。该研究揭示了 scVHL在NF-κB信号通路和病毒感染中的新作用，有助于深入阐明氧敏感通路调控动物先天性免疫的作用机制提供理论基础。.

Keywords: IκBα; Mandarin fish; NF-κB; Ranavirus; VHL.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Characteristics of mandarin fish scVHL
Figure 2
Figure 2
scVHL activated the NF-κB signaling pathway through interactions with scIKKα, scIKKβ, and scIκBα
Figure 3
Figure 3
scVHL regulated the NF-κB signaling pathway by promoting scIκBα K63 ubiquitination
Figure 4
Figure 4
NF-κB signaling pathway activation promoted MRV transcription and replication
Figure 5
Figure 5
scVHL activated the NF-κB pathway and enhanced MRV transcription and replication
Figure 6
Figure 6
Model of interplay between VHL and IκBα in the regulation of MRV replication
See this image and copyright information in PMC

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