Abstract
In mammals, cyclic GMP-AMP (cGAMP) synthase (cGAS) produces the cyclic dinucleotide 2'3'-cGAMP in response to cytosolic DNA and this triggers an antiviral immune response. cGAS belongs to a large family of cGAS/DncV-like nucleotidyltransferases that is present in both prokaryotes1 and eukaryotes2-5. In bacteria, these enzymes synthesize a range of cyclic oligonucleotides and have recently emerged as important regulators of phage infections6-8. Here we identify two cGAS-like receptors (cGLRs) in the insect Drosophila melanogaster. We show that cGLR1 and cGLR2 activate Sting- and NF-κB-dependent antiviral immunity in response to infection with RNA or DNA viruses. cGLR1 is activated by double-stranded RNA to produce the cyclic dinucleotide 3'2'-cGAMP, whereas cGLR2 produces a combination of 2'3'-cGAMP and 3'2'-cGAMP in response to an as-yet-unidentified stimulus. Our data establish cGAS as the founding member of a family of receptors that sense different types of nucleic acids and trigger immunity through the production of cyclic dinucleotides beyond 2'3'-cGAMP.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line
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Drosophila Proteins / metabolism
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Drosophila melanogaster / immunology*
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Drosophila melanogaster / metabolism
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Drosophila melanogaster / virology
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Female
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Humans
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Immunity, Innate / genetics
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Immunity, Innate / immunology
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Ligands
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Male
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Membrane Proteins / metabolism
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Models, Molecular
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NF-kappa B / metabolism
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Nucleotides, Cyclic / metabolism
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Nucleotidyltransferases / classification
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Nucleotidyltransferases / deficiency
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Nucleotidyltransferases / immunology*
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Nucleotidyltransferases / metabolism
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RNA, Double-Stranded / analysis
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RNA, Double-Stranded / immunology
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RNA, Double-Stranded / metabolism
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Receptors, Pattern Recognition / classification
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Receptors, Pattern Recognition / deficiency
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Receptors, Pattern Recognition / immunology
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Receptors, Pattern Recognition / metabolism*
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Viruses / immunology*
Substances
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Drosophila Proteins
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Ligands
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Membrane Proteins
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NF-kappa B
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Nucleotides, Cyclic
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RNA, Double-Stranded
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Receptors, Pattern Recognition
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STING1 protein, human
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Sting protein, Drosophila
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cyclic guanosine monophosphate-adenosine monophosphate
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Nucleotidyltransferases