The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

Ming, Sheng-Li; Zeng, Lei; Guo, Yanzhu; Zhang, Shuang; Li, Guoli; Ma, Ying-Xian; Zhai, Yunyun; Chang, Wen-Ru; Yang, Le; Wang, Jiang; Yang, Gangyi; Chu, Bei-Bei

doi:10.3389/fimmu.2020.575818

Cited by 14 publications

(9 citation statements)

References 63 publications

(75 reference statements)

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“…Third, in response to cytosolic DNA in human myeloid cells, the CGAS-STING1 pathway instead of AIM2 activates potassium efflux-mediated NLRP3 inflammasome via lysosomal STING1-mediated lysosomal cell death 147 . Consistent with this, G10 (an agonist of STING1) induces potassium efflux and NLRP3 activation in porcine cells 148 . Conversely, the inhibition of NLRP3 inflammasomes increases STING1-dependent IFN production 148 , while the activation of NLRP3 or AIM2 in murine macrophages leads to the inactivation of the STING1 pathway 149 , 150 , suggesting a yet unknown mechanism to balance the activation of STING1 and inflammasomes in response to infection.…”

Section: Sting1 In Cell Deathsupporting

confidence: 60%

The STING1 network regulates autophagy and cell death

Zhang

Kang

Tang

2021

Sig Transduct Target Ther

132

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Cell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.

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Section: Sting1 In Cell Deathsupporting

confidence: 60%

The STING1 network regulates autophagy and cell death

Zhang

Kang

Tang

2021

Sig Transduct Target Ther

132

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“…Conversely, stimulation of the cGAS-STING pathway is a novel approach to immune activation in cancer immune-therapy. Small-molecule STING agonists have been used to activate the cGAS-STING pathway and promote antitumor immunity ( 68 – 76 ). Additional work indicates STING agonists are effective in combinatorial therapies for infection ( 77 ).…”

Section: Cgas and Sting As Therapeutic Targetsmentioning

confidence: 99%

TREX1 as a Novel Immunotherapeutic Target

et al. 2021

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Mutations in the TREX1 3’ → 5’ exonuclease are associated with a spectrum of autoimmune disease phenotypes in humans and mice. Failure to degrade DNA activates the cGAS-STING DNA-sensing pathway signaling a type-I interferon (IFN) response that ultimately drives immune system activation. TREX1 and the cGAS-STING DNA-sensing pathway have also been implicated in the tumor microenvironment, where TREX1 is proposed to degrade tumor-derived DNA that would otherwise activate cGAS-STING. If tumor-derived DNA were not degraded, the cGAS-STING pathway would be activated to promote IFN-dependent antitumor immunity. Thus, we hypothesize TREX1 exonuclease inhibition as a novel immunotherapeutic strategy. We present data demonstrating antitumor immunity in the TREX1 D18N mouse model and discuss theory surrounding the best strategy for TREX1 inhibition. Potential complications of TREX1 inhibition as a therapeutic strategy are also discussed.

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“…Studies have reported four possible models [K + efflux, lysosomal damage, reactive oxygen species (ROS) and Ca 2+ mobilization] ( 20 ) for NLRP3 inflammasome activation ( Fig. 1 ), which may not be exclusive.…”

Section: Biology Of the Nlrp3 Inflammasomementioning

confidence: 99%

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

et al. 2023

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The inflammasome regulates innate immunity by serving as a signaling platform. The Nod-like receptor protein 3 (NLRP3) inflammasome, equipped with NLRP3, the adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1, is by far the most extensively studied and well-characterized inflammasome. A variety of stimuli can activate the NLRP3 inflammasome. When activated, the NLRP3 protein recruits the adaptor ASC protein and activates pro-caspase-1, resulting in inflammatory cytokine maturation and secretion, which is associated with inflammation and pyroptosis. However, the aberrant activation of the NLRP3 inflammasome has been linked to various inflammatory diseases, including atherosclerosis, ischemic stroke, Alzheimer's disease, diabetes mellitus and inflammatory bowel disease. Therefore, the NLRP3 inflammasome has emerged as a promising therapeutic target for inflammatory diseases. In the present review, systematic searches were performed using 'NLRP3 inhibitor(s)' and 'inflammatory disease(s)' as key words. By browsing the literature from 2012 to 2022, 100 articles were retrieved, of which 35 were excluded as they were reviews, editorials, retracted or unavailable online, and 65 articles were included. According to the retrieved literature, the current understanding of NLRP3 inflammasome pathway activation in inflammatory diseases was summarize, and inhibitors of the NLRP3 inflammasome pathway targeting the NLRP3 protein and other inflammasome components or products were highlighted. Additionally, the present review briefly discusses the current novel efforts in clinical research.

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The Human-Specific STING Agonist G10 Activates Type I Interferon and the NLRP3 Inflammasome in Porcine Cells

Cited by 14 publications

References 63 publications

The STING1 network regulates autophagy and cell death

The STING1 network regulates autophagy and cell death

TREX1 as a Novel Immunotherapeutic Target

Inhibitors of the NLRP3 inflammasome pathway as promising therapeutic candidates for inflammatory diseases (Review)

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