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Nucleic Acids Res. 2014 Jul;42(13):8243-57. doi: 10.1093/nar/gku569. Epub 2014 Jun 30.

Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING.

Author information

1
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China zpei@duke.edu.
2
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China Department of Biology, Duke University, Durham, NC 27708, USA.
3
Department of Biological Sciences, University of North Texas, TX 76203, USA.
4
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
5
Department of Biology, Duke University, Durham, NC 27708, USA.
6
Department of Immunology, Duke University, Durham, NC 27710, USA.
7
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China Department of Biology, Duke University, Durham, NC 27708, USA zpei@duke.edu.

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.

PMID:
24981511
PMCID:
PMC4117786
DOI:
10.1093/nar/gku569
[Indexed for MEDLINE]
Free PMC Article

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