cGAS–STING, an important signaling pathway in diseases and their therapy DOI Creative Commons
Qijie Li,

Ping Wu,

Qiujing Du

et al.

MedComm, Journal Year: 2024, Volume and Issue: 5(4)

Published: March 23, 2024

Abstract Since cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway was discovered in 2013, great progress has been made to elucidate the origin, function, and regulating mechanism cGAS–STING past decade. Meanwhile, triggering transduction mechanisms have continuously illuminated. plays a key role human diseases, particularly DNA‐triggered inflammatory making it potentially effective therapeutic target for inflammation‐related diseases. Here, we aim summarize ancient origin defense mechanism, as well triggers, transduction, cGAS–STING. We will also focus on important roles signal under pathological conditions, such infections, cancers, autoimmune neurological visceral inflammations, review drug development targeting pathway. The main directions potential obstacles research diseases cancers be discussed. These advancements expand our understanding cGAS–STING, provide theoretical basis further exploration open up new strategies promising intervention multiple

Language: Английский

Signaling pathways in obesity: mechanisms and therapeutic interventions DOI Creative Commons
Xue Wen, Bohan Zhang,

Beiyi Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Aug. 28, 2022

Abstract Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases risk of several diseases, such as type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver linked to lower life expectancy. Although lifestyle intervention (diet exercise) has remarkable effects on weight management, achieving long-term success at loss extremely challenging, prevalence continues rise worldwide. Over past decades, pathophysiology been extensively investigated, an increasing number signal transduction pathways have implicated obesity, making it possible fight more effective precise way. In this review, we summarize recent advances pathogenesis from both experimental clinical studies, focusing signaling their roles regulation food intake, glucose homeostasis, adipogenesis, thermogenesis, inflammation. We also discuss current anti-obesity drugs, well compounds trials, that target these signals. The evolving knowledge may shed light future direction research, move into new era precision medicine.

Language: Английский

Citations

247
The molecular basis for cellular function of intrinsically disordered protein regions DOI
Alex S. Holehouse, Birthe B. Kragelund

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 187 - 211

Published: Nov. 13, 2023

Language: Английский

Citations

227
SARS‐CoV‐2 ORF9b antagonizes type I and III interferons by targeting multiple components of the RIG‐I/MDA‐5–MAVS, TLR3–TRIF, and cGAS–STING signaling pathways DOI Open Access
Lulu Han,

Meng‐Wei Zhuang,

Jian Deng

et al.

Journal of Medical Virology, Journal Year: 2021, Volume and Issue: 93(9), P. 5376 - 5389

Published: April 29, 2021

Abstract The suppression of types I and III interferon (IFN) responses by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) contributes to the pathogenesis disease 2019 (COVID‐19). strategy used SARS‐CoV‐2 evade antiviral immunity needs further investigation. Here, we reported that ORF9b inhibited IFN production targeting multiple molecules innate signaling pathways. impaired induction IFNs Sendai virus poly (I:C). activation induced components cytosolic dsRNA‐sensing pathways RIG‐I/MDA5‐MAVS signaling, including RIG‐I, MDA‐5, MAVS, TBK1, IKKε, rather than IRF3‐5D, which is active form IRF3. also suppressed TRIF STING, are adaptor protein endosome RNA‐sensing pathway TLR3‐TRIF DNA‐sensing cGAS–STING respectively. A mechanistic analysis revealed interacted with TRIF, TBK1 impeded phosphorylation nuclear translocation In addition, facilitated replication vesicular stomatitis virus. Therefore, results showed negatively regulates thus facilitates viral replication. This study our understanding molecular mechanism through impairs provides an essential clue COVID‐19.

Language: Английский

Citations

209
Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy DOI Creative Commons

Juyan Zheng,

Junluan Mo,

Tao Zhu

et al.

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Aug. 27, 2020

Abstract Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator interferon genes (STING), are involved in mediating fundamental antimicrobial immunity promoting release type I interferons (IFNs) other inflammatory cytokines. Accumulating evidence suggests that activation cGAS-STING axis critical for antitumor immunity. The cytokines regulated cGAS-STING, especially IFNs, serve as bridges connecting with adaptive Accordingly, a growing number studies have focused on synthesis screening STING pathway agonists. However, chronic may lead to protumor phenotype certain malignancies. Hence, signaling must be orchestrated properly when agonists used alone or combination. In this review, we discuss dichotomous roles tumor development latest advances use

Language: Английский

Citations

207
Cellular functions of cGAS-STING signaling DOI
Chen Chen, Pinglong Xu

Trends in Cell Biology, Journal Year: 2022, Volume and Issue: 33(8), P. 630 - 648

Published: Nov. 24, 2022

Language: Английский

Citations

204
XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury DOI Creative Commons
Zheng Liu,

Mingming Wang,

Xun Wang

et al.

