Two cGAS-like receptors induce antiviral immunity in Drosophila

Andreas Holleufer, Kasper Grønbjerg Winther, Hans Henrik Gad, Xianlong Ai, Yuqiang Chen, Lihua Li, Ziming Wei, Huimin Deng, Jiyong Liu, Ninna Ahlmann Frederiksen, Bine Simonsen, Line Lykke Andersen, Karin Kleigrewe, Louise Dalskov, Andreas Pichlmair, Hua Cai (), Jean-Luc Imler () and Rune Hartmann ()
Additional contact information
Andreas Holleufer: Aarhus University
Kasper Grønbjerg Winther: University of Strasbourg, CNRS UPR9022
Hans Henrik Gad: Aarhus University
Xianlong Ai: School of Basic Medical Science, Guangzhou Medical University
Yuqiang Chen: School of Basic Medical Science, Guangzhou Medical University
Lihua Li: School of Basic Medical Science, Guangzhou Medical University
Ziming Wei: School of Basic Medical Science, Guangzhou Medical University
Huimin Deng: School of Basic Medical Science, Guangzhou Medical University
Jiyong Liu: School of Basic Medical Science, Guangzhou Medical University
Ninna Ahlmann Frederiksen: Aarhus University
Bine Simonsen: Aarhus University
Line Lykke Andersen: Technical University of Munich
Karin Kleigrewe: Technical University of Munich
Louise Dalskov: Aarhus University
Andreas Pichlmair: Technical University of Munich
Hua Cai: School of Basic Medical Science, Guangzhou Medical University
Jean-Luc Imler: University of Strasbourg, CNRS UPR9022
Rune Hartmann: Aarhus University

Nature, 2021, vol. 597, issue 7874, 114-118

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03800-z

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