Recent progress on the activation of the cGAS–STING pathway and its regulation by biomolecular condensation

Abstract

The cGAS-STING pathway, comprising the DNA sensor cyclic GMP-AMP synthetase (cGAS), the second messenger cyclic GMP-AMP (cGAMP), and the endoplasmic reticulum (ER) adaptor protein stimulator of interferon genes (STING), detects cytoplasmic double-stranded DNA (dsDNA) to trigger type I-interferon responses for host defense against pathogens. Previous studies defined a model for the allosteric activation of cGAS by DNA-binding, but recent work reveals other layers of mechanisms to regulate cGAS activation such as the phase condensation and metal ions, especially the discovery of Mn2+ as a cGAS activator. Activation of the 2’3’-cGAMP sensor STING requires translocating from ER to the Golgi apparatus. The sulfated glycosaminoglycans (sGAGs) at the Golgi are found to be the second STING ligands promoting STING oligomerization and activation in addition to 2’3’-cGAMP, while surpassed levels of 2’3’-cGAMP induce ER-located STING to form a highly organized ER membranous condensate named STING phase-separator to restrain STING activation. Here, we summarize recent advances in the regulation of cGAS-STING activation and their implications in physiological or pathological conditions, particularly focusing on the emerging complexity of the regulation.

Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy

“…Mn 2+ improves the sensitivity of cGAS to intracellular DNA and its catalytic activity, which can promote cGAS to generate cGAMP under the stimulation of low concentration of DNA [49]. In addition, Mn 2+ activated cGAS undergoes a similar conformational change to DNA-activated cGAS, but forms a unique helix to expand the catalytic pocket, allowing substrate entry and cGAMP synthesis [50,51]. Furthermore, Mn 2+ promotes the dimerization of c-di-GMP and 3' 3'-cGAMP, increasing enhanced cGAMP-STING a nity [52].…”

The multi-functional roles of the cGAS–STING signaling pathway in health and diseases

“…Various regulatory mechanisms operating at different levels in the innate immunity are used to control the expression and activities of STING and cGAS. As summarized by Yu et al. (2022) in this collection, STING is activated by binding not only to cGAMP but also to other cyclic dinucleotides from invaded bacteria, which triggers a conformational change and translocation of the protein from the ER to the Golgi apparatus to induce type I IFN response.…”

“…(2022) in this collection, STING is activated by binding not only to cGAMP but also to other cyclic dinucleotides from invaded bacteria, which triggers a conformational change and translocation of the protein from the ER to the Golgi apparatus to induce type I IFN response. At the Golgi, the activity of STING is also promoted by other ligands, such as the sulfated glycosaminoglycans, but suppressed by high cGAMP level-induced ER membranous condensation ( Yu et al., 2022 ). Similar to STING, the activity of cGAS is also regulated at multiple levels.…”

“…Similar to STING, the activity of cGAS is also regulated at multiple levels. cGAS is activated by binding not only to DNA but also to RNA and metal ions such as Mn 2+ and Zn 2+ ( Yu et al., 2022 ). The activity of cGAS is also regulated by its distinct cellular localization such as at the plasma membrane ( Barnett et al., 2019 ) or in the nucleus ( Bai and Liu, 2022 ).…”

“…The activity of cGAS is also regulated by its distinct cellular localization such as at the plasma membrane ( Barnett et al., 2019 ) or in the nucleus ( Bai and Liu, 2022 ). Other mechanisms regulating cGAS–STING signaling include chromatin tethering, caspase interaction, phosphorylation, and phase separation, which are comprehensively evaluated by several reviews in this collection ( Xiong et al., 2021 ; Zhong and Shu, 2021 ; Yu et al., 2022 ).…”