cGAS STING TBK1 IRF3

Pro-inflammatory cytokines upregulate the expression of the H2 O2 -producing NADPH oxidase dual oxidase 2 (DUOX2)2 which, when elevated, adversely affects survival from pancreatic ductal adenocarcinoma (PDAC). Because the cGAS-STING pathway is known to initiate pro-inflammatory cytokine expression following uptake of exogenous DNA, we examined whether activation of cGAS-STING could play a role in the generation of reactive oxygen species by PDAC cells. Here, we found that a variety of exogenous DNA species markedly increased the production of cGAMP, the phosphorylation of TBK1 and IRF3, and the translocation of phosphorylated IRF3 into the nucleus, leading to a significant, IRF3-dependent enhancement of DUOX2 expression, and a significant flux of H2 O2 in PDAC cells...

The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained...

The discovery of cGAMP in 2012 filled an important gap in our understanding of innate immune signaling. It has been known for over a century that DNA can induce immune responses, but the underlying mechanism was not clear. With the identification of STING as a key player in interferon induction, the DNA detector that activates STING was the last missing link in TBK1-IRF3 signaling. Somewhat unexpectedly, it turns out that nature relays the DNA danger signal through a small molecule. cGAMP is a cyclic dinucleotide produced from cyclodimerization of ATP and GTP upon detection of cytosolic DNA by cGAS, a previously uncharacterized protein, to promote the assembly of the STING signalosome...

Effective amelioration of ischemia/reperfusion (I/R)-induced intestinal injury and revealing its mechanisms remain the challenges in both preclinic and clinic. Potential mechanisms of naringin in ameliorating I/R-induced intestinal injury remain unknown. Based on pre-experiments, I/R-injured rat intestine in vivo and hypoxia-reoxygenation (H/R)-injured IEC-6 cells in vitro were used to verify that naringin-alleviated I/R-induced intestinal injury was mediated via deactivating cGAS-STING signaling pathway. Naringin improved intestinal damage using hematoxylin and eosin staining and decreased alanine aminotransferase and aspartate aminotransferase contents in plasma...

Cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of human immunodeficiency virus type 1 (HIV-1) and initiates antiviral immune response through cGAS-stimulator of interferon genes (STING)-TBK1-IRF3-type I interferon (IFN-I) signalingcascade. Here, we report that the HIV-1 p6 protein suppresses HIV-1-stimulated expression of IFN-I and promotes immune evasion. Mechanistically, the glutamylated p6 at residue Glu6 inhibits the interaction between STING and tripartite motif protein 32 (TRIM32) or autocrine motility factor receptor (AMFR)...

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra Chinensis (Turcz.) Baill. is a long-term used traditional Chinese medicine with the functions of tonifying the kidney and calming the heart, tonifying qi and engendering fluid. It can be used to treat insomnia and dreaminess, spermatorrhea, coughs, as well as liver and kidney deficiency of Yin or Yang Syndrome. Modern pharmacological studies have shown that Schisandra Chinensis regulates host immunity and exhibits anti-cancer, antiviral and liver-protecting effects...

STING is an endoplasmic reticulum-resident protein regulating innate immunity. After binding with cyclic guanosine monophosphate-AMP (cGAMP), STING translocates from the endoplasmic reticulum (ER) to the Golgi apparatus to stimulate TBK1 and IRF3 activation, leading to expression of type I interferon. However, the exact mechanism concerning STING activation remains largely enigmatic. Here, we identify tripartite motif 10 (TRIM10) as a positive regulator of STING signaling. TRIM10-deficient macrophages exhibit reduced type I interferon production upon double-stranded DNA (dsDNA) or cGAMP stimulation and decreased resistance to herpes simplex virus 1 (HSV-1) infection...

African swine fever virus (ASFV) causes feverous and hemorrhagic disease of domestic pigs and European wild boars with high mortality, yet no commercial vaccine is currently available. Several ASFV strains with natural deletion or gene-targeted knockout of multiple MGF360 and MGF505 genes are attenuated in vitro and in vivo, and can offer full protection against homologous challenge. However, the mechanisms underlying the protection are not fully understood. This study aims to investigate the effects of MGF360-12L of ASFV-SY18 on the cGAS-STING signaling pathway and explore the potential mechanisms...

TBK1 and IKKϵ are related, crucial kinases in antiviral immune signaling pathways downstream of cytosolic nucleic acid receptors such as cGAS and RIG-I-like receptors. Upon activation, they phosphorylate the transcription factors IRF3 and IRF7 and thereby initiate the expression of type I interferons and antiviral effectors. While point mutation-induced loss of TBK1 kinase activity results in clinical hyper-susceptibility to viral infections, a complete lack of TBK1 expression in humans is unexpectedly not associated with diminished antiviral responses...

Chitosan and its derivatives are widely used in vaccine adjuvants and delivery systems. Vaccine antigens encapsulated in or conjugated onto N-2-hydroxypropyl trimethyl ammonium chloride chitosan/N,O-carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) induce strong cellular, humoral, and mucosal immune responses, but the mechanism of action is not fully understood. Therefore, the purpose of this study was to explore the molecular mechanism of composite NPs by upregulating the cGAS-STING signalling pathway to enhance the cellular immune response...

