Review

环磷酸鸟苷-腺苷酸合酶识别DNA的物理特性

Cyclic GMP-AMP synthase recognizes the physical features of DNA

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ACTA PHARMACOLOGICA SINICA

影响因子:8.4

分区:医学2区 / 药学1区化学：综合2区

发表日期:2025 Feb

作者: Ling Dong, Yue-Ru Hou, Na Xu, Xiao-Qian Gao, Zhen Sun, Qing-Kai Yang, Li-Na Wang

DOI: 10.1038/s41401-024-01369-7

摘要

环磷酸鸟苷-腺苷酸合酶（cGAS）是细胞质DNA的主要感应蛋白，在先天免疫反应中发挥重要作用。cGAS与双链DNA（dsDNA）结合后，利用GTP和ATP合成第二信使环磷酸鸟苷-腺苷酸（cGAMP）。cGAMP随后结合到内质网中的干扰素基因刺激蛋白（STING），激活转录因子干扰素调节因子3（IRF3），引发Ⅰ型干扰素的产生。一个关键问题是cGAS如何区分自我与非我DNA。虽然cGAS可无差别地与DNA的磷酸骨架结合，但其激活受到DNA长度、DNA间距以及机械柔韧性等物理特性的影响。这表明，cGAS对DNA的识别可能依赖于这些物理特性。本文总结了近年来关于cGAS-STING途径在抗病毒防御、细胞衰老及抗肿瘤反应中的研究进展，重点介绍了基于DNA物理特性的识别机制。

Abstract

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.