Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany.
Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.
Nat Rev Mol Cell Biol. 2020 Sep;21(9):501-521. doi: 10.1038/s41580-020-0244-x. Epub 2020 May 18.
The cGAS-STING signalling axis, comprising the synthase for the second messenger cyclic GMP-AMP (cGAS) and the cyclic GMP-AMP receptor stimulator of interferon genes (STING), detects pathogenic DNA to trigger an innate immune reaction involving a strong type I interferon response against microbial infections. Notably however, besides sensing microbial DNA, the DNA sensor cGAS can also be activated by endogenous DNA, including extranuclear chromatin resulting from genotoxic stress and DNA released from mitochondria, placing cGAS-STING as an important axis in autoimmunity, sterile inflammatory responses and cellular senescence. Initial models assumed that co-localization of cGAS and DNA in the cytosol defines the specificity of the pathway for non-self, but recent work revealed that cGAS is also present in the nucleus and at the plasma membrane, and such subcellular compartmentalization was linked to signalling specificity of cGAS. Further confounding the simple view of cGAS-STING signalling as a response mechanism to infectious agents, both cGAS and STING were shown to have additional functions, independent of interferon response. These involve non-catalytic roles of cGAS in regulating DNA repair and signalling via STING to NF-κB and MAPK as well as STING-mediated induction of autophagy and lysosome-dependent cell death. We have also learnt that cGAS dimers can multimerize and undergo liquid-liquid phase separation to form biomolecular condensates that could importantly regulate cGAS activation. Here, we review the molecular mechanisms and cellular functions underlying cGAS-STING activation and signalling, particularly highlighting the newly emerging diversity of this signalling pathway and discussing how the specificity towards normal, damage-induced and infection-associated DNA could be achieved.
cGAS-STING 信号通路由第二信使环鸟苷酸-腺苷酸（cGAMP）合成酶和干扰素基因刺激物（STING）组成，可检测致病 DNA，从而引发涉及微生物感染的强烈 I 型干扰素反应的先天免疫反应。然而值得注意的是，除了检测微生物 DNA 外，DNA 传感器 cGAS 还可以被内源性 DNA 激活，包括来自基因毒性应激的核外染色质和来自线粒体的 DNA，使 cGAS-STING 成为自身免疫、无菌性炎症反应和细胞衰老的重要轴。最初的模型假设 cGAS 和 DNA 在细胞质中的共定位定义了该途径对非自身的特异性，但最近的工作表明 cGAS 也存在于细胞核和质膜中，这种亚细胞区室化与 cGAS 的信号特异性有关。进一步使 cGAS-STING 信号作为对感染因子的反应机制的简单观点复杂化的是，cGAS 和 STING 都被证明具有独立于干扰素反应的其他功能。这些功能包括 cGAS 在通过 STING 调节 DNA 修复和信号转导至 NF-κB 和 MAPK 以及 STING 介导的自噬和溶酶体依赖性细胞死亡中的非催化作用。我们还了解到，cGAS 二聚体可以多聚化并发生液-液相分离，形成生物分子凝聚物，这可能重要地调节 cGAS 激活。在这里，我们综述了 cGAS-STING 激活和信号转导的分子机制和细胞功能，特别强调了该信号通路新出现的多样性，并讨论了如何实现对正常、损伤诱导和感染相关 DNA 的特异性。
