Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway

Science. 2013 Feb 15;339(6121):786-91. doi: 10.1126/science.1232458. Epub 2012 Dec 20.

Abstract

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cyclic AMP / biosynthesis
  • Cyclic GMP / biosynthesis
  • Cytidine Triphosphate / metabolism
  • Cytosol / enzymology
  • Cytosol / immunology*
  • DNA / immunology*
  • DNA / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • Interferon Type I / biosynthesis*
  • Interferon-beta / biosynthesis*
  • Metabolic Networks and Pathways
  • Mice
  • Molecular Sequence Data
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / isolation & purification
  • Nucleotidyltransferases / metabolism*

Substances

  • Interferon Type I
  • Cytidine Triphosphate
  • Interferon-beta
  • Adenosine Triphosphate
  • DNA
  • Cyclic AMP
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse
  • Cyclic GMP

Associated data

  • GENBANK/KC294566
  • GENBANK/KC294567