小柯机器人

美国丹娜-法伯癌症研究所Philip J. Kranzusch团队发现，果蝇中的cGAS样受体感知RNA并控制3′2′-cGAMP信号传导。相关论文于2021年7月14日在线发表在《自然》杂志上。

研究人员表示，环状GMP-AMP合成酶（cGAS）是一种细胞膜DNA传感器，产生第二信使2′3′-cGAMP并控制哺乳动物细胞中先天免疫的激活。动物基因组通常编码多个与cGAS有预测同源性的蛋白，但这些酶的功能是未知的。

研究人员表明cGAS样受体（cGLR）是先天免疫传感器，能够识别不同的分子模式并催化不同的核苷酸第二信使信号的合成。人类和昆虫cGLR的晶体结构显示了一个与cGAS共享的核苷酸转移酶信号核心，以及一个被大量插入和删除修改的多样化主要配体结合表面。研究人员证明cGLR表面的重塑能够改变配体的特异性，并使用前向生化筛选来确定cGLR1作为模式生物黑腹果蝇的双链RNA传感器。

令人惊讶的是，RNA识别激活了果蝇cGLR1，使其合成新产物cG[3′-5′]pA[2′-5′]p（3′2′-cGAMP）。果蝇干扰素基因刺激因子（STING）与3′2′-cGAMP复合物的晶体结构解释了选择性的异构体识别，研究人员证明3′2′-cGAMP在体内诱导了一种增强的抗病毒状态，并免受病毒感染。与Toll样受体在病原体免疫中的功能相似，这些结果确立了cGLR是一个多样化的后生动物模式识别受体家族。

附：英文原文

Author: Kailey M. Slavik, Benjamin R. Morehouse, Adelyn E. Ragucci, Wen Zhou, Xianlong Ai, Yuqiang Chen, Lihua Li, Ziming Wei, Heike Bhre, Martin Knig, Roland Seifert, Amy S. Y. Lee, Hua Cai, Jean-Luc Imler, Philip J. Kranzusch

Issue&Volume: 2021-07-14

Abstract: Cyclic GMP–AMP synthase (cGAS) is a cytosolic DNA sensor that produces the second messenger 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 capable of recognizing divergent molecular patterns and catalyzing synthesis of distinct nucleotide second messenger signals. Crystal structures of human and insect cGLRs reveal a nucleotidyltransferase signaling core shared with cGAS and a diversified primary ligand-binding surface modified with significant insertions and deletions. We demonstrate that cGLR surface remodeling enables altered ligand specificity and use a forward biochemical screen to identify cGLR1 as a double-stranded RNA sensor in the model organism Drosophila melanogaster. Surprisingly, 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 (STING) in complex with 3′2′-cGAMP explains selective isomer recognition and we demonstrate that 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.

DOI: 10.1038/s41586-021-03743-5

Source: https://www.nature.com/articles/s41586-021-03743-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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