Characterization of Fish IRF3 as an IFN-Inducible Protein Reveals Evolving Regulation of IFN Response in Vertebrates
Characterization of Fish IRF3 as an IFN-Inducible Protein Reveals Evolving Regulation of IFN Response in Vertebrates
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鱼类 IRF3 作为 IFN 诱导蛋白的表征揭示了脊椎动物中 IFN 反应的不断变化的调节
DOI：
10.4049/jimmunol.1002401
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发表时间：
2010-12-15
影响因子：
4.4
通讯作者：
Gui, Jian-Fang
中科院分区：
文献类型：
--
作者：
Sun, Fan;Zhang, Yi-Bing;Gui, Jian-Fang
在哺乳动物中，IFN调节因子（IRF）3是调节I型IFN和IFN刺激基因（ISG）转录的关键因子。在这项研究中，我们描述了鲫鱼（Carassius auratus L.）IRF 3在激活鱼IFN和ISG中的作用。鱼类IRF 3与哺乳动物直系同源物具有很大的序列差异。哺乳动物IRF 3是组成性表达的，而鱼类IRF 3蛋白则被哺乳动物中的干扰素、聚IC和其他称为干扰素诱导剂的刺激物显着上调。鱼类IRF 3的IFN诱导特性与脊椎动物IRF 3基因5′侧翼调控区的比较分析一致，揭示了鱼类和两栖类中存在典型的IFN刺激反应元件，而四足动物中不存在。此外，IFN或多聚-IC诱导IRF 3的磷酸化和胞质到核的易位，这对于其功能似乎是必不可少的，因为磷酸模拟活性IRF 3表现出比野生型IRF 3更强的反式激活。最后，鱼IRF 3的过表达激活IFN的产生，这反过来又通过Stat 1途径触发ISG转录，而显性失活突变体IRF 3-DN的转染废除了ISG的多聚IC诱导，可能是由于IFN产生的阻断。因此，脊椎动物IRF 3对IFN应答的调节是另一个古老的特征。这些数据为脊椎动物IRF 3调节IFN应答的进化功能提供了证据。
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.