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Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE231556 | GEO | 2023/08/07

REPOSITORIES: GEO

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Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [ChIP-Seq]

Project description:Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A (Pdha) subunit using a CD4-cre recombinase-based strategy. Herein, we show that genetic ablation of PDC activity in T cells (TPdh-/-) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh-/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, including H3K27, a critical site for CD8+ T cell memory differentiation. Transcriptional and functional profiling revealed abnormal CD8+ memory T cell differentiation in vitro. Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.

2023-08-07 | GSE231433 | GEO

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [RNA-Seq]

2023-08-07 | GSE231553 | 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

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro

Project description:Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro

| PRJNA966906 | ENA

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [RNA-Seq]

Project description:Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [RNA-Seq]

| PRJNA966911 | ENA

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [ChIP-Seq]

Project description:Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory CD8+ T cell differentiation in vitro [ChIP-Seq]

| PRJNA965811 | ENA

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

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

| PRJNA966912 | ENA

Subunit and catalytic component stoichiometries of an in vitro reconstituted human pyruvate dehydrogenase complex.

Project description:The human pyruvate dehydrogenase complex (PDC) is a 9.5-megadalton catalytic machine that employs three catalytic components, i.e. pyruvate dehydrogenase (E1p), dihydrolipoyl transacetylase (E2p), and dihydrolipoamide dehydrogenase (E3), to carry out the oxidative decarboxylation of pyruvate. The human PDC is organized around a 60-meric dodecahedral core comprising the C-terminal domains of E2p and a noncatalytic component, E3-binding protein (E3BP), which specifically tethers E3 dimers to the PDC. A central issue concerning the PDC structure is the subunit stoichiometry of the E2p/E3BP core; recent studies have suggested that the core is composed of 48 copies of E2p and 12 copies of E3BP. Here, using an in vitro reconstituted PDC, we provide densitometry, isothermal titration calorimetry, and analytical ultracentrifugation evidence that there are 40 copies of E2p and 20 copies of E3BP in the E2p/E3BP core. Reconstitution with saturating concentrations of E1p and E3 demonstrated 40 copies of E1p heterotetramers and 20 copies of E3 dimers associated with the E2p/E3BP core. To corroborate the 40/20 model of this core, the stoichiometries of E3 and E1p binding to their respective binding domains were reexamined. In these binding studies, the stoichiometries were found to be 1:1, supporting the 40/20 model of the core. The overall maximal stoichiometry of this in vitro assembled PDC for E2p:E3BP:E1p:E3 is 40:20:40:20. These findings contrast a previous report that implicated that two E3-binding domains of E3BP bind simultaneously to a single E3 dimer (Smolle, M., Prior, A. E., Brown, A. E., Cooper, A., Byron, O., and Lindsay, J. G. (2006) J. Biol. Chem. 281, 19772-19780).

| S-EPMC2676041 | biostudies-literature

Monitoring phosphorylation of the pyruvate dehydrogenase complex.

Project description:The pyruvate dehydrogenase multienzyme complex (PDC) is a key regulatory point in cellular metabolism linking glycolysis to the citric acid cycle and lipogenesis. Reversible phosphorylation of the pyruvate dehydrogenase enzyme is a critical regulatory mechanism and an important point for monitoring metabolic activity. To directly determine the regulation of the PDC by phosphorylation, we developed a complete set of phospho-antibodies against the three known phosphorylation sites on the E1 alpha subunit of pyruvate dehydrogenase (PDHE1alpha). We demonstrate phospho-site specificity of each antibody in a variety of cultured cells and tissue extracts. In addition, we show sensitivity of these antibodies to PDH activity using the pyruvate dehydrogenase kinase-specific inhibitor dichloroacetate. We go on to use these antibodies to assess PDH phosphorylation in a patient suffering from Leigh's syndrome. Finally, we observe changes in individual phosphorylation states following a small molecule screen, demonstrating that these reagents should be useful for monitoring phosphorylation of PDHE1alpha and, therefore, overall metabolism in the disease state as well as in response to a myriad of physiological and pharmacological stimuli.

| S-EPMC2713743 | biostudies-literature

Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex.

Project description:The human pyruvate dehydrogenase complex (PDC) is regulated by reversible phosphorylation by four isoforms of pyruvate dehydrogenase kinase (PDK). PDKs phosphorylate serine residues in the dehydrogenase (E1p) component of PDC, but their amino-acid sequences are unrelated to eukaryotic Ser/Thr/Tyr protein kinases. PDK3 binds to the inner lipoyl domains (L2) from the 60-meric transacetylase (E2p) core of PDC, with concomitant stimulated kinase activity. Here, we present crystal structures of the PDK3-L2 complex with and without bound ADP or ATP. These structures disclose that the C-terminal tail from one subunit of PDK3 dimer constitutes an integral part of the lipoyl-binding pocket in the N-terminal domain of the opposing subunit. The two swapped C-terminal tails promote conformational changes in active-site clefts of both PDK3 subunits, resulting in largely disordered ATP lids in the ADP-bound form. Our structural and biochemical data suggest that L2 binding stimulates PDK3 activity by disrupting the ATP lid, which otherwise traps ADP, to remove product inhibition exerted by this nucleotide. We hypothesize that this allosteric mechanism accounts, in part, for E2p-augmented PDK3 activity.

| S-EPMC1142596 | biostudies-literature

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