Key Points Zebrafish fbxo3 negatively regulates antiviral responses. Zebrafish fbxo3 inhibits expression of antiviral response genes upon SVCV infection. Zebrafish fbxo3 promotes degradation of irf3 and irf7 by catalyzing ubiquitination. FBXO3, belongs to the F-box family of proteins, which has been reported to involve in host autoimmune and inflammatory responses by promoting its substrates for ubiquitylation. However, thus far, its physiological function in antiviral immunity remains elusive. In this study, we report that overexpression of zebrafish fbxo3 suppresses cellular antiviral responses. Moreover, disruption of fbxo3 in zebrafish increases the survival rate upon spring viremia of carp virus exposure. Further assays indicate that fbxo3 interacts with irf3/irf7 and specifically catalyzes K27-linked ubiquitination of irf3 and irf7, resulting in proteasomal degradation of irf3 and irf7. However, the F-box domain of fbxo3 is not required for fbxo3 to interact with irf3/irf7 and to inhibit transactivity of irf3 and irf7. This study provides novel insights into fbxo3 function and the underlying mechanisms. In addition, it sheds new light on the regulation of IFN-I signaling by F-box proteins.

中文翻译：

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斑马鱼 F-box 蛋白 fbxo3 通过促进转录因子 irf3 和 irf7 的 K27 相关多泛素化负调控抗病毒反应

要点斑马鱼 fbxo3 负向调节抗病毒反应。斑马鱼 fbxo3 抑制 SVCV 感染后抗病毒反应基因的表达。斑马鱼 fbxo3 通过催化泛素化促进 irf3 和 irf7 的降解。FBXO3 属于 F-box 蛋白家族，据报道其通过促进其泛素化底物参与宿主自身免疫和炎症反应。然而，迄今为止，其在抗病毒免疫中的生理功能仍然难以捉摸。在这项研究中，我们报告斑马鱼 fbxo3 的过度表达抑制细胞抗病毒反应。此外，斑马鱼中 fbxo3 的破坏增加了鲤鱼病毒暴露春季病毒血症的存活率。进一步的分析表明 fbxo3 与 irf3/irf7 相互作用并特异性催化 irf3 和 irf7 的 K27 连接的泛素化，导致 irf3 和 irf7 的蛋白酶体降解。然而，fbxo3 的 F-box 域不是 fbxo3 与 irf3/irf7 相互作用和抑制 irf3 和 irf7 的交互所必需的。这项研究提供了对 fbxo3 功能和潜在机制的新见解。此外，它还揭示了 F-box 蛋白对 IFN-I 信号的调控。