title: Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA.
abstract: Cytosolic DNA induces type I interferons and other cytokines that are important for antimicrobial defense but can also result in autoimmunity. This DNA signaling pathway requires the adaptor protein STING and the transcription factor IRF3, but the mechanism of DNA sensing is unclear. We found that mammalian cytosolic extracts synthesized cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP) in vitro from adenosine triphosphate and guanosine triphosphate in the presence of DNA but not RNA. DNA transfection or DNA virus infection of mammalian cells also triggered cGAMP production. cGAMP bound to STING, leading to the activation of IRF3 and induction of interferon-β. Thus, cGAMP functions as an endogenous second messenger in metazoans and triggers interferon production in response to cytosolic DNA.
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas, TX 75390-9148.|Howard Hughes Medical Institute University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Fenghe
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Biochemistry University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Heping
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biochemistry University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center Dallas, TX 75390-9148.|Howard Hughes Medical Institute University of Texas Southwestern Medical Center Dallas, TX 75390-9148.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D002457:Cell Extracts / Q000737:chemistry; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D003600:Cytosol / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D034622:RNA Interference; D015290:Second Messenger Systems / Q000276:immunology*; D014162:Transfection; D000099197:STING Protein
chemical_list: D002457:Cell Extracts; D000242:Cyclic AMP; D006152:Cyclic GMP; D004247:DNA; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; C532857:STING1 protein, human; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate