Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
University of Strasbourg, CNRS UPR9022, Strasbourg, France.
Nature. 2021 Sep;597(7874):114-118. doi: 10.1038/s41586-021-03800-z. Epub 2021 Jul 14.
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 prokaryotes and eukaryotes. In bacteria, these enzymes synthesize a range of cyclic oligonucleotides and have recently emerged as important regulators of phage infections. 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，环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）在细胞质 DNA 反应中产生环二核苷酸 2'3'-cGAMP，从而触发抗病毒免疫反应。cGAS 属于一个大型 cGAS/DncV 样核苷酸转移酶家族，存在于原核生物和真核生物中。在细菌中，这些酶合成一系列环寡核苷酸，最近它们已成为噬菌体感染的重要调节剂。在这里，我们在昆虫果蝇中鉴定出两种 cGAS 样受体（cGLR）。我们表明，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 激活以产生环二核苷酸 3'2'-cGAMP，而 cGLR2 以产生 2'3'-cGAMP 和 3'2'-cGAMP 的组合作为对未知刺激的反应。我们的数据确立了 cGAS 作为一个受体家族的创始成员，该家族通过产生 2'3'-cGAMP 以外的环二核苷酸来感应不同类型的核酸并触发免疫。
