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STING activated signalling pathways. STING activation leads to translocation from ER membranes to the perinuclear vesicles where it induces the signalling of two major pathways: the NF-κB -dependent proinflammatory response and the IRF3-dependent type I interferon response. The activation of mitochondrial antiviral adaptor MAVS also results in the activation of STING and recruitment of TBK1, which upregulates the transcription of antiviral chemokines via STAT6
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The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named “STimulator of INterferon Genes (STING)”. STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and...
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The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide that activates the antiviral response through the adapter protein Stimulator of Interferon Genes (STING). cGAMP is negatively charged and cannot passively cross cell membranes, but...
In cancer immunotherapy, the cyclic GMP–AMP synthase–stimulator of interferon genes (STING) pathway is an attractive target for switching the tumor immunophenotype from ‘cold’ to ‘hot’ through the activation of the type I interferon response. To develop a new chemical entity for STING activator to improve cyclic GMP-AMP (cGAMP)-induced innate immun...
TANK-binding kinase 1 (TBK1) is a key signalling component that drives the production of type-I interferons (IFNs), which have essential antiviral activities including against SARS-CoV-2. TBK1 and its homolog IκB kinase-ε (IKKε) can also induce the production of pro-inflammatory factors that contribute to pathogen clearance. While initially protect...
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Citations
... First, upon binding to cytosolic DNA, cGAS increases the levels of 2' 3'-cGAMP and canonical cyclic dinucleotide (CDN) [18], two secondary messengers synthesized from adenosine triphosphates (ATP) and guanosine triphosphates (GTP), in turn, promotes STING activation in the endoplasmic reticulum (ER) during a lengthdependent manner. In better words, the IFN immune response in the presence of cytosolic DNA can emerge at the short lengths of DNA, containing at least 20-40 base pairs (bp), which is entirely dependent on cGAS irrespective of DNA and its broad length span, ranging from the least stimulatory length to several kilobases [19]. ...
As a major component of innate immunity and a positive regulator of interferons, the Stimulator of interferon gene (STING) has an immunotherapy potential to govern a variety of infectious diseases. Despite the recent advances regarding vaccines against COVID-19, nontoxic novel adjuvants with the potential to enhance vaccine efficacy are urgently desired. In this connection, it has been well-documented that STING agonists are applied to combat COVID-19. This approach is of major significance for boosting immune responses most likely through an autophagy-dependent manner in susceptible individuals against infection induced by severe acute respiratory syndrome Coronavirus (SARS‑CoV‑2). Given that STING agonists exert substantial immunomodulatory impacts under a wide array of pathologic conditions, these agents could be considered novel adjuvants for enhancing immunogenicity against the SARS-related coronavirus. Here, we intend to discuss the recent advances in STING agonists’ recruitment to boost innate immune responses upon vaccination against SARS-related coronavirus infections. In light of the primordial role of autophagy modulation, the potential of being an antiviral vaccine adjuvant was also explored.
... cGAS detects cytoplasmic double-stranded host DNAs [11] that are often accumulated in tumor cells and synthesizes cyclic GMP-AMP (cGAMP). Additionally, cGAMP serves as a second messenger that activates STING-IRF3/ NF-κB signaling to induce type I interferons (IFN-I) production [12], which subsequently regulates the expression of hundreds of interferon-stimulated genes (ISGs) and exerts diverse functions in an autocrine or paracrine manner via JAK-STAT signaling [13]. ...
Purpose
Recent studies revealed a pro-tumor effect of constitutive Type-1 interferons (IFN-I) production and the downstream signaling activity in several malignancies. In contrast, heterogeneity and clinical significance of the signaling activity in gliomas remain unknown. Thus, we aimed to depict the heterogeneity and clinical significance of constitutive Type-1 interferon (IFN-I) production and the downstream signaling activity in gliomas.
Methods
We utilized multiplex immunofluorescence (mIF) on a 364 gliomas tissue microarray from our cohort. Moreover, we conducted bioinformatic analyses on the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases to investigate the heterogeneity and clinical significance of constitutive IFN-I signaling activity in gliomas.
