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Equilibrative Nucleoside Transporter 3 is an IFN-stimulated Gene that Facilitates Viral Genome Release

ABSTRACT: Equilibrative Nucleoside Transporter 3 is an IFN-stimulated Gene that Facilitates Viral Genome Release

PROVIDER: PRJNA896496 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22123100.fastq.gz	Fastqsanger.gz
	SRR22123101.fastq.gz	Fastqsanger.gz
	SRR22123102.fastq.gz	Fastqsanger.gz
	SRR22123103.fastq.gz	Fastqsanger.gz
	SRR22123104.fastq.gz	Fastqsanger.gz

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Similar Datasets

Equilibrative Nucleoside Transporter 3 is an IFN-stimulated Gene that Facilitates Viral Genome Release

Project description:An increasing body of evidence emphasizes the role of metabolic reprogramming in immune cells to fight off infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of Equilibrative Nucleoside Transporter 3 (ENT3, encoded by SoLute Carrier family 29 member 3, Slc29a3) is part of the innate immune response which is rapidly upregulated upon pathogen insults. The transcription of Slc29a3 is directly under the regulation of IFN-induced signaling, positioning this metabolite transporter as an Interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of ENT3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses for a survival advantage.

2022-11-08 | GSE216974 | GEO

Adenosine uptake through equilibrative nucleoside transporter-1 suppresses antitumor immunity by pyrimidine starvation

Project description:Immunosuppression by adenosine is an important cancer immune checkpoint. Extracellular adenosine signals through specific receptors and can be transported across the cell membrane through nucleoside transporters. While adenosine receptors are well-known to regulate tumor immunity, the impact of adenosine transporters remains unexplored. In this study, we investigated the effect on tumor immunity of equilibrative nucleoside transporter-1 (ENT1), the major regulator of extracellular adenosine concentrations. Using selective inhibitors and gene targeting approaches, we demonstrated that blocking or deleting host ENT1 significantly enhanced CD8+ T cell-dependent anti-tumor responses. Tumors inoculated into ENT1-deficient mice showed increased infiltration of effector CD8+ T cells with an enhanced cytotoxic transcriptomic profile and significant upregulation of granzyme B, IFN-g, IL-2, TNF-a and CXCL10. ENT1-deficiency was further associated with decreased tumor-infiltrating T regulatory cells and CD206high macrophages, and suppressed CCL17 production. ENT1-deficiency notably potentiated the therapeutic activity of PD-1 blockade. T cells upregulated ENT1 upon activation, and blocking ENT1 enhanced their function when co-cultured with cognate antigen/HLA-matched melanoma cells. Mechanistically, ENT1-mediated adenosine uptake inhibited the activity of phosphoribosylpyrophosphate synthetase (PRPS) in activated T cells, thereby suppressing production of uridine 5′-monophosphate (UMP) and its derivatives required for DNA and RNA synthesis. In summary, our study identified ENT1-mediated adenosine uptake as an important and previously unappreciated mechanism of adenosine-mediated immunosuppression via pyrimidine starvation that can be targeted to enhance antitumor T cell responses.

2024-10-13 | GSE279144 | GEO

Loss-of-function of the nucleoside transporter SLC29A3 drives ERK activation, establishing an alternative pathway for histiocytosis development

Project description:Histiocytoses are inflammatory myeloid neoplasms, driven by somatic activating mutations in mitogen-activated protein kinase (MAPK) genes. H syndrome is a genetic disorder caused by germline loss-of-function mutations in SLC29A3, encoding the lysosomal equilibrative nucleoside transporter 3 (ENT3). Patients with H syndrome are predisposed to develop histiocytosis, yet the mechanism is unclear. Here, we demonstrate that loss-of-function of ENT3 leads to MAPK signaling activation, via the nucleoside sensor Toll-like receptor (TLR). We show that H syndrome monocytes exhibit an inflammatory expression pattern, display elevated levels of phospho-ERK, and secrete enhanced amounts of inflammatory cytokines in a TLR8/MEK-dependent manner. Finally, MEK inhibitor therapy successfully eliminated a histiocytic tumor of a patient with H syndrome. These results demonstrate a yet-unrecognized link between a defect in a lysosomal transporter and pathological activation of MAPK signaling, a novel alternative pathway to histiocytosis development, and establish MEK inhibition as a promising new treatment for H syndrome.

