Differential regulation of IKKα-mediated activation of IRF3/7 by NIK
Differential regulation of IKKα-mediated activation of IRF3/7 by NIK
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DOI：
10.1016/j.molimm.2007.10.034
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发表时间：
2008-04
影响因子：
3.6
通讯作者：
Ruipeng Wang;Min Zhang;Ying Li;Feici Diao;Danying Chen;Z. Zhai;H. Shu
中科院分区：
文献类型：
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作者：
Ruipeng Wang;Min Zhang;Ying Li;Feici Diao;Danying Chen;Z. Zhai;H. Shu
I型干扰素（IFN）是先天免疫系统防御病毒感染的关键介质。干扰素调节因子（IRF）3和IRF 7是在响应病毒感染的I型IFN产生中起关键作用的转录因子。研究表明，蛋白激酶I kappaB激酶α（IKK α）在Toll样受体7/9（TLR7/9）信号级联中关键性地参与IRF7活化和IFN-α产生。然而，IKK α的过表达不激活IFN-α启动子。在这里，我们发现蛋白激酶核因子κ B诱导激酶（NIK）赋予IKK α激活IRF 3/7的能力。已有研究表明NIK可使IKK α的Ser-176和Ser-180残基磷酸化，这两个残基突变为谷氨酸，模拟其磷酸化，引起NF-κ B的组成性激活。然而，两个丝氨酸残基的突变对IKK α介导的IRF 3/7激活具有不同的影响。IKK α（S176 E）组成性激活IRF 3/7，而IKK α（S180 E）失去激活IRF 3/7的能力。这些发现表明IKK α介导的NF-κ B和IRF 3/7的激活受到NIK的差异调节，并且NIK在TLR 7/9介导的IFN-α产生中发挥重要作用。
Type I interferons (IFNs) are critical mediators of the innate immune system to defend viral infection. Interferon regulatory factor (IRF) 3 and IRF7 are transcription factors that play critical roles in type I IFN production in response to viral infection. It has been shown that the protein kinase I kappaB kinase alpha (IKKα) is critically involved in IRF7 activation and IFN-α production in Toll-like receptor 7/9 (TLR7/9) signaling cascades. However, overexpression of IKKα does not activate the IFN-α promoters. Here we show that the protein kinase nuclear factor kappaB-inducing kinase (NIK) confers IKKα the ability to activate IRF3/7. Previous studies have shown that NIK phosphorylates IKKα at Ser-176 and Ser-180 residues, and mutation of each of the two residues to glutamate, which mimics its phosphorylation, caused constitutive activation of NF-κB. However, mutation of the two serine residues has differential effects on IKKα-mediated activation of IRF3/7. While IKKα(S176E) constitutively activates IRF3/7, IKKα(S180E) losses its ability to activate IRF3/7. These findings suggest that IKKα-mediated activation of NF-κB and IRF3/7 are differentially regulated by NIK, and NIK plays an important role in TLR7/9-mediated IFN-α production.