IκB kinase ε (IKKε) regulates the balance between type I and type II interferon responses
IκB kinase ε (IKKε) regulates the balance between type I and type II interferon responses
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DOI：
10.1073/pnas.1119137109
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发表时间：
2011-12-27
影响因子：
11.1
通讯作者：
Maniatis, Tom
中科院分区：
文献类型：
--
作者：
Ng, Sze-Ling;Friedman, Brad A.;Maniatis, Tom
病毒感染诱导I型和II型干扰素(干扰素-I和干扰素-II)的产生，这是介导抗病毒反应的细胞因子。干扰素-I(干扰素-α和干扰素-β)诱导干扰素刺激的基因因子3(ISGF3)的组装，它是由STAT1、STAT2和干扰素调节因子9组成的多聚体转录激活复合体。干扰素-II(干扰素-γ)诱导STAT1同源二聚化形成伽马激活因子(GAF)复合体。ISGF3和GAF分别与位于干扰素-I和干扰素-II诱导基因上游的独特调控DNA序列特异性结合，激活不同组抗病毒基因的表达。I型和II型干扰素途径之间的平衡在协调先天免疫系统和获得性免疫系统中起着关键作用。在这里，我们证明了I kappa B激酶epsilon(Ikk Epsilon)对STAT1的磷酸化抑制了STAT1的同源二聚化，从而抑制了GAF的组装，但不会破坏ISGF3的形成。因此，病毒和/或干扰素-I激活IKK epsilon抑制GAF依赖的转录，促进ISGF3依赖的转录。在没有ikk epsilon的情况下，GAF依赖的转录被增强，而ISGF3介导的转录是代价，使细胞对感染的抵抗力降低。我们的结论是，ikk epsilon在调节干扰素-I和干扰素-II信号通路之间的平衡中起着关键作用。
Virus infection induces the production of type I and type II interferons (IFN-I and IFN-II), cytokines that mediate the antiviral response. IFN-I (IFN-alpha and IFN-beta) induces the assembly of IFN-stimulated gene factor 3 (ISGF3), a multimeric transcriptional activation complex composed of STAT1, STAT2, and IFN regulatory factor 9. IFN-II (IFN-gamma) induces the homodimerization of STAT1 to form the gamma-activated factor (GAF) complex. ISGF3 and GAF bind specifically to unique regulatory DNA sequences located upstream of IFN-I- and IFN-II-inducible genes, respectively, and activate the expression of distinct sets of antiviral genes. The balance between type I and type II IFN pathways plays a critical role in orchestrating the innate and adaptive immune systems. Here, we show that the phosphorylation of STAT1 by I kappa B kinase epsilon (IKK epsilon) inhibits STAT1 homodimerization, and thus assembly of GAF, but does not disrupt ISGF3 formation. Therefore, virus and/or IFN-I activation of IKK epsilon suppresses GAF-dependent transcription and promotes ISGF3-dependent transcription. In the absence of IKK epsilon, GAF-dependent transcription is enhanced at the expense of ISGF3-mediated transcription, rendering cells less resistant to infection. We conclude that IKK epsilon plays a critical role in regulating the balance between the IFN-I and IFN-II signaling pathways.