STING mediates immune responses in a unicellular choanoflagellate
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ABSTRACT:
PROVIDER: PRJNA729481 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14511552.fastq.gz | Fastqsanger.gz | |||
| SRR14511553.fastq.gz | Fastqsanger.gz | |||
| SRR14511554.fastq.gz | Fastqsanger.gz | |||
| SRR14511555.fastq.gz | Fastqsanger.gz | |||
| SRR14511556.fastq.gz | Fastqsanger.gz |
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Project description:To reconstruct the ancestry of animal innate immunity, we have developed the choanoflagellate Monosiga brevicollis, one of the closest living relatives of animals, as a model for studying mechanisms underlying pathogen recognition and immune response. We found that M. brevicollis is killed by exposure to Pseudomonas aeruginosa bacteria and selectively avoids ingesting them. Moreover, M. brevicollis expresses STING, which, in animals, activates innate immune pathways in response to cyclic dinucleotides during pathogen sensing. M. brevicollis STING increases the susceptibility of M. brevicollis to P. aeruginosa-induced cell death and is required for responding to the cyclic dinucleotide 2’3’ cGAMP. Furthermore, similar to animals, autophagic signaling in M. brevicollis is induced by 2’3’ cGAMP in a STING-dependent manner.
2021-05-13 | GSE174340 | GEO
Project description:Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as a central immune defense strategy to prevent the spread of bacteriophage viruses and other invasive genetic elements across a population. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to rapidly mobilize cognate death effectors. Here, we identify a large family of bacteriophage nucleotidyltransferases (NTases) which synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit NAD-depleting TIR effectors activated through a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of host TIR-STING suicide signaling. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphatase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a role for the alarmone-activated host toxin MazF as a key executioner of TIR-driven abortive infection. Phage NTases and counter-defenses like Atd1 preserve host viability to ensure virus propagation, and may be exploited as tools to modulate TIR and STING immune responses.
2023-03-27 | GSE222071 | GEO
Project description:The innate immune regulator stimulator of interferon genes (STING) mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines, which promotes the progression of various inflammatory and autoimmune diseases. Innate immune system plays a critical role in regulating obesity-induced islet dysfunction, whereas the potential effect of STING signaling remains unclear. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Knocking-out STING alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates cyclic AMP-GMP synthase (cGAS)-STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of β cell insulin secretory granules. Genetically or pharmacologically inhibiting STING activation boosts insulin secretion and hyperglycemia. Together, these findings reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in diet-induced obesity and suggest that selective blocking of the STING activation maybe a promising strategy for treating type 2 diabetes.
2025-07-11 | GSE207876 | GEO
Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.
2021-11-25 | GSE189384 | GEO
Project description:An HIV protein mediates immune evasion by targeting cGAS–STING signaling
| PRJNA782882 | ENA
Project description:Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with many human diseases, such as lysosomal storage disorders (LSD). How the cell detects lysosomal defects and then restores lysosomal function remain incompletely understood. Here, we show that STING mediates a common neuroinflammatory gene signature in three distinct lysosomal storage disorders, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi brain tissue revealed that STING also mediates the expression of a broad panel of lysosomal genes that are part of the CLEAR (Coordinated Lysosomal Expression and Regulation) signaling pathway, which is regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-seq analysis show that STING regulates lysosomal gene expression in microglia in LSD mice. Mechanistically, we show that STING activation in both human and mouse cells leads to TFEB dephosphorylation, nuclear translocation, and expression of target lysosomal genes. In addition, STING-mediated TFEB activation requires its proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Functionally, we show that the STING-proton channel-TFEB axis plays a role in facilitating lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control and recovery mechanism that responds to both genetic and chemically induced lysosomal dysfunction.
2025-04-23 | GSE283768 | GEO
Project description:Bacteriophage antidefense genes that neutralize TIR and STING immune responses
| PRJNA917585 | ENA
Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.
2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress
Project description:Animals have evolved unique repertoires of innate immune genes and pathways that provide their first line of defense against pathogens. To reconstruct the ancestry of animal innate immunity, we have developed the choanoflagellate Monosiga brevicollis, one of the closest living relatives of animals, as a model for studying mechanisms underlying pathogen recognition and immune response. We found that M. brevicollis is killed by exposure to Pseudomonas aeruginosa bacteria. Moreover, M. brevicollis expresses STING, which, in animals, activates innate immune pathways in response to cyclic dinucleotides during pathogen sensing. M. brevicollis STING increases the susceptibility of M. brevicollis to P. aeruginosa-induced cell death and is required for responding to the cyclic dinucleotide 2'3' cGAMP. Furthermore, similar to animals, autophagic signaling in M. brevicollis is induced by 2'3' cGAMP in a STING-dependent manner. This study provides evidence for a pre-animal role for STING in antibacterial immunity and establishes M. brevicollis as a model system for the study of immune responses.
| S-EPMC8592570 | biostudies-literature
Project description:The cGAS-STING pathway forms a major component of the innate immune system. cGAS-STING signalling is induced by detection of either foreign (i.e. pathogenic) or mislocalised host double stranded (ds)DNA present within the cytosol. STING acts as the major signalling hub, where it controls activation of transcription factors IRF3 and NF-B for expression of type I interferons and inflammatory cytokines, respectively. Under resting conditions STING resides on the ER membrane. However, following activation STING traffics to the Golgi to initiate downstream signalling, and subsequently to endolysosomal regions for degradation and termination of signalling. However, while STING is known to be degraded by lysosomes, the mechanisms controlling its delivery remain poorly defined. Here we utilised a mass spectrometry approach to assess phosphorylation changes in primary macrophages following STING activation. This identified a large number of phosphorylation events in proteins involved in intracellular transport, including vesicular trafficking. We utilised high-temporal microscopy to track STING vesicular transport in live macrophages. We observed that while macrophages exhibit rapid degradation of STING (i.e., 4-6 h), basal STING protein levels return slowly (i.e., >24 h). Despite STING protein recovery, ultimately macrophages remain unresponsive to re-challenge with STING ligands. Using a combination of imaging and biochemical approaches we subsequently identify that the endosomal complexes required for transport (ESCRT) pathway detects ubiquitinated STING on endosomes, which facilitates the degradation of STING. Disrupting ESCRT recognition of STING via knockdown of the ESCRT-0 component HRS or inhibiting ESCRT function via overexpression of a dominant negative form of VPS4a enhances STING signalling and cytokine production. Therefore, we have characterised the mechanisms that controls effective termination of STING signalling. Dysregulation of STING localisation or its degradation has been implicated in several diseases including autoimmune, autoinflammatory and neuroinflammatory diseases, hence a clearer understanding of STING degradation is imperative for a better understanding of STING-dependent disease pathologies.
2023-05-05 | PXD037108 | Pride