Wang Zhichao, Choi Myoung Kwon, Ban Tatsuma, Yanai Hideyuki, Negishi Hideo, Lu Yan, Tamura Tomohiko, Takaoka Akinori, Nishikura Kazuko, Taniguchi Tadatsugu
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5477-82. doi: 10.1073/pnas.0801295105. Epub 2008 Mar 28.
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.
DNA，无论是微生物来源还是宿主来源，当暴露于细胞胞质溶胶时都会引发免疫反应。我们之前报道过，干扰素调节因子（IFN）的DNA依赖性激活剂（DAI），也称为DLM-1/ZBP1，作为一种激活先天免疫系统的DNA传感器发挥作用。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。我们首先表明，DAI在体外直接与DNA相互作用，并且在体内它需要三个DNA结合域才能完全激活。我们还表明，人工诱导的DAI二聚化导致I型IFN基因的非DNA依赖性激活，从而为DAI激活的分子基础提供了更好的理解。此外，我们提供了额外DNA传感器存在的证据，其对胞质DNA介导的先天免疫反应具有正向或负向调节作用。这些结果总体上为DAI激活机制提供了见解，并揭示了DNA介导的保护性和病理性免疫反应背后的复杂调节机制。
