DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response

Central to innate immunity is the sensing of pathogen-associated molecular patterns by cytosolic and membrane-associated receptors(1-4). In particular, DNA is a potent activator of immune responses during infection or tissue damage(5-7), 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(8-10). 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 factors(12)). 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.