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.
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