Key Points Zebrafish NIK positively regulates antiviral response through the induction of IFN. IKKα phosphorylates the NIK at the residue Thr432. The IKKα–NIK complex mediates the activation of IRF3 and NF-κB. Visual Abstract Type I IFN mediates the innate immune system to provide defense against viral infections. NF-κB–inducing kinase (NIK) potentiates the basal activation of endogenous STING, which facilitates the recruitment of TBK1 with the ectopically expressed IRF3 to induce IFN production. Moreover, NIK phosphorylates IKKα and confers its ability to phosphorylate p100 (also known as NF-κB2) in mammals. Our study demonstrated that NIK plays a critical role in IFN production in teleost fish. It was found that NIK interacts with IKKα in the cytoplasm and that IKKα phosphorylates the NIK at the residue Thr432, which is different from the mammals. Overexpression of NIK caused the activation of IRF3 and NF-κB, which in turn led to the production of IFN and IFN-stimulated genes (ISGs). Furthermore, the ectopic expression of NIK was observed to be associated with a reduced replication of the fish virus, whereas silencing of endogenous NIK had an opposite effect in vitro. Furthermore, NIK knockdown significantly reduced the expression of IFN and key ISGs in zebrafish larvae after spring viremia of carp virus infection. Additionally, the replication of spring viremia of carp virus was enhanced in NIK knockdown zebrafish larvae, leading to a lower survival rate. In summary, our findings revealed a previously undescribed function of NIK in activating IFN and ISGs as a host antiviral response. These findings may facilitate the establishment of antiviral therapy to combat fish viruses.

中文翻译：

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斑马鱼 NIK 通过调节 IRF3 和 NF-κB 的激活来介导 IFN 诱导

要点 斑马鱼 NIK 通过诱导 IFN 正向调节抗病毒反应。IKKα 在残基 Thr432 处磷酸化 NIK。IKKα-NIK 复合物介导 IRF3 和 NF-κB 的激活。Visual Abstract I 型 IFN 介导先天免疫系统以提供针对病毒感染的防御。NF-κB 诱导激酶 (NIK) 增强内源性 STING 的基础激活，这促进了 TBK1 与异位表达的 IRF3 的募集以诱导 IFN 产生。此外，NIK 磷酸化 IKKα 并赋予其磷酸化哺乳动物 p100（也称为 NF-κB2）的能力。我们的研究表明 NIK 在硬骨鱼的 IFN 生产中起着关键作用。发现 NIK 与细胞质中的 IKKα 相互作用，并且 IKKα 在残基 Thr432 处磷酸化 NIK，这与哺乳动物不同。NIK 的过度表达导致 IRF3 和 NF-κB 的激活，进而导致 IFN 和 IFN 刺激基因 (ISG) 的产生。此外，观察到 NIK 的异位表达与鱼病毒复制减少有关，而内源性 NIK 的沉默在体外具有相反的效果。此外，在鲤鱼病毒感染春季病毒血症后，NIK 敲低显着降低了斑马鱼幼虫中 IFN 和关键 ISG 的表达。此外，鲤鱼病毒春季病毒血症在 NIK 敲除斑马鱼幼虫中的复制增强，导致存活率较低。总之，我们的研究结果揭示了 NIK 在激活 IFN 和 ISG 作为宿主抗病毒反应方面的先前未描述的功能。