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

Pan, Jing; Fei, Chen-Jie; Hu, Yang; Wu, Xiangyu; Nie, Li; Chen, Jiong

doi:10.24272/j.issn.2095-8137.2022.464

Cited by 35 publications

(12 citation statements)

References 351 publications

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“…After the second messenger cGAMP transmits the signal to STING, STING oligomerizes and then translocate from the endoplasmic reticulum to the Golgi. Activated STING allows activated IRF3 to form dimers and then translocate to the nucleus, and also activates the NF‐κB signalling pathway, which allows P65 to undergo nucleation [33]. To further validate our conclusions, in BMDMs, we examined the effect of EF on P65 nucleation under DMXAA stimulation using immunofluorescent antibody technique, and the results showed that EF indeed attenuated P65 nucleation (Figure 3a, c).…”

Section: Resultsmentioning

confidence: 67%

Flavonoid extracted from Epimedium attenuate cGAS‐STING‐mediated diseases by targeting the formation of functional STING signalosome

Wang,

Xu,

Wen

et al. 2024

Immunology

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Hyperactivation of the cyclic‐GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS‐STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti‐inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow‐derived macrophages (BMDMs), THP‐1 (Tohoku Hospital Pediatrics‐1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS‐STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN‐β, CXCL10 and ISG15) and pro‐inflammatory cytokines (IL‐6 and TNF‐α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK‐binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS‐STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non‐alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS‐STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS‐STING signalling pathway.

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Section: Resultsmentioning

confidence: 67%

Flavonoid extracted from Epimedium attenuate cGAS‐STING‐mediated diseases by targeting the formation of functional STING signalosome

Wang,

Xu,

Wen

et al. 2024

Immunology

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“…As aforementioned, the NF2m leading to the condensate formation abrogates the TBK1–IRF3 signaling, which contributes to cancer immune evasion. On the other hand, autoimmune diseases related to self-DNA recognition rely on the cGAS–STING-IRF3 pathway to induce type I interferon production [ 101 , 102 ]. Therefore, it is conceivable to apply the molecules targeting the phase separation to treat autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Phase Separation: The Robust Modulator of Innate Antiviral Signaling and SARS-CoV-2 Infection

Zheng

Gao

2023

Pathogens

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SARS-CoV-2 has been a pandemic threat to human health and the worldwide economy, but efficient treatments are still lacking. Type I and III interferons are essential for controlling viral infection, indicating that antiviral innate immune signaling is critical for defense against viral infection. Phase separation, one of the basic molecular processes, governs multiple cellular activities, such as cancer progression, microbial infection, and signaling transduction. Notably, recent studies suggest that phase separation regulates antiviral signaling such as the RLR and cGAS–STING pathways. Moreover, proper phase separation of viral proteins is essential for viral replication and pathogenesis. These observations indicate that phase separation is a critical checkpoint for virus and host interaction. In this study, we summarize the recent advances concerning the regulation of antiviral innate immune signaling and SARS-CoV-2 infection by phase separation. Our review highlights the emerging notion that phase separation is the robust modulator of innate antiviral signaling and viral infection.

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“…However, DNA at high temperatures faces disrupted structure and function, leading to DNA damage, including DNA double-strand breaks and base damage [ 15 ]. The aberrant presence of double-stranded DNA in the cytoplasm could be detected by cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the release of an intrinsic immune response via the binding of cGAMP to a stimulator of interferon gene (STING) dimers on the endoplasmic reticulum [ 16 , 17 , 18 ]. These responses help to maintain intracellular homeostasis and promote DNA repair, senescence, and the clearance of damaged cells [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Early Pulmonary Fibrosis-like Changes in the Setting of Heat Exposure: DNA Damage and Cell Senescence

Hou,

Zhang,

Wang

et al. 2024

IJMS

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It is well known that extreme heat events happen frequently due to climate change. However, studies examining the direct health impacts of increased temperature and heat waves are lacking. Previous reports revealed that heatstroke induced acute lung injury and pulmonary dysfunction. This study aimed to investigate whether heat exposure induced lung fibrosis and to explore the underlying mechanisms. Male C57BL/6 mice were exposed to an ambient temperature of 39.5 ± 0.5 °C until their core temperature reached the maximum or heat exhaustion state. Lung fibrosis was observed in the lungs of heat-exposed mice, with extensive collagen deposition and the elevated expression of fibrosis molecules, including transforming growth factor-β1 (TGF-β1) and Fibronectin (Fn1) (p < 0.05). Moreover, epithelial–mesenchymal transition (EMT) occurred in response to heat exposure, evidenced by E-cadherin, an epithelial marker, which was downregulated, whereas markers of EMT, such as connective tissue growth factor (CTGF) and the zinc finger transcriptional repressor protein Slug, were upregulated in the heat-exposed lung tissues of mice (p < 0.05). Subsequently, cell senescence examination revealed that the levels of both senescence-associated β-galactosidase (SA-β-gal) staining and the cell cycle protein kinase inhibitor p21 were significantly elevated (p < 0.05). Mechanistically, the cGAS–STING signaling pathway evoked by DNA damage was activated in response to heat exposure (p < 0.05). In summary, we reported a new finding that heat exposure contributed to the development of early pulmonary fibrosis-like changes through the DNA damage-activated cGAS–STING pathway followed by cellular senescence.

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

Cited by 35 publications

References 351 publications

Flavonoid extracted from Epimedium attenuate cGAS‐STING‐mediated diseases by targeting the formation of functional STING signalosome

Flavonoid extracted from Epimedium attenuate cGAS‐STING‐mediated diseases by targeting the formation of functional STING signalosome

Phase Separation: The Robust Modulator of Innate Antiviral Signaling and SARS-CoV-2 Infection

Early Pulmonary Fibrosis-like Changes in the Setting of Heat Exposure: DNA Damage and Cell Senescence

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