A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA
A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA
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DOI：
10.1073/pnas.0909545106
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发表时间：
2009-10-20
影响因子：
11.1
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
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作者：
Choi, Myoung Kwon;Wang, ZhiChao;Taniguchi, Tadatsugu
通过暴露在胞质溶胶内的DNA激活先天免疫应答已经获得了很多关注，并且在这种情况下，已经鉴定了几种胞质溶胶DNA传感器。然而，先前的研究揭示了冗余和复杂的机制的操作，并且仍然有待澄清如何实现DNA介导的多种先天免疫应答的唤起。在这里，我们表明，两个RIG-I样受体（RLR），RIG-I和MDA 5，被称为胞质RNA受体，非冗余功能的胞质DNA受体，导致选择性激活I型IFN基因。我们证明，在IFN信号缺陷细胞中，IFN诱导的RIG-I或MDA 5的过度表达导致I型IFN基因诱导在胞质DNA刺激后显著增强，而在它们不存在的情况下，诱导受损。有趣的是，DNA介导的其他细胞因子基因的诱导几乎不受RLRs的缺乏的影响。事实上，与激活转录因子IRF 3和NF-κ B的RNA-RLR途径不同，DNA-RLR途径主要负责IRF 3的激活，IRF 3对I型IFN基因转录至关重要，这说明DNA信号传导途径的故意分歧。预期，RLR途径也有助于对抗DNA病毒感染的复杂先天免疫应答。我们的研究可能会提供深入了解宿主防御机制的复杂性，阻碍免疫逃避含DNA的病原体。
The activation of the innate immune responses by DNA exposed within the cytosol has gained much attention and, in this context, several cytosolic DNA sensors have been identified. However, previous studies revealed the operation of redundant and complex mechanisms and it still remains to be clarified how the DNA-mediated evocation of diverse innate immune responses can be achieved. Here we show that two RIG-I-like receptors (RLRs), RIG-I and MDA5, known as cytosolic RNA receptors, nonredundantly function as cytosolic DNA receptors that lead to the selective activation of type I IFN genes. Wedemonstrate that overexpression of otherwise IFN-inducible RIG-I or MDA5 in IFN signal-deficient cells results in a marked enhancement of type I IFN gene induction upon cytosolic DNA stimulation, while in their absence the induction is impaired. Interestingly, the DNA-mediated induction of other cytokine genes was barely affected by the absence of RLRs. Indeed, unlike the RNA-RLR pathway that activates the transcription factors IRF3 and NF-kappa B, the DNA-RLR pathway is primarily responsible for the IRF3 activation critical for type I IFN gene transcription, illustrating a deliberate divergence of the DNA signaling pathways. Expectedly, the RLR pathway also contributes to intricate innate immune responses against infection by a DNA virus. Our study may provide insights into the complexity of host defense mechanisms that thwart immune evasion by DNA-containing pathogens.