Results
We observed high heterogeneity of the constitutive IFN-I signaling activity among glioma subtypes. Signaling increased with the WHO malignancy grade while decreasing in the gliomas with IDH mutations. Additionally, high IFN-I activity served as an independent predictor of unfavorable outcomes, and global DNA hypermethylation in IDH-mutant gliomas was associated with decreased IFN-I signaling activity. Positive correlations were observed between the IFN-I activity and glioma-associated inflammation, encompassing both anti-tumor and pro-tumor immune responses. Furthermore, the IFN-I activity varied significantly among tumor and immune cells in the glioma microenvironment (GME). Notably, a distinct pattern of IFN-I signaling activity distribution in GME cells was observed among glioma subtypes, and the pattern was independently associated with patient overall survival.
Conclusions
Constitutive IFN-I signaling activity varies significantly among glioma subtypes and represents a potential indicator for increased glioma inflammation and unfavorable clinical outcomes.
... Significance testing was performed with an unpaired one-tailed t test; error bars represent standard deviations. another serine, S358, may also contribute, or even that S366 in some cases may negatively regulate STING [8,10,[116][117][118]. ...
Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress anti-tumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This finding was unexpected given previous reports that type I interferon alpha (IFN-α) inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with type I interferon beta (IFN-β) upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), a hub adaptor protein through which multiple dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has also been associated with multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This finding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells.
... Type I interferon and additional transcription outputs, like tumour necrosis factor-alpha (TNF-) and interleukin-6 (IL-6), are significantly expressed towards the end of this chain of events, amplifying the inflammatory reaction. 74 To a large extent, IFN-I production is controlled by the cGAS-STING pathway. Several inflammatory diseases, collectively called ...
... 17,18 Vice versa, gain-of-function heterozygous mutations in the human STING gene have been linked to autoinflammatory diseases such as STING-associated vasculopathy with onset in infancy (SAVI) and familial chilblain lupus. 19 For example, the mutation V155M in human STING activates STING independently of its ligand cGAMP, leading to chronic IFN release and induction of interferon-stimulating genes (ISGs). 20,21 Post-translational modification (PTM) including phosphorylation, ubiquitination, palmitoylation, and SUMOylation have been reported to play an essential role in regulating STING function. ...
Sensing of human immunodeficiency virus type 1 (HIV-1) DNA is mediated by the cyclic GMP-AMP synthasestimulator
of interferon genes (cGAS-STING) signaling axis. Signal transduction and regulation of this cascade
is achieved by post-translational modifications. Here we show that cGAS-STING-dependent HIV-1 sensing
requires interferon-stimulated gene 15 (ISG15). ISG15 deficiency inhibits STING-dependent sensing of
HIV-1 and STING agonist-induced antiviral response. Upon external stimuli, STING undergoes ISGylation at
residues K224, K236, K289, K347, K338, and K370. Inhibition of STING ISGylation at K289 suppresses
STING-mediated type I interferon induction by inhibiting its oligomerization. Of note, removal of STING
ISGylation alleviates gain-of-function phenotype in STING-associated vasculopathy with onset in infancy
(SAVI). Molecular modeling suggests that ISGylation of K289 is an important regulator of oligomerization.
Taken together, our data demonstrate that ISGylation at K289 is crucial for STING activation and represents
an important regulatory step in DNA sensing of viruses and autoimmune responses.
... STING-mediated innate immunity plays a significant role in shaping host defense against microbe invasion and tumor growth. However, aberrant activation of STING can also alter immune balance, thereby leading to pathological conditions and human diseases [21,22]. ...
The stimulator of interferon genes (STING) is a master regulator of innate immunity, involved in several inflammatory diseases. Our previous data showed that sphingosine-1-phosphate (S1P) is released during inflammatory conditions in the lung. The aim of this study was to understand the interplay between S1P and STING during both physiological and pathological conditions. The mRNA levels of ceramidase (ASAH1), S1P precursor enzyme, and STING were inversely correlated in healthy lung tissues, but positively correlated in tumor tissues. The activation of STING induced higher expression of ASAH1 and was accompanied by IFN-β and IL-6 release. ASAH1 and sphingosine kinases (SPHK I/II) blockade significantly reduced IL-6, but not IFNβ, after STING activation. In support of this, taking advantage of a mouse model, we found that inflamed lungs had higher levels of inactive ASAH1 when STING was inhibited. This confirmed the human data, where higher levels of STING promoted the activation of ASAH1. Lung cancer patients positive to STING and ASAH1 mRNA levels had a dismal prognosis in that the overall survival was reduced compared to STING/ASAH1 negative patients. These data highlight that during physiological conditions, STING and the S1P axis do not interfere, whereas in lung cancer patients their interplay is associated to poor prognosis.
... As a multiple-domain protein, STING contains four N-terminal transmembrane helices (residues 1 to 136), one cyclic di-GMP binding domain (CBD; residues 151 to 339), and one C-terminal tail (CTT; residues 340 to 379). The CTT contains binding sites for TBK1 and IRF3 (42). Domain mapping analysis for STING revealed that the construct containing the CBD and CTT domains (residues 151 to 379) was mainly responsible for the binding with SARS-CoV-2 PLpro (Fig. 2F). ...
The SARS-CoV-2 papain-like protease (PLpro), which has deubiquitinating activity, suppresses the type I interferon (IFN-I) antiviral response. We investigated the mechanism by which PLpro antagonizes cellular antiviral responses. In HEK392T cells, PLpro removed K63-linked polyubiquitin chains from Lys289 of the stimulator of interferon genes (STING). PLpro-mediated deubiquitination of STING disrupted the STING-IKKε-IRF3 complex that induces the production of IFN-β and IFN-stimulated cytokines and chemokines. In human airway cells infected with SARS-CoV-2, the combined treatment with the STING agonist diABZi and the PLpro inhibitor GRL0617 resulted in the synergistic inhibition of SARS-CoV-2 replication and increased IFN-I responses. The PLpros of seven human coronaviruses (SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) and four SARS-CoV-2 variants of concern (α, β, γ, and δ) all bound to STING and suppressed STING-stimulated IFN-I responses in HEK293T cells. These findings reveal how SARS-CoV-2 PLpro inhibits IFN-I signaling through STING deubiquitination and a general mechanism used by seven human coronaviral PLpros to dysregulate STING and to facilitate viral innate immune evasion. We also identified simultaneous pharmacological STING activation and PLpro inhibition as a potentially effective strategy for antiviral therapy against SARS-CoV-2.
... Notably, activation of the cGAS-STING pathway is linked to SLE (49,50). For example, an activating mutation in STING causes lupus-like manifestations (51). ...
... For example, an activating mutation in STING causes lupus-like manifestations (51). To date, the connection between cGAS-STING activation in SLE has only been noted in the context of nuclear DNA present in the cytosol (50,52). Meanwhile, inhibition of VDAC-mediated cytosolic mtDNA release was beneficial in a mouse model of SLE (16), suggesting a role for cytosolic mtDNA in promoting SLE. ...
The recognition that cytosolic mtDNA activates cGAS-STING innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect TOP1MT function, P193L, was discovered in a family with multiple early-onset autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Although there was no previous genetic association between TOP1MT and autoimmune disease, the role of TOP1MT as a regulator of mtDNA led us to investigate whether TOP1MT could mediate the release of mtDNA to the cytosol, where it could then activate the cGAS-STING innate immune pathway known to be activated in SLE and other autoimmune diseases. Through analysis of cells with reduced TOP1MT expression, we show that loss of TOP1MT results in release of mtDNA to the cytosol, which activates the cGAS-STING pathway. We also characterized the P193L variant for its ability to rescue several TOP1MT functions when expressed in TOP1MT knockout cells. We show that the P193L variant is not fully functional, as its re-expression at high levels was unable to rescue mitochondrial respiration deficits, and only showed partial rescue for other functions, including repletion of mtDNA replication following depletion, nucleoid size, steady state mtDNA transcripts levels, and mitochondrial morphology. Additionally, expression of P193L at endogenous levels was unable to rescue mtDNA release-mediated cGAS-STING signaling. Overall, we report a link between TOP1MT and mtDNA release leading to cGAS-STING activation. Moreover, we show that the P193L variant has partial loss of function that may contribute to autoimmune disease susceptibility via cGAS-STING mediated activation of the innate immune system.
