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