2023-09-27 | GSE221581 | GEO

Free cholesterol primes the IFN-I response by facilitating the release of TLR9 from UNC93B1

Project description:Elevated cholesterol is positively associated with autoimmunity. However, it is unclear which mechanism directly link them. Here, we report that free cholesterol in the endolysosomal membrane regulates the IFN-I response in plasmacytoid dendritic cells (pDCs) by facilitating the release of TLR9 from UNC93B1. The cholesterol transporter NPC1 was highly expressed in pDCs, and conditional deletion of Npc1 via Cd11c-Cre (Npc1∆DC) impaired IFNα production by TLR9-stimulated pDCs. Npc1∆DC mice exhibited a weakened IFNα response to HSV-1 infection, and ameliorated anti-DNA autoantibodies and nephritis when crossed to B6.Sle1yaa transgenic lupus model. Mechanistically, through click chemistry-based proteome-wide screening, we found that the TLR chaperone UNC93B1 could bind to free cholesterol. The juxtamembrane cholesterol gradient, mediated by NPC1, promoted TLR9 release from UNC93B1. Increased membrane-bound cholesterol dramatically enhanced IFNα response by murine and human pDCs. Our results suggested that the participation of free cholesterol in TLR9 signaling could directly link elevated cholesterol with autoimmunity.

2025-01-18 | GSE253771 | GEO

IFN-stimulated Metabolite Transporter ENT3 Facilitates Viral Genome Release

Project description:An increasing amount of evidence emphasizes the role of metabolic reprogramming in immune cells to fight infections. However, little is known about the regulation of metabolite transporters that facilitate and support metabolic demands. In this study, we found that the expression of Equilibrative Nucleoside Transporter 3 (ENT3, encoded by Solute carrier family 29 member 3, Slc29a3) is part of the innate immune response, which is rapidly upregulated upon pathogen invasion. The transcription of Slc29a3 is directly regulated by type I interferon-induced signaling, demonstrating that this metabolite transporter is an Interferon-stimulated gene (ISG). Suprisingly, we unveil that several viruses, including SARS-CoV-2, require ENT3 to facilitate their entry into the cytoplasm. The removal or suppression of Slc29a3 expression is sufficient to significantly decrease viral replication in vitro and in vivo. Our study reveals that ENT3 is a pro-viral ISG co-opted by some viruses to gain a survival advantage.

| S-SCDT-10_15252-EMBR_202255286 | biostudies-other

Adenosine uptake through equilibrative nucleoside transporter-1 suppresses antitumor immunity by pyrimidine starvation

Project description:Adenosine uptake through equilibrative nucleoside transporter-1 suppresses antitumor immunity by pyrimidine starvation

| PRJNA1170965 | ENA

Identification of the IFN-stimulated genes in IFN-α2b-treated intrahepatic cholangiocarcinoma cells

Project description:Identification of the IFN-stimulated genes in IFN-α2b-treated intrahepatic cholangiocarcinoma cells

| PRJNA1057779 | ENA

Identification of the IFN-stimulated genes in IFN-α2b-treated intrahepatic cholangiocarcinoma cells

Project description:Interferon-α2b (IFN-α2b) is a highly active cytokine protein that belongs to the interferon-α (IFN-α) family. As a pleiotropic cytokine, IFN-α2b has beneficial antiviral, antitumour, antiparasitic, and immunomodulatory activities. In vivo and in vitro, IFN-α2b can activate the JAK-STAT pathway (also known as IFN-I pathway) and function by inducing the transcription of downstream IFN-stimulated genes (ISGs).To identify the ISGs in intrahepatic cholangiocarcinoma (ICCA) cells and evaluate the therapeutic value of IFN-α2b, ICCA cells were treated with recombinant IFN-α2b protein. Total RNA samples were extracted and used for RNA-seq. Certain ISGs (e.g., MXs, IFITs, OASs) were found to be significantly upregulated upon IFN-α2b treatment.

2025-01-20 | GSE252095 | GEO

Gene expression in human macrophages stimulated with IFN-alpha and IL10

Project description:Human monocyte-derived macrophages were stimulated with IFN-alpha or IL-10, and then gene expression was evaluated.

2021-03-01 | GSE114841 | GEO

KBM7 genetrap mutant cells stimulated with TNF-alpha and IFN-gamma

Project description:Transcriptional response of KBM7 cells to IFN-gamma or TNF-alpha was investigated in control or cells with genetrap insertions in JAK2 or TNFRS1A, respectively. The experiment shows that, as expected, cells lacking JAK2 or TNFRS1A expression display a severly blunted response to the tested cytokines. KBM7 genetrap mutant cells stimulated with TNF-alpha and IFN-gamma Sample WT_1 corresponds with the control sample for the IFN-gamma stimulation; Sample WT_2 corresponds with the control sample for the TNF-alpha stimulation. As the expected differences between the samples was large, only single replicates were performed for each condition

2013-08-09 | E-GEOD-48848 | biostudies-arrayexpress

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