Two cGAS-like receptors induce antiviral immunity in Drosophila

Nature. 2021 Sep;597(7874):114-118. doi: 10.1038/s41586-021-03800-z. Epub 2021 Jul 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / immunology*
  • Drosophila melanogaster / metabolism
  • Drosophila melanogaster / virology
  • Female
  • Humans
  • Immunity, Innate / genetics
  • Immunity, Innate / immunology
  • Ligands
  • Male
  • Membrane Proteins / metabolism
  • Models, Molecular
  • NF-kappa B / metabolism
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / classification
  • Nucleotidyltransferases / deficiency
  • Nucleotidyltransferases / immunology*
  • Nucleotidyltransferases / metabolism
  • RNA, Double-Stranded / analysis
  • RNA, Double-Stranded / immunology
  • RNA, Double-Stranded / metabolism
  • Receptors, Pattern Recognition / classification
  • Receptors, Pattern Recognition / deficiency
  • Receptors, Pattern Recognition / immunology
  • Receptors, Pattern Recognition / metabolism*
  • Viruses / immunology*


  • Drosophila Proteins
  • Ligands
  • Membrane Proteins
  • NF-kappa B
  • Nucleotides, Cyclic
  • RNA, Double-Stranded
  • Receptors, Pattern Recognition
  • STING1 protein, human
  • Sting protein, Drosophila
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Nucleotidyltransferases