Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules
Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-sensing molecules
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DOI：
10.1073/pnas.0801295105
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发表时间：
2008-04-08
影响因子：
11.1
通讯作者：
Taniguchi, Tadatsugu
中科院分区：
文献类型：
--
作者：
Wang, ZhiChao;Choi, Myoung Kwon;Taniguchi, Tadatsugu
DNA，无论是微生物来源的还是宿主来源的，当暴露在细胞胞浆中时，都会引起免疫反应。我们以前报道过DNA依赖的干扰素调节因子激活剂(DAI)，也被称为DLm-1/ZBP1，其功能是作为DNA传感器激活天然免疫系统。在本研究中，我们研究了DAI和其他分子对复杂DNA传感系统的调节。我们首先证明了DAI在体外直接与DNA相互作用，在体内需要三个DNA结合域才能完全激活。我们还发现，人工诱导的DAI二聚化导致了I型干扰素基因的DNA不依赖于DNA的激活，从而为DAI激活的分子基础提供了更好的理解。此外，我们提供了其他DNA传感器存在的证据，无论是积极的还是消极的调节胞浆DNA介导的先天免疫反应。这些结果为深入了解DAI的激活机制和揭示DNA介导的保护性免疫反应和病理性免疫反应的复杂调控机制提供了依据。
DNA, whether it is microbe-derived or host-derived, evokes immune responses when exposed to the cytosol of a cell. We previously reported that DNA-dependent activator of IFN regulatory factors (DAI), also referred to as DLM-1/ZBP1, functions as a DNA sensor that activates the innate immune system. In the present study, we examined the regulation of the complex DNA-sensing system by DAI and other molecules. We first show that DAI directly interacts with DNA in vitro and that it requires three DNA-binding domains for full activation in vivo. We also show that the artificially induced dimerization of DAI results in the DNA-independent activation of type I IFN genes, thereby providing a better understanding for the molecular basis of DAI activation. Furthermore, we provide evidence for the presence of additional DNA sensors, either positively or negatively regulating cytosolic DNA-mediated innate immune responses. These results in toto provide insights into the mechanism of DAI activation and reveal the complex regulatory mechanisms underlying DNA-mediated protective and pathologic immune responses.