Cystic fibrosis (CF) is a rare autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation is F508del-CFTR (ΔF) which leads the encoded ion channel towards misfolding and premature degradation. The disease is characterized by chronic bronchopulmonary obstruction, inflammation and airways colonization by bacteria, which are the major cause of morbidity and mortality. The STING pathway is the main signaling route activated in the presence of both self and pathogen DNA, leading to Type I Interferon (IFN I) production and the innate immune response...

Epstein-Barr virus (EBV) has developed effective strategies to evade host innate immune responses. Here we reported on mitigation of type I interferon (IFN) production by EBV deubiquitinase (DUB) BPLF1 through cGAS-STING and RIG-I-MAVS pathways. The two naturally occurring forms of BPLF1 exerted potent suppressive effect on cGAS-STING-, RIG-I- and TBK1-induced IFN production. The observed suppression was reversed when DUB domain of BPLF1 was rendered catalytically inactive. The DUB activity of BPLF1 also facilitated EBV infection by counteracting cGAS-STING- and TBK1-mediated antiviral defense...

African swine fever (ASF) is a devastating infectious disease of pigs caused by the African swine fever virus (ASFV), which poses a great danger to the global pig industry. Many viral proteins can suppress with interferon signaling to evade the host's innate immune responses. Therefore, the development of an effective vaccine against ASFV has been dampened. Recent studies have suggested that the L83L gene may be integrated into the host genome, weakening the host immune system, but the underlying mechanism is unknown...

SARS-CoV-2 is a poor inducer of innate antiviral immunity, and the underlying mechanism still needs further investigation. Here, we reported that SARS-CoV-2 NSP7 inhibited the production of type I and III IFNs by targeting the RIG-I/MDA5, TLR3-TRIF, and cGAS-STING signaling pathways. SARS-CoV-2 NSP7 suppressed the expression of IFNs and IFN-stimulated genes induced by poly (I:C) transfection and infection with Sendai virus or SARS-CoV-2 virus-like particles. NSP7 impaired type I and III IFN production activated by components of the cytosolic dsRNA-sensing pathway, including RIG-I, MDA5, and MAVS, but not TBK1, IKKε, and IRF3-5D, an active form of IRF3...

To study the clinical significance of manganese (Mn) in the serum of children with infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) infection, we analyzed the correlation between Mn and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and explored the immune pathogenesis of EBV infection. Children diagnosed with IM comprised the IM group, and healthy children during the same period were selected as the normal control group. Real-time reverse transcription-polymerase chain reaction was used to detect the mRNA expression levels of cGAS, STING , Tank-binding kinase 1 ( TBK1 ), interferon regulatory factor 3 ( IRF3 ), and related inflammatory factors, and Mn in serum was detected by inductively coupled plasma mass spectrometry...

Nutrient sensing and damage sensing are two fundamental processes in living organisms. While hyperglycemia is frequently linked to diabetes-related vulnerability to microbial infection, how body glucose levels affect innate immune responses to microbial invasion is not fully understood. Here, we surprisingly found that viral infection led to a rapid and dramatic decrease in blood glucose levels in rodents, leading to robust AMPK activation. AMPK, once activated, directly phosphorylates TBK1 at S511, which triggers IRF3 recruitment and the assembly of MAVS or STING signalosomes...

Systemic inflammatory responses often result in sepsis and inhibition of inflammation is one strategy for sepsis treatment. In this study, we designed and synthesized 32 novel hederagenin (HD) derivatives with modifications at the A-ring, C-28, and C-23 positions and screened their anti-inflammatory activities in vitro, finding multiple compounds with potential anti-inflammatory activity. Of these, compound 1 was the most effective and was used for subsequent investigations into its mechanism of action and in vivo activity...

The innate immune DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (IFN) gene (STING) pathway exerts strong antiviral activity through downstream IFN production; however, it has been recently recognized that an IFN-independent activity of STING also plays an important role in antiviral functions. Nevertheless, the IFN-independent antiviral activity of STING is not fully understood. Here, we showed that porcine STING (pSTING) played a critical role against herpes simplex virus 1 (HSV-1) and vesicular stomatitis virus (VSV) infections, and IFN-defective mutants, including pSTING pLxIS sub, S365A, and △CTT, all exhibited similar antiviral functions, compared to wild-type (WT) pSTING...

The innate immune DNA sensing cGAS-STING signaling pathway has been widely recognized for inducing interferons (IFNs) and subsequent antiviral state. In addition to IFN, the cGAS-STING pathway also elicits other cell autonomous immunity events including autophagy and apoptosis. However, the downstream signaling events of this DNA sensing pathway in livestock have not been well defined. Here, we systematically analyzed the porcine STING (pSTING) induced IFN, autophagy and apoptosis, revealed the distinct dynamics of three STING downstream events, and established the IFN independent inductions of autophagy and apoptosis...

Persistent infection and tumorigenesis by papillomaviruses (PVs) require viral manipulation of various cellular processes, including those involved in innate immune responses. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an essential innate immune sensing system, that recognizes DNA and trigger potent antiviral effector responses. In this study, we found that bovine PV (BPV) E5 protein, the major oncoprotein of bovine delta PVs, interacts with STING but not with cGAS in a spontaneous BPV infection of neoplastic urothelial cells of cattle...