Cai Hua, Li Lihua, Slavik Kailey, Huang Jingxian, Yin Ting, Hédelin Léna, Xiang Zhangmin, Yang Yunyun, Li Xiaoyan, Chen Yuqiang, Wei Ziming, Deng Huimin, Chen Di, Jiao Renjie, Martins Nelson, Meignin Carine, Kranzusch Philip, Imler Jean-Luc
bioRxiv. 2023 May 9:2023.05.08.539652. doi: 10.1101/2023.05.08.539652.
In mammals, the enzyme cGAS senses the presence of cytosolic DNA and synthesizes the cyclic dinucleotide (CDN) 2'3'-cGAMP. This CDN binds to and activates the protein STING to trigger immunity. We recently discovered in the model organism two cGAS-like receptors (cGLRs) that activate STING-dependent antiviral immunity and can produce 3'2'-cGAMP, in addition to 2'3'-cGAMP. Here we explore CDN-mediated immunity in 14 different species covering 50 million years of evolution and report that 2'3'-cGAMP and 3'2'-cGAMP fail to control infection by C virus in and . Using an accurate and sensitive mass spectrometry method, we discover an unexpected diversity of CDNs produced in a cGLR-dependent manner in response to viral infection in , including a novel CDN, 2'3'-c-di-GMP. We show that 2'3'-c-di-GMP is the most potent STING agonist identified so far in and that this molecule also activates a strong antiviral transcriptional response in . Our results shed light on the evolution of cGLRs in flies and provide a basis for the understanding of the function and regulation of this emerging family of PRRs in animal innate immunity.
在哺乳动物中，cGAS酶可感知胞质DNA的存在并合成环二核苷酸（CDN）2'3'-cGAMP。这种CDN与蛋白STING结合并激活它，从而触发免疫反应。我们最近在模式生物中发现了两种类cGAS受体（cGLRs），它们可激活依赖STING的抗病毒免疫反应，并且除了能产生2'3'-cGAMP外，还能产生3'2'-cGAMP。在此，我们探究了涵盖5000万年进化历程的14个不同物种中CDN介导的免疫反应，并报告称2'3'-cGAMP和3'2'-cGAMP无法在[具体物种1]和[具体物种2]中控制C病毒感染。通过一种准确且灵敏的质谱方法，我们发现[具体物种3]在病毒感染后以cGLR依赖的方式产生了意想不到的多种CDN，包括一种新型CDN，即2'3'-c-di-GMP。我们表明，2'3'-c-di-GMP是迄今为止在[具体物种3]中鉴定出的最有效的STING激动剂，并且该分子在[具体物种3]中也能激活强烈的抗病毒转录反应。我们的研究结果揭示了果蝇中cGLRs的进化情况，并为理解这一新兴的模式识别受体家族在动物先天免疫中的功能和调控提供了基础。
