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

Nature. 2007 Jul 26;448(7152):501-5. doi: 10.1038/nature06013. Epub 2007 Jul 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytoplasm / genetics
  • Cytoplasm / immunology
  • Cytoplasm / metabolism
  • Cytosol / immunology
  • Cytosol / metabolism*
  • DNA / immunology*
  • DNA / metabolism
  • Fibroblasts
  • Glycoproteins / genetics
  • Glycoproteins / immunology*
  • Glycoproteins / metabolism
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Mice
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA-Binding Proteins

Substances

  • Glycoproteins
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • RNA-Binding Proteins
  • Zbp1 protein, mouse
  • DNA
  • Protein-Serine-Threonine Kinases