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.

中文翻译：

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cGAS-STING信号传导的分子机制和细胞功能。

cGAS-STING信号转导轴由第二信使环GMP-AMP（cGAS）的合酶和干扰素基因的环GMP-AMP受体刺激物（STING）组成，可检测致病性DNA以触发涉及强I型的先天性免疫反应干扰素对微生物感染的反应。然而，值得注意的是，除了感测微生物DNA之外，DNA传感器cGAS还可以被内源性DNA激活，包括遗传毒性应激导致的核外染色质和线粒体释放的DNA，将cGAS-STING定位为自身免疫，无菌炎症反应和细胞衰老的重要轴心。 。最初的模型假定cGAS和DNA在细胞质中的共定位可定义非自我途径的特异性，但最近的研究表明cGAS也存在于细胞核和质膜中，并且这种亚细胞区室化与cGAS的信号传导特异性有关。进一步混淆了cGAS-STING信号传导作为对传染原的响应机制的简单观点，cGAS和STING均具有独立于干扰素响应的其他功能。这些涉及cGAS在通过STING调节NF-κB和MAPK调节DNA修复和信号转导以及STING介导的自噬和溶酶体依赖性细胞死亡的诱导中的非催化作用。我们还了解到，cGAS二聚体可以多聚并进行液-液相分离，形成生物分子缩合物，可以重要地调节cGAS活化。在这里，我们回顾了cGAS-STING激活和信号传导的分子机制和细胞功能，