Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a major responder to the pathogenic DNA of viruses and bacteria. Upon DNA binding, cGAS becomes enzymatically active to generate the second messenger cGAMP, leading to activation of inflammatory genes, type I interferon production, autophagy, and cell death. Following genotoxic stress, cGAS can also respond to endogenous DNA, deriving from mitochondria, endogenous retroelements, and chromosomes to affect cellular signaling, secretion, and cell fate decisions. However, under unperturbed conditions, signaling from self-DNA is largely, but not completely, inhibited. Here we review how endogenous DNA is exposed to cGAS, how signaling is attenuated but activated under pathological conditions, and how low-level signaling under unperturbed conditions might prime antipathogenic responses.

环 GMP-AMP (cGAMP) 合酶 (cGAS) 是病毒和细菌致病性 DNA 的主要反应物。DNA 结合后，cGAS 变得具有酶活性以产生第二信使 cGAMP，导致炎症基因激活、I 型干扰素产生、自噬和细胞死亡。在基因毒性应激之后，cGAS 还可以对源自线粒体、内源性逆转录元件和染色体的内源性 DNA 做出反应，以影响细胞信号、分泌和细胞命运决定。然而，在不受干扰的条件下，来自自身 DNA 的信号在很大程度上（但不是完全）被抑制。在这里，我们回顾了内源性 DNA 如何暴露于 cGAS，信号如何在病理条件下减弱但被激活，以及在未受干扰的条件下低水平信号如何可能引发抗病原反应。