环 GMP-AMP 合酶 (cGAS) 是一种主要的胞质 DNA 传感器，在先天免疫中发挥着重要作用。与双链 DNA (dsDNA) 结合后，cGAS 利用 GTP 和 ATP 合成第二信使环 GMP-AMP (cGAMP)。然后，cGAMP 与内质网中的干扰素基因接头蛋白刺激物 (STING) 结合，导致转录因子干扰素调节因子 3 (IRF3) 的激活，并随后诱导 I 型干扰素。一个重要的问题是 cGAS 如何区分自身 DNA 和非自身 DNA。虽然 cGAS 不受歧视地与 DNA 的磷酸盐主链结合，但其激活受到 DNA 长度、DNA 间距离和机械灵活性等物理特征的影响。这表明 cGAS 对 DNA 的识别可能依赖于这些物理特征。在本文中，我们总结了 cGAS-STING 通路参与抗病毒防御、细胞衰老和抗肿瘤反应的最新研究进展，并重点关注基于物理特征的 DNA 识别机制。© 2024。作者，下中国科学院上海药物研究所、中国药理学会独家授权。

Cyclic GMP-AMP synthase (cGAS) is a major cytosolic DNA sensor that plays a significant role in innate immunity. Upon binding to double stranded DNA (dsDNA), cGAS utilizes GTP and ATP to synthesize the second messenger cyclic GMP-AMP (cGAMP). The cGAMP then binds to the adapter protein stimulator of interferon genes (STING) in the endoplasmic reticulum, resulting in the activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent induction of type I interferon. An important question is how cGAS distinguishes between self and non-self DNA. While cGAS binds to the phosphate backbone of DNA without discrimination, its activation is influenced by physical features such as DNA length, inter-DNA distance, and mechanical flexibility. This suggests that the recognition of DNA by cGAS may depend on these physical features. In this article we summarize the recent progress in research on cGAS-STING pathway involved in antiviral defense, cellular senescence and anti-tumor response, and focus on DNA recognition mechanisms based on the physical features.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.