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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

ABSTRACT: Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

PROVIDER: PRJNA923691 | ENA |

REPOSITORIES: ENA

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Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

Project description:Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in Th17 cells is unknown. Here, we show that PDH is essential for the generation of a unique glucose-derived citrate pool needed for Th17 cell proliferation, survival and effector function. In vivo, mice harboring a T cell-specific deletion of PDH were less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increased glutaminolysis, glycolysis, and lipid uptake in an mTOR-dependent manner. However, cellular citrate remained critically low in mutant Th17 cells, which interfered with oxidative phosphorylation (OXPHOS), lipid synthesis and histone acetylation crucial for the transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restored their metabolism and function, identifying a metabolic feedback loop within central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.

2023-03-02 | GSE222878 | GEO

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq II)

2023-03-02 | GSE222881 | GEO

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq I)

2023-03-02 | GSE222880 | GEO

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

Project description:Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (ATAC-Seq)

| PRJNA923693 | ENA

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq II)

Project description:Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq II)

| PRJNA923696 | ENA

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq I)

Project description:Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions (RNA-Seq I)

| PRJNA923694 | ENA

Pyruvate dehydrogenase fuels a critical citrate pool that is essential for Th17 cell effector functions

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-02 | GSE222882 | GEO

Activation of the pyruvate dehydrogenase complex dictates tumour progression in prostate cancer

Project description:Metabolism in cancer serves to provide energy and key biomolecules that sustain cell growth, a process that is frequently accompanied by decreased mitochondrial use of glucose. Importantly, metabolic intermediates including mitochondrial metabolites are central substrates for post-translational modifications at the core of cellular signalling and epigenetics. However, the molecular means that coordinate the use of mitochondrial metabolites for anabolism and nuclear protein modification are poorly understood. Here, we unexpectedly found that genetic and pharmacological inactivation of Pyruvate Dehydrogenase A1 (PDHA1), a subunit of pyruvate dehydrogenase complex (PDC) that regulates mitochondrial metabolism16 inhibits prostate cancer development in different mouse and human xenograft tumour models. Intriguingly, we found that lipid biosynthesis was strongly affected in prostate tumours upon PDC inactivation. Mechanistically, we found that nuclear PDC controls the expression of Sterol regulatory element-binding transcription factor (SREBF) target genes by mediating histone acetylation whereas mitochondrial PDC provides cytosolic citrate for lipid synthesis in a coordinated effort to sustain anabolism. In line with the oncogenic function of PDC in prostate cancer, we find that PDHA1 and the PDC activator, Pyruvate dehydrogenase phospatase 1 (PDP1), are frequently amplified and overexpressed at both gene and protein level in these tumours. Taken together, our findings demonstrate that both mitochondrial and nuclear PDC sustains prostate tumourigenesis by controlling lipid biosynthesis thereby pointing at this complex as a novel target for cancer therapy.

2018-02-21 | GSE74245 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro [ATAC-Seq]

Project description:The chromatin landscape was assessed in effector and memory T-cells obtained from wildtype and pyruvate dehydrogenase knockout mouse. Disruption of the metabolic processes involving pyruvate dehydrogenase can affect T-cell differentiation through epigenetic and metabolic mechanisms.

2023-08-07 | GSE231554 | GEO

Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma

Project description:T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion either to lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and oxidative phosphorylation. Both groups had improved primary and memory recall responses following infection with murine gammaherpesvirus-68 (MHV-68). However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, after B cell lymphoma challenge the engineered CD8+ T cells produced smaller effector populations in the tumor, resulting in larger tumors and poorer survival compared with control cells. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.

2024-10-16 | GSE279041 | GEO

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