Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance
Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance
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DOI：
10.1371/journal.ppat.1007420
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发表时间：
2018-11-01
期刊：
影响因子：
6.7
通讯作者：
Boulant, Steeve
中科院分区：
文献类型：
--
作者：
Pervolaraki, Kalliopi;Talemi, Soheil Rastgou;Boulant, Steeve
目前认为I型和III型干扰素（IFN）具有冗余功能。然而，上皮细胞上的III型IFN受体的优先分布表明上皮表面的功能差异。在这里，使用人肠上皮细胞，我们可以表明，虽然I型和III型IFN赋予细胞抗病毒状态，但它们具有不同的动力学。I型IFN信号传导的特征在于干扰素刺激基因（ISG）的急性强诱导，并赋予快速抗病毒保护。相反，与I型IFN相比，缓慢作用的III型IFN介导的抗病毒保护的特征在于以延迟的方式较弱地诱导ISG。此外，虽然转录谱显示两种IFN诱导相似的ISG集，但它们的时间表达严格依赖于IFN，从而导致独特的抗病毒环境。使用数据驱动的数学建模和实验验证的组合，我们解决了ISG表达的这种差异动力学的分子原因。我们可以证明，这些动力学差异是内在的每个信号转导途径，而不是由于不同的表达水平的相应的IFN受体。我们报告说，III型IFN是专门定制的，不仅由于其受体的限制，而且还提供了一个独特的抗病毒环境相比，I型IFN的靶细胞在特定的细胞类型中发挥作用。我们认为，这种特定的环境是关键的表面，经常受到挑战的细胞外环境。
It is currently believed that type I and III interferons (IFNs) have redundant functions. However, the preferential distribution of type III IFN receptor on epithelial cells suggests functional differences at epithelial surfaces. Here, using human intestinal epithelial cells we could show that although both type I and type III IFNs confer an antiviral state to the cells, they do so with distinct kinetics. Type I IFN signaling is characterized by an acute strong induction of interferon stimulated genes (ISGs) and confers fast antiviral protection. On the contrary, the slow acting type III IFN mediated antiviral protection is characterized by a weaker induction of ISGs in a delayed manner compared to type I IFN. Moreover, while transcript profiling revealed that both IFNs induced a similar set of ISGs, their temporal expression strictly depended on the IFNs, thereby leading to unique antiviral environments. Using a combination of data-driven mathematical modeling and experimental validation, we addressed the molecular reason for this differential kinetic of ISG expression. We could demonstrate that these kinetic differences are intrinsic to each signaling pathway and not due to different expression levels of the corresponding IFN receptors. We report that type III IFN is specifically tailored to act in specific cell types not only due to the restriction of its receptor but also by providing target cells with a distinct antiviral environment compared to type I IFN. We propose that this specific environment is key at surfaces that are often challenged with the extracellular environment.