1. Department of Immunology, and,
2. 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
3. Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, and
4. Department of Laboratory Medicine, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-0815, Japan
5. 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
6. 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 receptors^{1, 2, 3, 4}. In particular, DNA is a potent activator of immune responses during infection or tissue damage^{5, 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 responses^{8, 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.

1. Department of Immunology, and,
2. 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
3. Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, and
4. Department of Laboratory Medicine, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-0815, Japan
5. 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
6. 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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