Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
Nat Rev Nephrol. 2022 Sep;18(9):558-572. doi: 10.1038/s41581-022-00589-6. Epub 2022 Jun 22.
Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP-AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2',3'-cyclic GMP-AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS-STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS-STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.
细胞配备有众多能够识别核酸的传感器，这些传感器可能是为了防御病毒而进化出来的。一旦被触发，这些传感器就会刺激 I 型干扰素和其他细胞因子的产生，从而激活免疫细胞并促进抗病毒状态。进化上保守的酶环鸟苷酸-腺苷酸合酶（cGAS）是最近发现的 DNA 传感器之一。在配体结合后，cGAS 二聚化并合成二核苷酸第二信使 2'，3'-环鸟苷酸-腺苷酸（cGAMP），cGAMP 与内质网蛋白干扰素基因刺激因子（STING）具有高亲和力结合，从而引发炎症反应。cGAS 结合的 DNA 不受序列限制，只需长度大于 45 个核苷酸即可；因此，cGAS 也可以被自身基因组或线粒体 DNA 所刺激。这种广泛的特异性可能解释了为什么 cGAS-STING 途径与许多自身炎症性、自身免疫性和神经退行性疾病有关；该途径也可能在急性和慢性肾损伤中被激活。使用合成的环状二核苷酸或 cGAMP 代谢抑制剂来对 cGAS-STING 途径进行治疗干预，有望增强癌症或病毒感染中的免疫反应。相比之下，cGAS 或 STING 的抑制剂可能在该促炎途径长期激活的疾病中有用。
