title: DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response.
abstract: Central to innate immunity is the sensing of pathogen-associated molecular patterns by cytosolic and membrane-associated receptors. In particular, DNA is a potent activator of immune responses during infection or tissue damage, 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. Here we report on a candidate DNA sensor, previously named DLM-1 (also called Z-DNA binding protein 1 (ZBP1)), for which biological function had remained unknown; we now propose the alternative name DAI (DNA-dependent activator of IFN-regulatory factors). 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.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Takaoka
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Wang
authors.forename: Myoung Kwon
authors.initials: MK
authors.lastname: Choi
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yanai
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Ban
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ohba
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003600:Cytosol / Q000276:immunology / Q000378:metabolism*; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D005347:Fibroblasts; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D006023:Glycoproteins; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016601:RNA-Binding Proteins; C402632:Zbp1 protein, mouse; D004247:DNA; D017346:Protein Serine-Threonine Kinases