cGAS is activated by DNA in a length-dependent manner

EMBO Rep. 2017 Oct;18(10):1707-1715. doi: 10.15252/embr.201744017. Epub 2017 Aug 10.

Abstract

Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length-dependent manner. This is observed over a wide length-span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length-dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections.

Keywords: STING; cGAS; DNA sensing; interferon; length dependence.

MeSH terms

  • Cell Line
  • Cytosol / immunology
  • Cytosol / metabolism
  • DNA / chemistry*
  • DNA / genetics
  • DNA / immunology*
  • DNA / metabolism
  • Enzyme Activation
  • Humans
  • Immunity, Innate
  • Interferon Type I / biosynthesis*
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Membrane Proteins / metabolism
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Signal Transduction

Substances

  • Interferon Type I
  • Membrane Proteins
  • STING protein, human
  • DNA
  • MB21D1 protein, human
  • Nucleotidyltransferases