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

Top Cited Papers
Publisher Website
Google Scholar
Abstract
DNA is a potent activator of immune responses. This has been known for more than 40 years, but the mechanism involved is still unclear. Now Takaoka et al. have identified a cytosolic DNA sensor that's involved in the innate immune response. The molecule is interferon-inducible protein DLM-1/ZBP1. No biological function had been found for this before, hence a renaming as DAI, (for DNA-dependent activator of IFN-regulatory factors). The identification of DAI as a key DNA sensor may offer new insight into the signalling mechanisms underlying DNA associated antimicrobial immunity and autoimmune disorders. DNA is a potent activator of immune responses during infection and tissue damage. This paper identifies the cytoplasmic DNA sensor as the interferon-inducible protein DLM1/ZBP1 which they have renamed DAI. 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.