State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Wuhan, China.
J Immunol. 2010 Dec 15;185(12):7573-82. doi: 10.4049/jimmunol.1002401. Epub 2010 Nov 17.
In mammals, IFN regulatory factor (IRF) 3 is a critical player in modulating transcription of type I IFN and IFN-stimulated genes (ISGs). In this study, we describe the roles of crucian carp (Carassius auratus L.) IRF3 in activating fish IFN and ISGs. Fish IRF3 exhibits a large sequence divergence from mammalian orthologs. Whereas mammalian IRF3 is constitutively expressed, fish IRF3 protein is significantly upregulated by IFN, poly-IC, and other stimuli known as IFN inducers in mammals. The IFN-inducible property of fish IRF3 is consistent with the comparative analysis of 5' flanking regulatory region of vertebrate IRF3 genes, which reveals the presence of typical IFN-stimulated response elements in fish and amphibians, but an absence in tetrapods. Furthermore, either IFN or poly-IC induces phosphorylation and cytoplasmic-to-nuclear translocation of IRF3, which seems essential for its function in that phosphomimic active IRF3 exhibits stronger transactivation than wild type IRF3. Finally, overexpression of fish IRF3 activates production of IFN that in turn triggers ISG transcription through Stat1 pathway, whereas transfection of dominant negative mutant IRF3-DN abrogates poly-IC induction of ISGs, probably owing to blockade of IFN production. Therefore, regulation of IFN response by vertebrate IRF3 is another ancient trait. These data provide evidence of the evolving function of vertebrate IRF3 on regulating IFN response.
在哺乳动物中，干扰素调节因子（IRF）3 是调节 I 型干扰素和干扰素刺激基因（ISGs）转录的关键因子。在这项研究中，我们描述了鲤鱼（Carassius auratus L.）IRF3 在激活鱼类 IFN 和 ISGs 中的作用。鱼类 IRF3 与哺乳动物同源物的序列差异很大。虽然哺乳动物的 IRF3 是组成型表达的，但鱼类的 IRF3 蛋白在 IFN、poly-IC 和其他在哺乳动物中被称为 IFN 诱导剂的刺激下显著上调。鱼类 IRF3 的 IFN 诱导特性与脊椎动物 IRF3 基因 5'侧翼调控区的比较分析一致，该分析揭示了鱼类和两栖动物中存在典型的 IFN 刺激反应元件，但在四足动物中不存在。此外，IFN 或 poly-IC 诱导 IRF3 的磷酸化和细胞质到核内转位，这似乎是其功能所必需的，因为磷酸模拟活性的 IRF3 表现出比野生型 IRF3 更强的转录激活活性。最后，鱼 IRF3 的过表达激活 IFN 的产生，反过来通过 Stat1 途径触发 ISG 转录，而转染显性负突变体 IRF3-DN 会破坏 poly-IC 诱导的 ISGs，可能是由于 IFN 产生受阻。因此，脊椎动物 IRF3 对 IFN 反应的调节是另一个古老的特征。这些数据为脊椎动物 IRF3 在调节 IFN 反应方面的进化功能提供了证据。
