STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
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DOI：
10.1038/nature08476
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发表时间：
2009-10-08
期刊：
影响因子：
64.8
通讯作者：
Barber GN
中科院分区：
文献类型：
--
作者：
Ishikawa H;Ma Z;Barber GN
先天免疫系统对于早期检测入侵病原体和启动细胞宿主防御对策至关重要，其中包括产生I型干扰素(IFN)。然而，关于先天免疫系统是如何对以DNA为基础的微生物做出反应的，人们知之甚少。在这里，我们证明了刺激物(干扰素基因的刺激物)在各种DNA病原体感染后产生的非CpG胞内DNA物种诱导干扰素的过程中起着关键作用。小鼠胚胎成纤维细胞以及巨噬细胞和树突状细胞(暴露于细胞内B型DNA、DNA病毒单纯疱疹病毒1(HSV-1)或单核细胞增生性李斯特菌)等抗原提呈细胞需要STING才能启动有效的干扰素产生。因此，Sting基因敲除小鼠在暴露于HSV-1后容易受到致命性感染。STING在促进DNA介导的先天免疫反应中的重要性进一步明显，因为在STING缺陷动物中，由质粒DNA疫苗诱导的细胞毒性T细胞反应减少。在细胞内DNA存在的情况下，STING与坦克结合蛋白1(TBK1)从内质网重新定位到含有外囊成分Sec5的核周小泡(也称为EXOC2)。总之，我们的研究表明，刺痛对于宿主抵御HSV-1等DNA病原体是必不可少的，并有助于DNA疫苗的佐剂活性。
The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting-knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines.