The cGAS-STING signaling pathway was needed for IFN-β production induced by LGG in dendritic cells (DCs) (Table 2). The capacity of cGAS to initiate STING activation by eCDNs prompted us to investigate whether cGAS directly senses endocytosed eCDNs. Additionally, tumor cells and MDSCs may impede STING signaling by upregulating Gal9 or via other . Thus, the STING-independent function of cGAS in suppressing genomic instability contributes to cell viability after radiation and chemotherapy, and it may be . 1), study has revealed that cGAS interacted with Beclin-1 to trigger autophagy, which would reduce cGAMP production independent of STING activation [].Similarly, activation of STING could be achieved in a cGAS-independent manner. It has been detected that the activation of cGAS-STING is usually impaired in multiple cancers by epigenetic hypermethylation [46]. The cGAS-STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. STING signalling contributes to the pathology in Niemann-Pick disease type C independent of cGAS- and cGAMP Summary: Scientists at the University of Texas Southwestern Medical Center in Dallas, Texas, uncovered a cGAS- and cGAMP-independent mode of STING activation as the driver of Niemann-Pick disease type C (NPC1). cGAS/STING: novel perspectives of the classic pathway This is potentially . Activated STING translocates from the ER to the Golgi apparatus, where STING recruits and activates the kinase TBK1 that mediates the phosphorylation of IRF3 and NF-κB. (2020) support a cGAS-independent mechanism of STING activation by PERK in neurons during TBI. cGAS-STING pathway in DC In tumor microenvironment, cGAS-STING in DC plays an important role in the cross-presentation and priming of tumor-specific CD8+ Tcell(Fig.2). During intracellular bacterial infections, activation of STING can be accomplished via two different mechanisms. . Control of innate immunity by the cGAS-STING pathway Non-canonical Activation of the DNA Sensing Adaptor STING by ATM and ... cGAS‐STING pathway activator enhances the inhibitory effect of irradiation on NSCLC cells According to a previous study, 8 the small molecule diABZI was able to activate the cGAS‐STING pathway. Upon DNA binding, cGAS produces the second messenger cGAMP (cyclic guanosine monophosphate adenosine monophosphate), which activates the adaptor protein STING (STimulator of INterferon Genes, also known as transmembrane protein 173, TMEM173). cGAS-independent STING activation in response to DNA damage. - Abstract ... The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer However, it is not clear how STING is activated in this setting. It has been detected that the activation of cGAS-STING is usually impaired in multiple cancers by epigenetic hypermethylation [46]. In- N.Y., J.G., and Z.C. cGas is a nucleotidyl transferase enzyme which catalyzes the conversion of ATP and GTP into a novel cyclic dinucleotide, cGMP-AMP (cGAMP) which in turn binds and activates Sting. ture of canonical STING activation, sev-eral findings by Sen et al. or reset password. The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory ... KSHV primary infection can activate a STING-cGAS-dependent IFN-β response. DDX41 is required for cGAS-STING activation against DNA virus infection ... ISG induction upon fractionated irradiation occurs independent of STING, IFN-β or IFN-λ. AbstractThe recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. Although the function of cGAS-STING in protozoan infection has been characterized, little is known about the activation of this pathway in helminth infection. The activation of DNA-PK by free DNA ends leads to STING-independent IRF3 phosphorylation and type I IFN production . Brucella abortus triggers a cGAS-independent STING pathway to induce ... The activation of cGAS or STING within T and B lymphocytes can slow down proliferation or trigger apoptosis (30, 35, 36). A cGAS-independent role of STING has been observed during RNA virus infection. 114, 115 Interestingly, the activation of cGAS-STING signaling pathway can also be observed in other Intervention of cGAS‒STING signaling in sterile inflammatory diseases ... In this light, it is worth noting that many RNA . Noncanonical STING signaling in response to etoposide-induced DNA damage could be activated by DNA-repair . Recently, evidence has shown that self-DNA release and cGAS-STING pathway over-activation can drive lung disease, making this pathway a promising therapeutic target for inflammatory lung disease. Hansen AL, Jensen SK, Sun C, Thomsen MK et al (2016) Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses. cGAS facilitates sensing of extracellular cyclic ... - EMBO Press Considering that radiation-induced DNA damage needs cells mitotic progression for up to 24-72 h to accumulate into cytosol [], we hypothesized that synchronizing delivery of Mn 2+ into tumor with RT-induced accumulation of DNA damage by sustained-release of Mn 2+ may prime the antitumor . The authors have no financial conflicts of interest. The intrinsic function of the cGAS-STING pathway facilitates type-I interferon (IFN) inflammatory signaling responses and other cellular processes such as autophagy, cell survival . Mitochondrial damage and activation of the cytosolic DNA sensor cGAS ... Conversely, DMXAA stimulation significantly induced expression of the L929 ISRE-reporter cells, in line with direct activation of mouse Sting (Figure 4D and E). recent studies have revealed cGAS-STING activities that impact cells in