Redox Biology, Journal Year: 2022, Volume and Issue: 52, P. 102305 - 102305

Published: March 28, 2022

Hepatocellular cell death and macrophage proinflammatory activation contribute to the pathology of various liver diseases, during which XBP1 plays an important role. However, function mechanism in thioacetamide (TAA)-induced acute injury (ALI) remains unknown. Here, we investigated effects inhibition on promoting hepatocellular pyroptosis activate STING signaling ALI. While both TAA- LPS-induced ALI triggered hepatocytes, hepatocyte-specific knockout mice exhibited exacerbated with increased enhanced activation. Mechanistically, mtDNA released from TAA-stressed hepatocytes could be engulfed by macrophages, further inducing a cGAS- dose-dependent manner. deficiency ROS production promote activating NLRP3/caspase-1/GSDMD signaling, facilitated extracellular release mtDNA. Moreover, impaired mitophagy was found deficient reversed PINK1 overexpression. Mitophagy restoration also inhibited mice. Activation XBP1-mediated pathway were observed human livers Collectively, these findings demonstrate that promotes hepatocyte impairing mtDNA/cGAS/STING providing potential therapeutic targets for

Language: Английский

Citations

200
Type I interferon-mediated tumor immunity and its role in immunotherapy DOI Creative Commons

Renren Yu,

Bo Zhu, Degao Chen

et al.

Cellular and Molecular Life Sciences, Journal Year: 2022, Volume and Issue: 79(3)

Published: March 1, 2022

Immune checkpoint blockade (ICB) therapies have achieved remarkable clinical responses in patients with many different types of cancer; however, most who receive ICB monotherapy fail to achieve long-term responses, and some tumors become immunotherapy-resistant even hyperprogressive. Type I interferons (IFNs) been demonstrated inhibit tumor growth directly indirectly by acting upon immune cells, respectively. Furthermore, accumulating evidence indicates that endo- exogenously enhancing type IFNs a synergistic effect on anti-tumor immunity. Therefore, trials studying new treatment strategies combine IFN inducers are currently progress. Here, we review the cellular sources their roles regulation microenvironment. In addition, highlight immunotherapies based combination therapy between ICBs.

Language: Английский

Citations

190
Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy DOI
Jie Yan, Guohao Wang, Lisi Xie

et al.

Advanced Materials, Journal Year: 2021, Volume and Issue: 34(10)

Published: Dec. 29, 2021

Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization immunomodulation may overcome these obstacles for advanced radiotherapy. Here, authors propose cooperated with stimulator interferon genes (STING) pathway activation strategy fabricating novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF4 :Nd@NaLuF4 @PEG-polyphenol/Mn (DSPM). amphiphilic PEG-polyphenol successfully coordinates (radiosensitizer) Mn2+ via robust coordination. After cell internalization, pH-responsive disassembly DSPM triggers release their payloads, wherein radiosensitizer sensitizes cells to X-ray promote STING activation. This remarkably benefits dendritic maturation, anticancer therapeutics in primary tumors, accompanied immune therapeutic performance against metastatic tumors. Therefore, powerful mediated immunostimulation is highlighted here optimize

Language: Английский

Citations

181
Pharmacological activation of STING blocks SARS-CoV-2 infection DOI Creative Commons
Minghua Li, Max Ferretti,

Baoling Ying

et al.

Science Immunology, Journal Year: 2021, Volume and Issue: 6(59)

Published: May 18, 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic, resulting millions of infections and deaths with few effective interventions available. Here, we demonstrate that SARS-CoV-2 evades interferon (IFN) activation in epithelial cells, delayed response bystander cells. Since pretreatment IFNs can block viral infection, reasoned pharmacological innate immune pathways could control infection. To identify potent antiviral agonists, screened panel 75 microbial ligands activate diverse signaling identified cyclic dinucleotides (CDNs), canonical STING as antiviral. CDNs have poor bioavailability, tested the small molecule agonist diABZI, found it potently inhibits infection strains including variants concern (B.1.351) by transiently stimulating IFN signaling. Importantly, diABZI restricts replication primary human bronchial cells mice vivo. Our study provides evidence may represent promising therapeutic strategy to SARS-CoV-2.

Language: Английский

Citations

164
Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis DOI Creative Commons
Rui Ding, Haiyan Li, Yaqi Liu

et al.

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 10, 2022

Neuroinflammation-induced injury is intimately associated with poor prognosis in patients cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) axis a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as crucial mediator neuroinflammation ischemic stroke. However, the role cGAS-STING modulating post-CVST inflammation and underlying mechanisms involved remain unclear.A CVST model was induced by ferric chloride male C57BL/6J mice. selective cGAS inhibitor RU.521, STING agonist 2'3'-cGAMP, siRNA were delivered intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C dihydroethidium western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA flow cytometry.cGAS, STING, NLRP3 GSDMD significantly upregulated after mostly microglia mouse brain. triggered release dsDNA into cytoplasm elicited an inflammatory response via activating axis. RU.521 decreased levels downstream cytokines, suppressed expressions inflammasome pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- IL-1β, IL-1β/pro-IL-1β. Besides, treatment also reduced oxidative stress, lessened numbers neutrophils, ameliorated neuronal apoptosis, degeneration along neurological deficits post-CVST. 2'3'-cGAMP delivery enhanced related mediators, pyroptosis-relevant proteins, whereas these alterations abrogated silencing siRNA.Our data demonstrate that repression diminishes neuroinflammatory burden highlight this approach potential therapeutic tactic CVST-mediated pathologies.

Language: Английский

Citations

126