title: DNA-Mediated Cyclic GMP-AMP Synthase-Dependent and -Independent Regulation of Innate Immune Responses.
abstract: Cytoplasmic DNA activates cyclic GMP-AMP synthase (cGAS) to produce cyclic 2'-5'3'-5'GMP-AMP dinucleotide (2'5 'cGAMP). The binding of 2'5'cGAMP to an adaptor protein, stimulator of IFN genes (STING), activates a transcription factor, IFN regulatory factor 3, leading to the induction of IFN and chemokine gene expression. In this study, we found that the 2'5'cGAMP-dependent STING activation induced highly upregulated CXCL10 gene expression. Formation of a distinct STING dimer, which was detected by native PAGE, was induced by 2'5'cGAMP, but not 3'-5'3'-5'cGAMP. Analysis of DNase II(-/-) mice, which constitutively produce IFN-β and CXCL10, showed the accumulation of 2'5'cGAMP in their fetal livers and spleens, suggesting that the undigested DNA accumulating in DNase II(-/-) cells may have leaked from the lysosomes into the cytoplasm. The DNase II(-/-) mouse embryonic fibroblasts produced 2'5'cGAMP in a cGAS-dependent manner during apoptotic cell engulfment. However, cGAS deficiency did not impair the STING-dependent upregulation of CXCL10 in DNase II(-/-) mouse embryonic fibroblasts that was induced by apoptotic cell engulfment or DNA lipofection. These results suggest the involvement of a cGAS-independent additional DNA sensor(s) that induces the STING-dependent activation of innate immunity.
authors: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, University of Tokushima, Tokushima 770-8503, Japan; and.
authors: Kou
authors: K
authors: Motani
authors: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Shinji
authors: S
authors: Ito
authors: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan; snagata@mfour.med.kyoto-u.ac.jp.
authors: Shigekazu
authors: S
authors: Nagata
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C530855:Sting1 protein, mouse; D000099197:STING Protein; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase