Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling [U937_DOX_RNA_Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325690 | GEO | 2026/05/21
REPOSITORIES: GEO
Similar Datasets
Project description:STING agonists are promising innate immune therapies and can synergize with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. How STING agonists such as cGAMP and its analogs enter and induce STING activation and toxicity in T cells is unclear despite known transporters for other cell types. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter in activated primary mouse and human T cells. T cells upregulate this transporter upon activation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.
2026-05-21 | GSE325689 | GEO
Project description:The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer, yet our understanding about the regulatory mechanisms for this pathway in different types of cancer is very limited. In this study, we discover that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silences the expression of arginosuccinate synthase 1 (ASS1), a urea cycle enzyme catalyzing the production of arginine from aspartate and citrulline, and thereby diverts the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication in KRAS-mutant NSCLC. Specifically, KRAS signaling facilitates a hypo-acetylated state in the promoter region of ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impedes the recruitment of the transcription factor c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cancer cells impairs the biosynthesis of arginine and renders growth dependency on SLC7A1, an arginine transmembrane transport, to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models obtains a substantial therapeutic benefit in inhibiting KRAS-driven NSCLC growth. Together, our findings uncover a new role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability in treating KRAS-mutant NSCLC.
2024-01-20 | GSE253688 | GEO
Project description:We report positional cloning and characterization of a novel Sting allele that fails to activate IFN production in the wild-derived mice of MOLF/Ei strain in response to HSV (Herpes Simplex Virus) and Listeria monocytogenes both in vitro and in vivo. We show that previously uncharacterized mutations in the N-terminal of STING are responsible for low levels of IFN due to failure of MOLF STING to respond to cytosolic STING agonists such as 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or poly(deoxyadenylic-deoxythymidylic) acid (dAdT). Using Next-Generation Sequencing (NGS) for the analysis of DNA-responses in congenic C57BL6.StingMOLF/MOLF (MOLF STING) mouse macrophages, we show that these mutations in MOLF/Ei discriminate in responses between different STING agonists. Macrophages from C57BL6.StingB6/B6¬ (B6 STING), or B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. To examine differential gene regulation downstream of murine Tmem173 (STING) allelic variants. We stimulated macrophages from B6 mice congenic for MOLF STING; macrophages from B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control. One replicate of RNA-seq reads after each stimulation provided. Conditions are peritoneal macrophages from B6 congenic mice expressing: B6 STING, MOLF STING, or STING KO stimulated with 2â3âcGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), poly(deoxyadenylic-deoxythymidylic) acid (dAdT), or no treatment. This constitutes a total of 12 reads analyzed in this data set.
2016-07-05 | E-GEOD-68140 | biostudies-arrayexpress
Project description:2’3’-cyclic GMP-AMP (cGAMP) is a cyclic dinucleotide second messenger in which guanosine and adenosine are connected by one 3’-5’ and one 2’-5’ phosphodiester linkage. It is formed in the cytosol upon detection of pathogenic DNA by the enzyme guanosine-monophosphate-adenosine monophosphate synthase (cGAS). cGAMP subsequently binds to the adaptor protein stimulator of interferon genes (STING) to elicit an innate immune response leading to the production of type I interferons and cytokines. STING agonists are a highly promising avenue for an immuno-oncological anticancer therapy. A particular challenge with cyclic dinucleotide STING agonists are the two negative charges of the phosphodiester linkages, which strongly reduce the ability of such compounds to penetrate cell membranes. The development of cell-permeable STING agonists that can stimulate the immune system to enhance their anticancer potency is currently of utmost importance in the field. Here, we report the development of a dideoxy derivative of cGAMP as a phosphotriester prodrug, where the negative charge of the phosphate backbone has been masked with a thioester. We found that this thioester-protected compound features a dramatic increase in its cellular potency that rises from EC50 = 5 µM to 25 nM. The new compound is envisioned to enable an efficient STING-agonist-based anticancer therapy.
2025-05-07 | PXD057395 | Pride
Project description:High-grade meningioma remains a therapeutic challenge to medical oncologists. It is urgent to uncover novel molecular targets. Solute carrier family 7 member 1 (SLC7A1) was highly expressed in high-grade meningioma and associated with poor prognosis of patients. SLC7A1 knockdown significantly inhibited the proliferation and invasion of malignant meningioma cells. In addition, the small-molecule drug AZ628 showed an excellent antiproliferative effect on malignant meningioma cells, indicating that it is a potential antitumor drug for high-grade meningioma. Our study revealed the essential roles of SLC7A1 in the malignant progression of meningioma, suggesting SLC7A1 as a potential antitumor target for high-grade meningioma.
2025-09-27 | GSE244554 | GEO
Project description:We report positional cloning and characterization of a novel Sting allele that fails to activate IFN production in the wild-derived mice of MOLF/Ei strain in response to HSV (Herpes Simplex Virus) and Listeria monocytogenes both in vitro and in vivo. We show that previously uncharacterized mutations in the N-terminal of STING are responsible for low levels of IFN due to failure of MOLF STING to respond to cytosolic STING agonists such as 2’3’cGAMP, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) or poly(deoxyadenylic-deoxythymidylic) acid (dAdT). Using Next-Generation Sequencing (NGS) for the analysis of DNA-responses in congenic C57BL6.StingMOLF/MOLF (MOLF STING) mouse macrophages, we show that these mutations in MOLF/Ei discriminate in responses between different STING agonists. Macrophages from C57BL6.StingB6/B6¬ (B6 STING), or B6 STING expressing littermates were stimulated as a positive control for STING activation, and STING -/- (STING KO) macrophages served as a negative control.
2016-01-03 | GSE68140 | GEO
Project description:The volume-regulated anion channel (VRAC) is a hexameric complex formed by LRRC8 proteins. VRACs are responsible for the regulatory volume decrease (RVD) after hypotonic cell swelling by mediating the efflux of chloride. Besides chloride, LRRC8 proteins transport other molecules including immunomodulatory cyclic dinucleotides (CDNs) such as 2’3’cGAMP. Here we identify LRRC8C as a critical component of VRACs in T cells, where its deletion abolishes VRAC currents and RVD. We find that LRRC8C mediates the transport of 2’3’cGAMP in T cells. T cells of Lrrc8c-/- mice have increased cell cycle progression, proliferation, survival, Ca2+ influx and cytokine production in vitro and enhanced T cell mediated immunity in vivo. We used RNA sequencing of CD4+ T cells from wild-type (WT) and Lrrc8c-/- mice to determine the effects of impaired cGAMP signaling in T cells. T cells of Lrrc8c-/- mice had impaired p53 signaling which was associated with decreased p53 expression. We found that uptake of 2’3’cGAMP and other CDNs via LRRC8C results in STING activation and p53 accumulation. Inhibition of STING in WT T cells recapitulates the phenotype of LRRC8C-deficient T cells whereas overexpression of p53 inhibits enhanced T cell function in the absence of LRRC8C. These findings establish cGAMP uptake through LRRC8C and subsequent STING-p53 signaling as a novel inhibitory signaling pathway in T cells and adaptive immunity.
2021-12-31 | GSE163679 | GEO
Project description:The goal of this project is to identify interacting proteins of Flag-tagged STING before and after cGAMP stimulation. STING knockout (STING-KO) BJ cells stably re-expressing Flag-STING were treated with 1 M cGAMP and whole cell lysates were harvested 30 min later for IP with anti-Flag M2 affinity gel. STING-KO cells without Flag-STING expression were used as a negative control.
2025-12-07 | PXD059426 | Pride
Project description:Daphnia magna has been used extensively to evaluate organism- and population-level responses to pollutants in acute toxicity and reproductive toxicity tests. We have previously reported that exposure to juvenile hormone (JH) agonists results in a reduction of reproductive function and production of male offspring in a cyclic parthenogenesis, D. magna. Recent advances in molecular techniques have provided tools to better understand the responses to pollutants in aquatic organisms including D. magna. DNA microarray was used to evaluate gene expression profiles of neonatal daphnids exposed to JH agonists; methoprene (125, 250 and 500 ppb), fenoxycarb (0.5, 1 and 2 ppb), and epofenonane (50, 100 and 200 ppb). Exposure to these JH analogs resulted in chemical specific patterns of gene expression. The heat map analyses based on hierarchical clustering revealed a similar pattern between treatments with a high dose of methoprene and with epofenonane. In contrast, treatment with low to middle doses of methoprene resulted in similar profiles to fenoxycarb treatments. Hemoglobin and JH epoxide hydrolase genes clustered to be JH-responsive genes. These data suggest that fenoxycarb has high activity as a JH agonist, methoprene shows high toxicity and epofenonane works through a different mechanism compared with other JH analogs, agreeing with data of previously reported toxicity tests. In conclusion, D. magna DNA microarray is useful for classification of JH analogs and identification of JH-responsive genes. Juvenile hormone agonists induced gene expression in daphnids neonates was measured at 48 hours after exposure to methoprene (125, 250, 500 ppb), fenoxycarb (0.5, 1, 2 ppb), epofenonane (50, 100, 200) and DMF as a control. Three independent experiments were performed at each chemicals.
2013-12-31 | E-GEOD-47990 | biostudies-arrayexpress
Project description:The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage. Cytosolic DNA triggers immune responses by activating the cGAS/STING pathway. The binding of DNA to the cytosolic enzyme cGAMP synthase (cGAS), activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic[G(2’,5’)pA(3’,5’)] (2’3’-cGAMP). 2’3’-cGAMP, a cyclic dinucleotide (CDN), activates the protein ‘stimulator of interferon genes’ (STING), which in turn activates the transcription factors IRF3 and NF-κB promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2’3’-cGAMP produced by malignant cells and other CDNs, including CDNs produced by bacteria and synthetic CDNs used in cancer immunotherapy, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter for CDNs. CDN uptake and functional responses are inhibited by depleting SLC19A1 from human cells and enhanced by overexpressing SLC19A1. In both human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates, as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer, host responsiveness to CDN-producing pathogenic microorganisms, and potentially in certain inflammatory diseases.
2019-09-01 | GSE134371 | GEO