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

Andreas Holleufer¹, Kasper Grønbjerg Winther², Hans Henrik Gad¹, Xianlong Ai³, Yuqiang Chen³, Lihua Li³, Ziming Wei³, Huimin Deng³, Jiyong Liu³, Ninna Ahlmann Frederiksen¹, Bine Simonsen¹, Line Lykke Andersen⁴, Karin Kleigrewe⁵, Louise Dalskov¹, Andreas Pichlmair^4,6, Hua Cai⁷, Jean-Luc Imler^8,9, Rune Hartmann¹⁰

1. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
2. University of Strasbourg, CNRS UPR9022, Strasbourg, France.
3. Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China.
4. Institute of Virology, Technical University of Munich, Munich, Germany.
5. Bavarian Center for Biomolecular Mass Spectrometry, Technical University of Munich, Freising, Germany.
6. German Center for Infection Research (DZIF), Munich partner site, Munich, Germany.
7. Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China. chjorbe@hotmail.com.
8. University of Strasbourg, CNRS UPR9022, Strasbourg, France. jl.imler@ibmc-cnrs.unistra.fr.
9. Sino-French Hoffmann Institute, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, China. jl.imler@ibmc-cnrs.unistra.fr.
10. Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. rh@mbg.au.dk.

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.

Presented By Kasper Winther | ORCID iD