State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang 315211, China.
Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Meishan Campus, Ningbo University, Ningbo, Zhejiang 315832, China.
Zool Res. 2023 Jan 18;44(1):183-218. doi: 10.24272/j.issn.2095-8137.2022.464.
The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.
先天免疫系统通过多种方式保护宿主免受外部病原体和内部损伤。由环鸟苷酸-腺苷酸合酶 (cGAS)、干扰素基因刺激物 (STING) 和下游信号适配器组成的 cGAS-STING 信号通路在防御微生物 DNA 和内部损伤相关 DNA 的保护性免疫防御中发挥着重要作用，并且与各种免疫相关疾病有关。cGAS 在与 DNA 结合后，经历构象变化和 DNA 连接的液-液相分离，产生 2'3'-cGAMP，用于激活内质网 (ER) 定位的 STING。然而，进一步的研究表明，cGAS 主要表达在核内，并严格锚定在染色质上，以防止与核 DNA 结合，其功能与胞质定位的 cGAS 不同。详细描绘该途径，包括其结构、信号和调节机制，对于充分理解 cGAS-STING 激活和信号的多样性具有重要意义，并将有益于炎症性疾病和癌症的治疗。在这里，我们综述了 cGAS-STING 信号通路上述方面的最新进展，并讨论了进一步研究的新途径。
