Convergence of the NF-κB and interferon signaling pathways in the regulation of antiviral defense and apoptosis
Convergence of the NF-κB and interferon signaling pathways in the regulation of antiviral defense and apoptosis
复制标题
DOI：
10.1196/annals.1299.042
复制
发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Lin, RT
中科院分区：
文献类型：
--
作者：
Hiscott, J;Grandvaux, N;Lin, RT
广泛表达的干扰素调节因子3（IRF-3）在病毒感染后直接激活，并作为立即早期1型干扰素（IFN）基因的关键激活剂发挥作用。在诱导表达组成型活性IRF-3的Jurkat T细胞中使用DNA微阵列分析（8，556个基因），鉴定了由IRF-3直接调控的几个靶基因。在被IRF-3上调的基因中，有一部分是已知的IFN刺激基因（ISG）的转录本，包括ISG 56，它是翻译起始的抑制剂。IRF-3激活需要C-末端Ser/Thr残基的磷酸化-（382）GGASSLENTVDLHISNSHPLSLTSDQY（408）。使用C-末端点突变和一种新的磷酸特异性抗体，Ser 396的特点是在体内所需的最小磷酸受体位点的IRF-3激活后仙台病毒（SeV）感染，表达病毒核衣壳，或双链RNA（dsRNA）治疗。靶向并激活IRF-3和IRF-7的病毒活化激酶（VAK）活性的身份仍然是理解干扰素信号传导的关键缺失环节。我们报道IKK相关激酶IKK 3/TBK-1是VAK的组成部分，介导IRF-3和IRF-7磷酸化，因此在抗病毒反应的发展中功能性地连接NF-κ B和IRF通路。
The ubiquitously expressed interferon regulatory factor 3 (IRF-3) is directly activated following virus infection and functions as a key activator of the immediate-early Type 1 interferon (IFN) genes. Using DNA microarray analysis (8,556 genes) in Jurkat T cells inducibly expressing constitutively active IRF-3, several target genes directly regulated by IRF-3 were identified. Among the genes upregulated by IRF-3 were transcripts for a subset of known IFN-stimulated genes (ISGs), including ISG56, which functions as an inhibitor of translation initiation. Phosphorylation of C-terminal Ser/Thr residues-(382)GGASSLENTVDLHISNSHPLSLTSDQY(408)-is required for IRF-3 activation. Using C-terminal point mutations and a novel phosphospecific antibody, Ser396 was characterized as the minimal phosphoacceptor site required in vivo for IRF-3 activation following Sendai virus (SeV) infection, expression of viral nucleocapsid, or double-stranded RNA (dsRNA) treatment. The identity of the virus-activated kinase (VAK) activity that targets and activates IRF-3 and IRF-7 has remained a critical missing link in the understanding of interferon signaling. We report that the IKK-related kinases-IKKepsilon/TBK-1-are components of VAK that mediate IRF-3 and IRF-7 phosphorylation and thus functionally link the NF-kappaB and IRF pathways in the development of the antiviral response.