胞浆DNA感受器环状GMP-AMP合酶的多维调控机制

doi:10.6040/j.issn.1671-7554.0.2026.1163

摘要/Abstract

摘要： 异常定位或不适当暴露的DNA能够强烈激活固有免疫信号通路。在感染过程中,病毒、细菌等病原体的核酸物质构成关键的病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)。病理条件下,宿主自身DNA,如泄露到胞质的线粒体DNA和染色体DNA等,也能作为危险相关分子模式(damage-associated molecular patterns, DAMPs),激发强烈的炎症反应。环状GMP-AMP合酶(cyclic GMP-AMP synthase, cGAS)是细胞内DNA的关键识别受体,被激活后合成第二信使环状GMP-AMP(cyclic GMP-AMP, cGAMP),启动干扰素基因刺激因子(stimulator of interferon genes, STING)依赖的信号级联反应,诱导I型干扰素(type I interferons, IFN-I)和促炎性细胞因子等的表达,在感染性疾病、衰老、肿瘤及自身免疫病等多种病理过程中发挥重要作用。本文将从DNA特征、cGAS调控、cGAMP动态以及DNA的可及性四个维度,阐述cGAS活性的调控机制,以期为多种人类疾病相关的急性和慢性炎症开辟新的治疗思路。

关键词: 环状GMP-AMP合酶, 第二信使环状GMP-AMP, 调控机制, 固有免疫

Abstract: Aberrantly localized or inappropriately exposed DNA potently activates innate immune signaling pathways. During infection, nucleic acids from pathogens such as viruses and bacteria serve as critical pathogen-associated molecular patterns(PAMPs). Under pathological conditions, host-derived DNA, including mitochondrial DNA and chromosomal DNA, can also act as danger-associated molecular patterns(DAMPs)to elicit potent inflammatory responses. Cyclic GMP-AMP synthase(cGAS)is the primary intracellular DNA sensor. Upon activation, cGAS synthesizes the second messenger cGAMP to initiate STING-dependent signaling cascades, leading to the production of type I interferons and proinflammatory cytokines, and plays important roles in various pathological processes including infectious diseases, aging, cancer, and autoimmune diseases. This review systematically discusses the regulatory mechanisms of cGAS activation from four perspectives: DNA features, cGAS regulation, cGAMP dynamics, and DNA accessibility to cGAS, aiming to open new therapeutic avenues for acute and chronic inflammation associated with diverse human diseases.

Key words: Cyclic GMP-AMP synthase, Cyclic GMP-AMP, Regulatory mechanisms, Innate immunity

中图分类号:

R392

赵春媛,吕梦瑶,赵伟. 胞浆DNA感受器环状GMP-AMP合酶的多维调控机制[J]. 山东大学学报 (医学版), 2026, 64(10): 26-35.

ZHAO Chunyuan, LYU Mengyao, ZHAO Wei. Multifaceted regulation of the DNA sensor cyclic GMP-AMP synthase[J]. Journal of Shandong University (Health Sciences), 2026, 64(10): 26-35.

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