cGAS-like receptors sense RNA and control 3′2′-cGAMP signalling in Drosophila

Kailey M. Slavik, Benjamin R. Morehouse, Adelyn E. Ragucci, Wen Zhou, Xianlong Ai, Yuqiang Chen, Lihua Li, Ziming Wei, Heike Bähre, Martin König, Roland Seifert, Amy S. Y. Lee, Hua Cai, Jean-Luc Imler and Philip J. Kranzusch ()
Additional contact information
Kailey M. Slavik: Harvard Medical School
Benjamin R. Morehouse: Harvard Medical School
Adelyn E. Ragucci: Harvard Medical School
Wen Zhou: Harvard Medical School
Xianlong Ai: Guangzhou Medical University
Yuqiang Chen: Guangzhou Medical University
Lihua Li: Guangzhou Medical University
Ziming Wei: Guangzhou Medical University
Heike Bähre: Hannover Medical School
Martin König: Hannover Medical School
Roland Seifert: Hannover Medical School
Amy S. Y. Lee: Dana-Farber Cancer Institute
Hua Cai: Guangzhou Medical University
Jean-Luc Imler: Guangzhou Medical University
Philip J. Kranzusch: Harvard Medical School

Nature, 2021, vol. 597, issue 7874, 109-113

Abstract: Abstract Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger cG[2′–5′]pA[3′–5′]p (2′3′-cGAMP) and controls activation of innate immunity in mammalian cells1–5. Animal genomes typically encode multiple proteins with predicted homology to cGAS6–10, but the function of these uncharacterized enzymes is unknown. Here we show that cGAS-like receptors (cGLRs) are innate immune sensors that are capable of recognizing divergent molecular patterns and catalysing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signalling core shared with cGAS and a diversified primary ligand-binding surface modified with notable insertions and deletions. We demonstrate that surface remodelling of cGLRs enables altered ligand specificity and used a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. We show that RNA recognition activates Drosophila cGLR1 to synthesize the novel product cG[3′–5′]pA[2′–5′]p (3′2′-cGAMP). A crystal structure of Drosophila stimulator of interferon genes (dSTING) in complex with 3′2′-cGAMP explains selective isomer recognition, and 3′2′-cGAMP induces an enhanced antiviral state in vivo that protects from viral infection. Similar to radiation of Toll-like receptors in pathogen immunity, our results establish cGLRs as a diverse family of metazoan pattern recognition receptors.

Date: 2021
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DOI: 10.1038/s41586-021-03743-5

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