Departments of Immunology and Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
Departments of Immunology and Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA.
Immunity. 2024 Apr 9;57(4):718-730. doi: 10.1016/j.immuni.2024.02.019.
The cGAS-STING intracellular DNA-sensing pathway has emerged as a key element of innate antiviral immunity and a promising therapeutic target. The existence of an innate immune sensor that can be activated by any double-stranded DNA (dsDNA) of any origin raises fundamental questions about how cGAS is regulated and how it responds to "foreign" DNA while maintaining tolerance to ubiquitous self-DNA. In this review, we summarize recent evidence implicating important roles for cGAS in the detection of foreign and self-DNA. We describe two recent and surprising insights into cGAS-STING biology: that cGAS is tightly tethered to the nucleosome and that the cGAMP product of cGAS is an immunotransmitter acting at a distance to control innate immunity. We consider how these advances influence our understanding of the emerging roles of cGAS in the DNA damage response (DDR), senescence, aging, and cancer biology. Finally, we describe emerging approaches to harness cGAS-STING biology for therapeutic benefit.
cGAS-STING 细胞内 DNA 感应途径已成为先天抗病毒免疫的关键因素和有前途的治疗靶点。存在一种先天免疫传感器，可被任何来源的双链 DNA(dsDNA)激活，这就提出了一些基本问题，即 cGAS 如何受到调控，以及它如何在对无处不在的自身 DNA 保持耐受的同时，对“外来” DNA 做出反应。在这篇综述中，我们总结了最近的证据，这些证据表明 cGAS 在检测外来和自身 DNA 方面具有重要作用。我们描述了 cGAS-STING 生物学的两个最近和令人惊讶的见解：cGAS 与核小体紧密结合，并且 cGAS 的 cGAMP 产物是一种免疫递质，可远距离作用以控制先天免疫。我们考虑这些进展如何影响我们对 cGAS 在 DNA 损伤反应 (DDR)、衰老、老化和癌症生物学中新兴作用的理解。最后，我们描述了利用 cGAS-STING 生物学带来治疗益处的新兴方法。
