title: Cyclic GMP-AMP as an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA.
abstract: The innate immune system functions as the first line of defense against invading bacteria and viruses. In this context, the cGAS/STING [cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase/STING] signaling axis perceives the nonself DNA associated with bacterial and viral infections, as well as the leakage of self DNA by cellular dysfunction and stresses, to elicit the host's immune responses. In this pathway, the noncanonical cyclic dinucleotide 2',3'-cyclic GMP-AMP (2',3'-cGAMP) functions as a second messenger for signal transduction: 2',3'-cGAMP is produced by the enzyme cGAS upon its recognition of double-stranded DNA, and then the 2',3'-cGAMP is recognized by the receptor STING to induce the phosphorylation of downstream factors, including TBK1 (TANK binding kinase 1) and IRF3 (interferon regulatory factor 3). Numerous crystal structures of the components of this cGAS/STING signaling axis have been reported and these clarify the structural basis for their signal transduction mechanisms. In this review, we summarize recent progress made in the structural dissection of this signaling pathway and indicate possible directions of forthcoming research.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Omura
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; email: ishitani@bs.u-tokyo.ac.jp , nureki@bs.u-tokyo.ac.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
mesh_terms: D000818:Animals; D001419:Bacteria; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000737:chemistry / Q000276:immunology; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D009712:Nucleotides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D009713:Nucleotidyltransferases / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015290:Second Messenger Systems / Q000235:genetics / Q000276:immunology*; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D050838:Interferon Regulatory Factor-3; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; D017346:Protein Serine-Threonine Kinases; C494232:IRF3 protein, human; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C403191:TBK1 protein, human; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
keywords: STING; cGAMP; cGAS; innate immune system; type I interferon