unexpectedly diverse manners. Independent of intracellular STING activation, cGAMP can transfer to adjacent . CDNs produced by cGAS bind to STING in the ER inducing a conformational change in the molecule that leads to relocation of STING and TBK1 to the perinuclear region of the cell resulting in activation ( 16 ). Email. Bars, 100 μm. Additionally, DNA/cGAS-independent mode of STING activation has also been characterized in the progression of several sterile inflammatory diseases. In response to Brucella DNA, STING and the AIM2 inflammasome directly instigate caspase-1 activation and IL-1β secretion in macrophages in a cGAS-independent manner [59]. Increased activation of cGAS‐STING pathway enhances radiosensitivity of ... (FP) of IAV reportedly interacts with STING to antagonize type I IFN production in a STING-dependent but cGAS-independent manner 89. More recently, it was reported that ATM inhibition could activate a type 1 IFN response in pancreatic tumor cells that could enhance ICB therapy in a cGAS/STING-independent manner . Interferon stimulated genes (ISGs) can be induced independent of the interferons known to mediate this response, or the upstream regulator protein STING. cGAS-STING pathway downregulates the expression of anti-apoptosis protein BCL2 and upregulates the abundance of pro-apoptosis protein BCL2-associated X (BAX) . Overview of cGAS activation and cGAS-STING signaling. Streptococcal M protein promotes IL-10 production by cGAS-independent ... Mock (no DNA) was set as 1. cGAS KO cells serve as a negative control. Due to the limited number of studies, it is still unclear how the cGAS/STING pathway regulates the interplay between hepatocytes and macrophages during sterile inflammatory injury in the liver. PDF cGAS-independent STING activation in response to DNA damage For example, several instances of STING-mediated induction of programed cell death have been reported40-49 Figure 1. In concordance with the crucial role for cGAS and STING in NLRP3 activation, direct activation of STING by the endogenous second messenger cGAMP led to STING-and NLRP3-dependent, but cGAS . Interferon- and STING-independent induction of type I interferon ... Investigation of the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice confirmed activation of key neuroinflammatory pathways in biochemical studies and indicated a mechanistic link between microglial-associated neuro inflammation and neurodegeneration in the aged TBI brain. . This demonstrates that the function of STING during the response to nuclear DNA damage involves its non-canonical activation in a cGAS- and cGAMP-independent manner. This review focuses on the molecular mechanism of cGAS-dependent and cGAS-independent STING signaling under various disease conditions, particularly highlighting the diverse initiators upon this . However, the molecular mechanisms involved in the above studies, especially those responsible for triggering spontaneous activation of the type 1 IFN response in . Streptococcal M protein promotes IL-10 production by cGAS-independent ... The STING1-MYD88 complex drives ACOD1/IRG1 expression and function in ... or. cGAS-STING, an important pathway in cancer immunotherapy In addition to genetic and cytological consequences, mitotic errors induce inflammation and immunosurveillance through the activation of the viral DNA sensor cyclic GMP-AMP synthase (cGAS) (13, 14).Upon binding to DNA, cGAS synthesizes 2′3'-cyclic GMP-AMP (cGAMP) which in turn activates STING followed by TBK1 and IRF3, ultimately leading to induction of type I interferon (IFN) expression . Interestingly, A-T patient skin fibroblasts prematurely undergo cellular senescence and accumulate micronuclei in culture (Lan et al., 2019). We show that cGAMP administration at 1 to 10 µg increased STING dimers, TBK1 phosphorylation (pTBK1),. cGAS usually detects cytosolic DNA during infection with intracellular pathogens. STING is an adaptor protein that is expressed in macrophages, dendritic cells (DCs), and lymphocytes, as well as endothelial and epithelial cells ().Macrophages, as major professional antigen-presenting cells (APCs), are best known for their ability to prime the host defense by engulfing foreign pathogens ().The DNA contained in pathogens would activate the cGAS-STING signal pathway of . During conventional DNA sensing, STING translocates from the ER to peri-nuclear foci and gets phosphorylated by TBK1 at Serine 366 ( Dobbs et al., 2015 , Liu et al., 2015 ). cGAS-independent STING activation in response to DNA damage A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of ... Our understanding of innate immune responses made a leap forward in 1989 when Charles A. Janeway Jr. proposed a system of non-clonal, germline encoded sensors which he deemed pattern recognition receptors (PRRs) []. cGAS-independent STING activation in response to DNA damage Using gene targeting, RNA interference and inhibitors, we found that the innate immune response to Etoposide required STING but, unexpectedly, was independent of cGAS. 5 A and B). An important unanswered question . Inhibition of the cGAS‐STING pathway ... - Wiley Online Library RAW cGAS and STING knockout cells infected with B. thailandensis had significantly less cell death as compared to B. thailandensis-infected wild-type cells (Fig. Activation of cGAS-dependent antiviral responses by DNA ... - OUP Academic Spotlight on Innate Immune Science: cGAS-STING's Role in Human SLE ... including Drosophila melanogaster (26, 45).