DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
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DOI：
10.1038/nature06013
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发表时间：
2007-07-26
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
--
作者：
Takaoka, Akinori;Wang, ZhiChao;Taniguchi, Tadatsugu
先天免疫的核心是通过胞质和膜相关受体感知病原体相关分子模式(1-4)。特别是，DNA 是感染或组织损伤期间免疫反应的有效激活剂 (5-7)，并且有证据表明，除了膜相关 Toll 样受体 9 之外，一种未识别的胞质 DNA 传感器也可以激活 I 型干扰素 (IFN) 和其他免疫反应 (8-10)。在这里，我们报告了一种候选 DNA 传感器，以前称为 DLM-1（也称为 Z-DNA 结合蛋白 1 (ZBP1)）(11)，其生物学功能仍然未知；我们现在提出替代名称 DAI（DNA 依赖性 IFN 调节因子激活剂 (12)）。在小鼠成纤维细胞中人工表达 IFN 诱导型 DAI (DLM-1/ZBP1) 可选择性增强 DNA 介导的 I 型 IFN 和其他参与先天免疫的基因的诱导。另一方面，细胞中 DAI (DLM-1/ZBP1) 信使 RNA 的 RNA 干扰会在各种来源的 DNA 刺激下抑制该基因诱导程序。此外，DAI (DLM-1/ZBP1) 与双链 DNA 结合，从而增强其与 IRF3 转录因子和 TBK1 丝氨酸/苏氨酸激酶的关联。这些观察结果强调了 DAI (DLM-1/ZBP1) 在 DNA 介导的先天免疫反应激活中的不可或缺的作用，并可能为 DNA 相关抗菌免疫和自身免疫性疾病背后的信号机制提供新的见解。
Central to innate immunity is the sensing of pathogen-associated molecular patterns by cytosolic and membrane-associated receptors(1-4). In particular, DNA is a potent activator of immune responses during infection or tissue damage(5-7), and evidence indicates that, in addition to the membrane-associated Toll-like receptor 9, an unidentified cytosolic DNA sensor(s) can activate type I interferon (IFN) and other immune responses(8-10). Here we report on a candidate DNA sensor, previously named DLM-1 ( also called Z-DNA binding protein 1 (ZBP1))(11), for which biological function had remained unknown; we now propose the alternative name DAI (DNA-dependent activator of IFN-regulatory factors(12)). The artificial expression of otherwise IFN-inducible DAI (DLM-1/ ZBP1) in mouse fibroblasts selectively enhances the DNA-mediated induction of type I IFN and other genes involved in innate immunity. On the other hand, RNA interference of messenger RNA for DAI (DLM-1/ ZBP1) in cells inhibits this gene induction programme upon stimulation by DNA from various sources. Moreover, DAI (DLM-1/ZBP1) binds to double-stranded DNA and, by doing so, enhances its association with the IRF3 transcription factor and the TBK1 serine/threonine kinase. These observations underscore an integral role of DAI (DLM-1/ZBP1) in the DNA-mediated activation of innate immune responses, and may offer new insight into the signalling mechanisms underlying DNA- associated antimicrobial immunity and autoimmune disorders.