Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

作者：Jing Pan, 宁波大学农产品质量安全危害因子与风险防控国家重点实验室, 浙江 宁波 315211, 中国, Chen-Jie Fei, Yang Hu, Xiangyu Wu, Li Nie, Jiong Chen, 宁波大学梅山校区海洋学院生物化学与分子生物学实验室, 浙江 宁波 315832, 中国, 浙江省海洋生物工程重点实验室, 浙江 宁波 315832, 中国 · 发表于：动物学研究 · 年份：2023 · DOI：10.24272/j.issn.2095-8137.2022.464 · 被引用次数：120 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Immune Response and Inflammation

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.