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Letter
Nature 448, 501-505 (26 July 2007) | doi:10.1038/nature06013; Received 13 March 2007; Accepted 13 June 2007; Published online 8 July 2007
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DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
Akinori Takaoka1,3,6, ZhiChao Wang1,6, Myoung Kwon Choi1,6, Hideyuki Yanai1, Hideo Negishi1, Tatsuma Ban1, Yan Lu1, Makoto Miyagishi2, Tatsuhiko Kodama5, Kenya Honda1, Yusuke Ohba4 & Tadatsugu Taniguchi1
- Department of Immunology, and,
- Department of 21st Century Center of Excellence Program, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, and
- Department of Laboratory Medicine, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-0815, Japan
- Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan
- These authors contributed equally to this work.
Correspondence to: Tadatsugu Taniguchi1 Correspondence and requests for materials should be addressed to T.T. (Email: tada@m.u-tokyo.ac.jp).
Abstract
Central to innate immunity is the sensing of pathogen-associated molecular patterns by cytosolic and membrane-associated receptors1, 2, 3, 4. In particular, DNA is a potent activator of immune responses during infection or tissue damage5, 6, 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 responses8, 9, 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 factors12). 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.
- Department of Immunology, and,
- Department of 21st Century Center of Excellence Program, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
- Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, and
- Department of Laboratory Medicine, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-0815, Japan
- Department of Molecular Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan
- These authors contributed equally to this work.
Correspondence to: Tadatsugu Taniguchi1 Correspondence and requests for materials should be addressed to T.T. (Email: tada@m.u-tokyo.ac.jp).
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