title: Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.
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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Wu
authors.forename: Fenghe
authors.initials: F
authors.lastname: Du
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D003570:Cytidine Triphosphate / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000276:immunology*; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis*; D016899:Interferon-beta / Q000096:biosynthesis*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008969:Molecular Sequence Data; D009713:Nucleotidyltransferases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D006152:Cyclic GMP; D003570:Cytidine Triphosphate; D004247:DNA; D007370:Interferon Type I; D016899:Interferon-beta; D009713:Nucleotidyltransferases; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse