Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism
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ABSTRACT:
PROVIDER: PRJNA1124004 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29411118_1.fastq.gz | Fastqsanger.gz | |||
| SRR29411118_2.fastq.gz | Fastqsanger.gz | |||
| SRR29411119_1.fastq.gz | Fastqsanger.gz | |||
| SRR29411119_2.fastq.gz | Fastqsanger.gz | |||
| SRR29411120_1.fastq.gz | Fastqsanger.gz |
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Project description:The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Addi-tionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and at-tenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-car-bon metabolism, and epigenetic regulation of Treg differentiation and suppressive function
2025-06-06 | GSE269846 | GEO
Project description:Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Here, using integrative metabolomics and transcriptomics analyses, we show a heterogeneity between metabolite and transcript profiles. Specifically, the level of serine in HCC tissues is increased, whereas the expression of phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme in serine biosynthesis pathway, is dramatically downregulated. Interestingly, the increased serine level is obtained by enhanced PHGDH catalytic activity due to protein arginine methyltransferase 1 (PRMT1)-mediated methylation of PHGDH at arginine 236. PRMT1-mediated PHGDH methylation and activation potentiates serine synthesis, ameliorates oxidative stress, and promotes HCC growth in vitro and in vivo. FBXO7, an E3 ubiquitin ligase which is downregulated in human HCC tissues, ubiquitinates and downregulates PRMT1 to suppress PHGDH methylation and serine synthesis, leading to the inhibition of HCC cell growth. Furthermore, PRMT1-mediated PHGDH methylation correlates with PHGDH hyperactivation and serine accumulation in human HCC tissues, and is predictive of poor prognosis of HCC patients. Notably, blocking PHGDH methylation with a TAT-tagged non-methylated peptide inhibits serine synthesis and restrains HCC growth, both in an HCC patient-derived xenograft (PDX) model and subcutaneous HCC cell-derived xenograft model. Overall, our findings reveal a novel regulatory mechanism of PHGDH activity and serine synthesis, and suggest PHGDH methylation as a potential therapeutic vulnerability in HCC.
2022-07-11 | GSE207435 | GEO
Project description:Cancer cells are often addicted to de novo serine synthesis to support their survival and rapid proliferation. However, how serine synthesis is regulated in cancer is not well understood. Our recent report demonstrated that protein arginine methyltransferase 1 (PRMT1) is upregulated in hepatocellular carcinoma (HCC) and methylates phosphoglycerate dehydrogenase (PHGDH, the first and rate-limiting enzyme in serine synthesis) at arginine 236, thereby activating PHGDH and promoting serine synthesis. Nevertheless, the mechanisms underlying upregulation of PRMT1 and regulation of PRMT1-PHGDH axis in HCC remain unknown. Here, using label-free quantitative proteomics analysis, we identified the potential interacting proteins of PRMT1.
2024-02-01 | PXD049069 |
Project description:Serine synthesis is crucial for tumor growth and survival, but its regulatory mechanism in cancer remains elusive. Phosphoglycerate dehydrogenase (PHGDH) is the first rate-limiting enzyme in serine biosynthesis pathway. Here, we analyzed immunoprecipitated PHGDH from human HEK293T cells by liquid chromatography tandem mass spectrometry (LC-MS/MS), and identified the potential interacting proteins of PHGDH.
2022-07-29 | PXD035287 |
Project description:Serine is a non-essential amino acid that is generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition to serine synthesis, exogenous serine is taken up by cells and can also fuel tumor growth. Interestingly, colon cancer cells increase expression of serine biosynthesis enzymes in the absence of exogenous serine, suggesting a compensatory adaptive response to reduced availability of serine. This study explored the relative contributions of exogenous and synthesized serine to colon cancer cell growth, metabolism and response to anti-cancer therapy.
2021-11-04 | GSE144506 | GEO
Project description:A hallmark of Idiopathic Pulmonary Fibrosis is the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by lung fibroblasts requires de novo synthesis of glycine, the most abundant amino acid in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts through mTORC1 and ATF4-dependent transcriptional programs. SHMT2, the final enzyme of the de novo serine/glycine synthesis pathway, transfers a one-carbon unit from serine to tetrahydrofolate (THF), producing glycine and 5,10-methylene-THF (meTHF). meTHF is converted back to THF in the mitochondrial one-carbon (1C) pathway through the sequential actions of MTHFD2 (which converts meTHF to 10-formyl-THF), and either MTHFD1L, which produces formate, or ALDH1L2, which produces CO2. It is unknown how the mitochondrial 1C pathway contributes to glycine biosynthesis or collagen protein production in fibroblasts, or fibrosis in vivo. Here, we demonstrate that TGF-β induces the expression of MTHFD2, MTHFD1L, and ALDH1L2 in human lung fibroblasts. MTHFD2 expression was required for TGF-β-induced cellular glycine accumulation and collagen protein production.
2025-07-16 | GSE302114 | GEO
Project description:Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine can stimulate glutathione (GSH) synthesis and feeds into the one-carbon metabolic cycle essential for effector T cell (Teff) responses. However, serine’s functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis, and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc-ablation does not impair Treg differentiation, the mutant mice develop severe spontaneous autoimmunity and show enhanced anti-tumor responses. Gclc-deficient Tregs exhibit increased serine metabolism, mTOR activation and proliferation but FoxP3 was downregulated. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity to Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
2020-04-01 | GSE145311 | GEO
Project description:Here, we demonstrate that virus-infected macrophages display decreased expression of serine synthesis pathway (SSP) enzymes. Suppressing the SSP key enzyme phosphoglycerate dehydrogenase (PHGDH) by genetic approaches enhanced IFN-b-mediated antiviral innate immunity in vitro and in vivo. To further explore its mechanism, we used high-throughput sequencing technology (RNA-seq) to assess gene expression in PHGDH-deficiency BMDMs and RAW264.7 macrophages.
2021-01-29 | GSE165684 | GEO
Project description:CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME regulates Treg cell differentiation is not understood. Here we measured 630 metabolites in the TME and found that substrates required for the synthesis of sphingolipids, serine and palmitic acid, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits anti-tumor immunity.
2024-03-08 | GSE213756 | GEO
Project description:Here we show that suppressing the serine biosynthesis pathway, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase or by exogenous serine and glycine restriction, robustly enhances polarization of interferon-g-activated macrophages (M(IFN-g)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo.To further explore its mechanism, we used high-throughput sequencing technology (RNA-seq) to assess gene expression in serine-deficiency or not BMDMs
2022-02-19 | GSE196840 | GEO