title: Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING.
abstract: Cyclic GMP-AMP (cGAMP) synthase (cGAS) is recently identified as a cytosolic DNA sensor and generates a non-canonical cGAMP that contains G(2',5')pA and A(3',5')pG phosphodiester linkages. cGAMP activates STING which triggers innate immune responses in mammals. However, the evolutionary functions and origins of cGAS and STING remain largely elusive. Here, we carried out comprehensive evolutionary analyses of the cGAS-STING pathway. Phylogenetic analysis of cGAS and STING families showed that their origins could be traced back to a choanoflagellate Monosiga brevicollis. Modern cGAS and STING may have acquired structural features, including zinc-ribbon domain and critical amino acid residues for DNA binding in cGAS as well as carboxy terminal tail domain for transducing signals in STING, only recently in vertebrates. In invertebrates, cGAS homologs may not act as DNA sensors. Both proteins cooperate extensively, have similar evolutionary characteristics, and thus may have co-evolved during metazoan evolution. cGAS homologs and a prokaryotic dinucleotide cyclase for canonical cGAMP share conserved secondary structures and catalytic residues. Therefore, non-mammalian cGAS may function as a nucleotidyltransferase and could produce cGAMP and other cyclic dinucleotides. Taken together, assembling signaling components of the cGAS-STING pathway onto the eukaryotic evolutionary map illuminates the functions and origins of this innate immune pathway.
authors: College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China zpei@duke.edu.
authors: Xiaomei
authors: X
authors: Wu
authors: College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China Department of Biology, Duke University, Durham, NC 27708, USA.
authors: Fei-Hua
authors: FH
authors: Wu
authors: Department of Biological Sciences, University of North Texas, TX 76203, USA.
authors: Xiaoqiang
authors: X
authors: Wang
authors: College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
authors: Lilin
authors: L
authors: Wang
authors: Department of Biology, Duke University, Durham, NC 27708, USA.
authors: James N
authors: JN
authors: Siedow
authors: Department of Immunology, Duke University, Durham, NC 27710, USA.
authors: Weiguo
authors: W
authors: Zhang
authors: College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China Department of Biology, Duke University, Durham, NC 27708, USA zpei@duke.edu.
authors: Zhen-Ming
authors: ZM
authors: Pei
mesh_terms: D000818:Animals; D056897:Choanoflagellata / Q000235:genetics; D004268:DNA-Binding Proteins / Q000737:chemistry; D019143:Evolution, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000145:classification; D051379:Mice; D009348:Nematoda / Q000235:genetics; D009713:Nucleotidyltransferases / Q000737:chemistry* / Q000145:classification; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase; C578391:cGAS protein, mouse