Li Yao, Slavik Kailey M, Morehouse Benjamin R, de Oliveira Mann Carina C, Mears Kepler, Liu Jingjing, Kashin Dmitry, Schwede Frank, Kranzusch Philip J
Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
bioRxiv. 2023 Feb 22:2023.02.22.529553. doi: 10.1101/2023.02.22.529553.
cGAS (cyclic GMP-AMP synthase) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates the protein STING and downstream immunity. Here we discover cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in animal innate immunity. Building on recent analysis in , we use a bioinformatic approach to identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screen of 140 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of alternative nucleotide signals including isomers of cGAMP and cUMP-AMP. Using structural biology, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Together our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
环鸟苷酸-腺苷酸合成酶（cGAS）是人类细胞中的一种酶，可控制对胞质DNA的免疫反应。结合DNA后，cGAS会合成一种核苷酸信号2'3'-环鸟苷酸-腺苷酸（cGAMP），该信号会激活蛋白干扰素基因刺激蛋白（STING）及下游免疫反应。在此，我们发现类cGAS受体（cGLRs）构成了动物先天免疫中模式识别受体的一个主要家族。基于近期的分析，我们采用生物信息学方法，在几乎所有后生动物门中鉴定出3000多种cGLRs。对140种动物cGLRs进行的正向生化筛选揭示了一种保守的信号传导机制，包括对双链DNA（dsDNA）和双链RNA（dsRNA）配体的反应以及包括cGAMP异构体和cUMP-AMP在内的替代核苷酸信号的合成。利用结构生物学，我们解释了不同核苷酸信号的合成如何使细胞能够控制离散的cGLR-STING信号通路。我们的研究结果共同揭示了cGLRs是一个广泛存在的模式识别受体家族，并建立了支配动物免疫中核苷酸信号传导的分子规则。
