Innate Immunity Sensing Cytosolic DNA

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

How do cells sense cytosolic viral DNA when infected and trigger a response that helps the body clear these cells? Takaoka et al. provide insight into this question by characterizing a protein previously named DLM-1 or ZPB1, which they rename DAI for their discovery that it appears to function as a DNA-dependent activator of interferon (IFN) regulatory factors. Expression of the gene encoding DAI is stimulated by IFN, which is a common positive feedback mechanism for participants of the IFN pathway. Thus, Takaoka et al. showed that in cells overexpressing DAI, there were enhanced responses (increased expression of IFN genes) to synthetic DNA [poly(dA-dT)•poly(dT-dA)], bacterial DNA, viral DNA, or mammalian DNA, but not to synthetic RNA. Analysis of the response in mouse embryo fibroblasts deficient in various interferon regulatory factors (IRFs) suggested that IRF3 and IRF7 were important for IFN gene induction in response to poly(dA-dT)•poly(dT-dA). When DAI was knocked down by RNAi methods in mouse fibroblasts, increased expression of IFN genes, formation of an IRF3 dimer, and activation of the transcription factor NF-B in response to DNA was reduced. In addition, the response to infection with a DNA virus was impaired, but not that to an RNA virus. DAI directly interacted with poly(dA-dT)•poly(dT-dA) in the cytosol based on fluorescence resonance energy transfer (FRET) experiments in cells containing labeled DAI and labeled synthetic DNA and based on an assay in which DAI pulled down poly(dA-dT)•poly(dT-dA). Coimmunoprecipitation experiments with transfected cells suggested that DNA stimulated the formation of a complex containing DAI, IRF3, and the kinase TBK1. Thus, DAI may be another weapon in the cell's arsenal against viral infection (see commentary by Chi and Flavell).

A. Takaoka, Z. Wang, M. K. Choi, H. Yanai, H. Negishi, T. Ban, Y. Lu, M. Miyagishi, T. Kodama, K. Honda, Y. Ohba, T. Taniguchi, DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448, 501-505 (2007). [PubMed]

H. Chi, R. A. Flavell, Sensing the enemy within. Nature 448, 423-424 (2007). [PubMed]