Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France.
Université Paris-Saclay, INRAE, IERP UE0907, Jouy-en-Josas, France.
Front Immunol. 2021 Feb 23;12:637399. doi: 10.3389/fimmu.2021.637399. eCollection 2021.
Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.
先天免疫途径是细胞抵御从细菌到后生动物等病原体感染的第一道防线。这些途径在识别病原体相关分子模式（PAMPs）后被膜和胞质模式识别受体激活。此外，其中一些细胞传感器还可以识别来自受损或死亡细胞的内源性危险相关分子模式（DAMPs），从而触发先天免疫反应。在胞质核酸传感器中，环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）在 I 型干扰素（IFNs）反应的激活和促炎细胞因子的产生中起着至关重要的作用。事实上，cGAS 在结合核酸后合成 cGAMP，这是一种介导 STING 信号通路激活的第二信使。cGAS-STING 途径在进化过程中的功能保守突出了其在宿主细胞对病原体感染的监测中的重要性。除了它们在免疫中的功能外，cGAS 和 STING 还在核功能和肿瘤发展中发挥主要作用。因此，cGAS-STING 现在被认为是一个有吸引力的靶点，可以识别新的生物标志物，并设计针对自身炎症和自身免疫性疾病以及传染病和癌症的治疗方法。在这里，我们回顾了关于 cGAS 结构和从细菌到后生动物的进化的现有知识，并介绍了其在防御病原体和癌症方面的主要功能，以及与 STING 的联系。将讨论与物种特异性相关的研究 cGAS-STING 途径的相关模型的优缺点，并在将其整合到针对 cGAG 和/或 STING 的治疗筛选测定中时讨论其优缺点。
