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 eukaryotes^2,3,4,5. In bacteria, these enzymes synthesize a range of cyclic oligonucleotides and have recently emerged as important regulators of phage infections^6,7,8. 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.

在哺乳动物中，环状 GMP-AMP (cGAMP) 合酶 (cGAS) 响应胞质 DNA 产生环状二核苷酸 2'3'-cGAMP，这会触发抗病毒免疫反应。cGAS 属于 cGAS/DncV 样核苷酸转移酶大家族，存在于原核生物¹和真核生物^2,3,4,5中。在细菌中，这些酶合成一系列环状寡核苷酸，最近已成为噬菌体感染^6,7,8的重要调节剂。在这里，我们确定了昆虫黑腹果蝇中的两种 cGAS 样受体 (cGLR). 我们显示 cGLR1 和 cGLR2 激活 Sting 和 NF-κB 依赖性抗病毒免疫以响应 RNA 或 DNA 病毒的感染。cGLR1 被双链 RNA 激活以产生环状二核苷酸 3'2'-cGAMP，而 cGLR2 响应尚未确定的刺激产生 2'3'-cGAMP 和 3'2'-cGAMP 的组合。我们的数据将 cGAS 确立为受体家族的创始成员，这些受体能够感知不同类型的核酸并通过产生超过 2'3'-cGAMP 的环状二核苷酸来触发免疫。