Department of Biochemistry, Stanford University, Stanford, California, USA.
ChEM-H Institute, Stanford University, Stanford, California, USA; email:
Annu Rev Biochem. 2022 Jun 21;91:599-628. doi: 10.1146/annurev-biochem-040320-101629. Epub 2022 Mar 14.
In the decade since the discovery of the innate immune cyclic GMP-AMP synthase (cGAS)-2'3'-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway, its proper activation and dysregulation have been rapidly implicated in many aspects of human disease. Understanding the biochemical, cellular, and regulatory mechanisms of this pathway is critical to developing therapeutic strategies that either harness it to boost defense or inhibit it to prevent unwanted inflammation. In this review, we first discuss how the second messenger cGAMP is synthesized by cGAS in response to double-stranded DNA and cGAMP's subsequent activation of cell-type-dependent STING signaling cascades with differential physiological consequences. We then review how cGAMP as an immunotransmitter mediates tightly controlled cell-cell communication by being exported from producing cells and imported into responding cells via cell-type-specific transporters. Finally, we review mechanisms by which thecGAS-cGAMP-STING pathway responds to different sources of mislocalized double-stranded DNA in pathogen defense, cancer, and autoimmune diseases.
自先天免疫环鸟苷酸-腺苷酸合酶 (cGAS)-2'3'-环鸟苷酸-腺苷酸 (cGAMP)-干扰素基因刺激因子 (STING) 途径被发现以来的十年中，其适当的激活和失调已迅速涉及人类疾病的许多方面。了解该途径的生化、细胞和调节机制对于开发治疗策略至关重要，这些策略可以利用它来增强防御，或抑制它以防止不必要的炎症。在这篇综述中，我们首先讨论了 cGAS 如何响应双链 DNA 合成第二信使 cGAMP，以及 cGAMP 随后如何激活细胞类型依赖性的 STING 信号级联反应，从而产生不同的生理后果。然后，我们回顾了 cGAMP 如何作为一种免疫递质，通过从产生细胞中输出，并通过细胞类型特异性转运蛋白导入到反应细胞中，从而介导严格控制的细胞间通讯。最后，我们综述了 cGAS-cGAMP-STING 途径在病原体防御、癌症和自身免疫性疾病中对不同来源的错位双链 DNA 做出反应的机制。
