Holleufer, A., Winther, K.G., Gad, H.H., Ai, X., Chen, Y., Li, L., Wei, Z., Deng, H., Liu, J., Frederiksen, N.A., Simonsen, B., Andersen, L.L., Kleigrewe, K., Dalskov, L., Pichlmair, A., Cai, H., Imler, J.L., Hartmann, R. (2021). Two cGAS-like receptors induce antiviral immunity in Drosophila.  Nature 597(7874): 114--118.

FBrf0250901

Research paper

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.