Fas-associated death domain-containing protein-mediated antiviral innate immune signaling involves the regulation of Irf7
Fas-associated death domain-containing protein-mediated antiviral innate immune signaling involves the regulation of Irf7
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DOI：
10.4049/jimmunol.178.4.2429
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发表时间：
2007-02-15
影响因子：
4.4
通讯作者：
Barber, Glen N.
中科院分区：
文献类型：
--
作者：
Balachandran, Siddharth;Venkataraman, Thiagarajan;Barber, Glen N.
病毒感染后I型（α β）IFN的诱导对于刺激有效的抗病毒宿主防御是必要的。在成纤维细胞中，一部分主要基因（包括编码IFN-β和IFN-α 4的基因）直接由病毒复制过程中产生的细胞内dsRNA诱导。这些初级I型IFN诱导IFN调节因子（IRF）-7的表达，这是产生IFN-α亚型的第二级联和进一步建立完全抗病毒状态所需的。在此之前，我们已经报道了Fas相关的死亡结构域蛋白（FADD）在控制TLR非依赖性先天免疫应答病毒感染的作用。本研究中的数据表明，FADD不仅是有效的初级基因诱导所必需的，而且对于诱导Irf 7和有效表达次级IFN-α和其他抗病毒基因也是必不可少的。IRF-7的异位过表达部分地挽救了dsRNA反应性和IFN-α的产生，并且IRF-7的组成型活性变体在Fadd（-/-）鼠胚胎成纤维细胞中显示正常活性。MC 159是一种由传染性软疣痘病毒编码的FADD相互作用病毒蛋白，被发现抑制IRF-7上游的dsRNA激活的信号传导事件。这些数据表明，FADD的抗病毒活性涉及调节IFN-a亚型的IRF-7依赖性产生和随后诱导次级抗病毒基因。
The induction of type I (alpha beta) IFN following virus infection is necessary for the stimulation of effective antiviral host defense. In fibroblasts, a subset of primary genes (including those encoding IFN-beta and IFN-alpha 4) are induced directly by intracellular dsRNA generated by the virus during its replication. These primary type I IFNs induce expression of IFN regulatory factor (IRF)-7, required for production of a second cascade of IFN-alpha subtypes and the further establishment of a complete antiviral state. Previously, we had reported on a role for Fas-associated death domain-containing protein (FADD) in the control of TLR-independent innate immune responses to virus infection. Our data in this study demonstrate that FADD is not only required for efficient primary gene induction, but is also essential for induction of Irf7 and effective expression of secondary IFN-alpha s and other antiviral genes. Ectopic overexpression of IRF-7 partially rescued dsRNA responsiveness and IFN-alpha production, and a constitutively active variant of IRF-7 displayed normal activity in Fadd(-/-) murine embryonic fibroblasts. MC159, a FADD-interacting viral protein encoded by the molluscum contagiosum poxvirus was found to inhibit dsRNA-activated signaling events upstream of IRF-7. These data indicate that FADD's antiviral activity involves regulation of IRF-7-dependent production of IFN-a subtypes and consequent induction of secondary antiviral genes.