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 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.

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Figure 1: DAI (DLM-1/ZBP1) is a positive regulator for type I IFN induction by cytosolic DNA.
Figure 2: DAI (DLM-1/ZBP1) is critical for B-DNA-mediated IRF3 activation and Ifnb mRNA expression.
Figure 3: Interaction of DAI (DLM-1/ZBP1) with B-DNA in the cytoplasm.
Figure 4: Interaction of DAI (DLM-1/ZBP1) with IRF3 and TBK1.

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Acknowledgements

We thank A. Katoh and M. Kidokoro for the vaccinia virus (MO) genome for ligand stimulation; T. Fujita and M. Yoneyama for RIG-I cDNA; J. Miyazaki for pCAGGS; A. Miyawaki for Venus; R. Kuroda for her support for CD spectrometry; Toray Industries for murine IFN-β; J. V. Ravetch for advice; Y. Fujita, R. Takeda and M. Shishido for technical assistance; and D. Savitsky for critical reading of the manuscript. This work was supported in part by a grant for Advanced Research on Cancer and a Grant-In-Aid for Scientific Research on Priority Areas, and for Scientific Research, from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Z.W. and H.N. are research fellows of the Japan Society for the Promotion of Science. M.K.C. is a research fellow of the Korea Science and Engineering Foundation.

Author Contributions A.T., Z.W., M.K.C., H.Y., H.N., T.B., Y.L. and T.T. conceived the research, planned experiments and analyses, and largely conducted experiments. K.H. and M.M. helped to design RNAi experimental protocols. T.K. performed microarray experiments and data analysis. Fluorescence microscopy and FRET analysis were conducted by Y.O. T.T. oversaw the entire project.

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Correspondence to Tadatsugu Taniguchi.

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Takaoka, A., Wang, Z., Choi, M. et al. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501–505 (2007). https://doi.org/10.1038/nature06013

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