Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The IKK complex and TBK1/IKKε are recruited to STING through distinct mechanisms to activate NF-κB signaling

ABSTRACT: STING is a highly conserved signaling molecule that coordinates an antiviral innate immune response through activation of the NF-κB and IRF3 signaling pathways. In addition to an antiviral response, STING-mediated NF-κB signaling also leads to an inflammatory response, which can cause substantial pathology. However, the molecular mechanism whereby STING drives inflammation is poorly understood, and this has hindered the development of anti-inflammatory strategies targeting this pathway. Here, we define an evolutionarily conserved mechanism whereby STING activates NF-κB signaling via recruitment of IKKγ in an M1-linked ubiquitin-dependent manner. We also show that the more recently evolved C-terminal tail of STING cooperates with the IKKγ-IKK complex for NF-κB-dependent expression of pro-inflammatory genes in mammalian cells through the kinases TBK1/IKKε. Thus, the expression of the key inflammatory genes CCL3 and CCL4 requires the formation of M1-linked ubiquitin and the activation of NF-κB, but we do not detect a role for IRF3 in STING-driven NF-κB signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310522 | GEO | 2026/09/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

FADD is recruited to activated STING oligomers initiating caspase mediated NF-κB activation in Drosophila melanogaster

Project description:STING is an evolutionarily conserved key regulator of innate immunity. In mammals, STING activates two distinct signaling pathways, the IRF3 and the NF-κB pathways, which act in conjunction to drive antiviral immunity. While the molecular mechanism of STING-mediated IRF3 activation has been untangled by extensive work during the last decade, how STING activates NF-κB signaling remains poorly understood. The versatile FADD/Caspase 8 axis is widely used in various immune signaling pathways throughout the animal kingdom and here we show that this axis participates downstream of STING in the activation of the Drosophila NF-kB like transcription factor Relish. We provide a detailed structural model illustrating how FADD interacts with two separate STING dimers in the activated oligomerized form of STING, thus providing a molecular explanation for the signal-dependent recruitment of FADD. In the classic IMD signaling pathway, FADD interacts with IMD in a structural distinct but functional related manner, highlighting how the two pathways differentially utilize the adapter FADD.

2026-04-09 | PXD054811 | Pride

Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation

Project description:Stimulator of Interferon Genes (STING) is a key regulator of type I interferon and pro-inflammatory responses during infection, cellular stress, and cancer. Here we reveal a mechanism for how STING balances activation of IRF3- and NF-κB-dependent transcription, and discover that acquisition of discrete signaling modules in the vertebrate STING C-terminal tail (CTT) shapes downstream immunity. As a defining example, we identify a motif appended to the CTT of zebrafish STING that inverts the typical vertebrate signaling response and results in dramatic NF-κB activation and weak IRF3-interferon signaling. We determine a co-crystal structure that explains how this CTT sequence recruits TRAF6 as a new binding partner, and demonstrate that the minimal motif is sufficient to reprogram human STING and immune activation in macrophage cells. Together, our results define the STING CTT as a linear signaling hub that can acquire modular motifs to readily adapt downstream immunity.

2019-06-10 | GSE128363 | GEO

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

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

RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I

Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, TBK1, IKKε, IKKβ, and NF-κB p65. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

2024-11-11 | PXD028160 | Pride

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

2013-10-10 | GSE51199 | GEO

Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways

Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.

2024-01-22 | GSE253724 | GEO

Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways

2024-01-24 | GSE253681 | GEO

Global proteomic analysis reveals key proteins through which miR-146a regulates NO production in the context of the inflammation pathway

Project description:Inflammation, while essential for host defense, can become detrimental when dysregulated. MicroRNA-146a (miR-146a) is a well-known anti-inflammatory regulator, primarily targeting the NF-κB pathway. However, its comprehensive mechanisms remain incompletely understood. This study aimed to elucidate the broader impact of miR-146a overexpression on the proteome of lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages using quantitative proteomics. Transfection with a miR-146a mimic resulted in its significant upregulation and the downregulation of known targets, Traf6 and Irak1, at the mRNA level. Global proteomic analysis identified 1232 differentially expressed proteins (DEPs). Pathway enrichment analysis revealed downregulation of proteins associated with IL-6 signaling and NF-κB-related transcription factors (Rel, Nfkb2, Cebpb), alongside decreased expression of pro-inflammatory mediators (Nlrp3, Nos2, Ptgs2). Interestingly, downregulation of Stat2 and interferon-stimulated genes, as well as upregulation of type II interferon signaling components, were also observed. Quantitative RT-PCR and parallel reaction monitoring (PRM) largely validated the proteomic findings for Ptgs2, S100a8, Nos2, Mapkapk2, and Irf3. Functionally, miR-146a overexpression significantly reduced LPS-induced nitric oxide and IL-6 production. These findings demonstrate that miR-146a exerts multifaceted anti-inflammatory effects in macrophages beyond its direct targets in the NF-κB pathway, impacting key inflammatory mediators and potentially modulating interferon signaling, thus providing novel insights into its regulatory mechanisms and therapeutic potential.

2026-09-07 | PXD064135 | Pride

TPPU alleviate cartilage degradation in temporomandibular joint osteoarthritis by inhibiting M1 macrophage polarization through the EETs/IL-17/NF-KB signaling pathway

Project description:In the treatment of inflammatory diseases, TPPU has shown potential therapeutic effects on a variety of inflammatory conditions, including reshaping the body's pro-inflammatory/anti-inflammatory balance by stabilizing endogenous anti-inflammatory substances EETs. In cardiovascular diseases, TPPU can regulate the NF-κB signaling pathway to modulate macrophage polarization and reduce inflammation. To explore the mechanism of TPPU in regulating M1 macrophages in TMJOA, we treated M1 macrophages with TPPU. In short, we attempted to verify the key signaling molecules and pathways regulated by TPPU in M1 macrophages.

2025-01-01 | GSE285011 | GEO

A pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics

Project description:Pseudogenes are thought to be inactive gene sequences, but recent evidence of extensive pseudogene transcription raised the question of potential function. Here we discover and characterize the sets of lncRNAs induced by inflammatory signaling via TNFα. TNFα regulates hundreds of lncRNAs, including 54 pseudogene lncRNAs, several of which show exquisitely selective expression in response to specific cytokines and microbial components in a NF-κB-dependent manner. Lethe, a pseudogene lncRNA, is selectively induced by proinflammatory cytokines via NF-κB or glucocorticoid receptor agonist, and functions in negative feedback signaling to NF-κB. Lethe interacts with NF-κB subunit RelA to inhibit RelA DNA binding and target gene activation. Lethe level decreases with organismal age, a physiological state associated with increased NF-κB activity. These findings suggest that expression of pseudogenes lncRNAs are actively regulated and constitute functional regulators of inflammatory signaling. RNA profiles of wild type (WT) MEFs treated with TNF-alpha were generated by deep sequencing using Illumina GAIIx. Examination of H3K4me3 histome modification in MEF.

2013-08-05 | E-GEOD-47494 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data