... The myenteric plexus produced IFNβ in response to both c-di-GMP and AdVCA (p < 0.01;Figure 4A) indicating that ENS STING can be canonically activated by bacterial c-di-GMP. However, there are a variety of other STING ligands including the microbial-produced CDN 3,3-cGAMP, the host-produced CDN 2,3-cGAMP, and the murine pharmacologic agonist DMXAA.22,24,25,50,51 Differential responses to these ligands by the ENS may suggest specified function of ENS ...
Background
Appropriate host–microbe interactions are essential for enteric glial development and subsequent gastrointestinal function, but the potential mechanisms of microbe–glial communication are unclear. Here, we tested the hypothesis that enteric glia express the pattern recognition receptor stimulator of interferon genes (STING) and communicate with the microbiome through this pathway to modulate gastrointestinal inflammation.
Methods
In situ transcriptional labeling and immunohistochemistry were used to examine STING and IFNβ expression in enteric neurons and glia. Glial‐STING KO mice (Sox10CreERT2+/−;STINGfl/fl) and IFNβ ELISA were used to characterize the role of enteric glia in canonical STING activation. The role of glial STING in gastrointestinal inflammation was assessed in the 3% DSS colitis model.
Results
Enteric glia and neurons express STING, but only enteric neurons express IFNβ. While both the myenteric and submucosal plexuses produce IFNβ with STING activation, enteric glial STING plays a minor role in its production and seems more involved in autophagy processes. Furthermore, deleting enteric glial STING does not affect weight loss, colitis severity, or neuronal cell proportions in the DSS colitis model.
Conclusion
Taken together, our data support canonical roles for STING and IFNβ signaling in the enteric nervous system through enteric neurons but that enteric glia do not use these same mechanisms. We propose that enteric glial STING may utilize alternative signaling mechanisms and/or is only active in particular disease conditions. Regardless, this study provides the first glimpse of STING signaling in the enteric nervous system and highlights a potential avenue of neuroglial‐microbial communication.
... 4 STING protein has four transmembrane domains, a CDN binding domain, and interaction sites for TBK1 and IRF3 (interferon regulatory factor 3) at the tail. 5 STING-associated vasculopathy with onset in infancy (SAVI) is a rare autoinflammatory disease with autosomal dominant inheritance, caused by gain-of-function mutations in the human TMEM173 gene, which is located at the chromosome 5q31.2 encoding a STING protein, 6,7 and is identified in infants who suffer from severe and chronic vasculopathy, cutaneous vasculitis, systemic inflammation, and interstitial lung disease. ...
... We evaluated 10 individuals in the family (II:1,2,3,5; III: 3,5,7,8,9,10). Clinical exome sequencing was performed for the proband and her three children at the first step. ...
Objectives: This study aimed to reveal the genetic background of patients in the two-generation family suffering from rheumatoid arthritis, psoriatic arthropathy pain, scratches, and bruises.
Patients and methods: A clinical exome sequencing analysis was performed in 10 individuals in the same family using the Sophia Genetics clinical exome solution kit.
Results: A novel V194L mutation in the TMEM173 gene was identified in three members of the family. Two of the family members were treated with the JAK3 inhibitor tofacitinib and recovered completely one month after the treatment.
Conclusion: The V194L mutation was reported for the first time in this study, and a positive response was achieved with tofacitinib.
