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Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism

Wesley H Godfrey, Kaho Cho, Xiaojing Deng

    Biorxiv : the Preprint Server for Biology
    |July 9, 2024
    PubMed

    Insights

    Phosphoglycerate mutase (PGAM) regulates regulatory T cell (Treg) function by impacting serine synthesis and one-carbon metabolism. Inhibiting PGAM or serine metabolism modulates Treg activity and autoimmune responses.

    Area of Science:

    • Immunology and Metabolism
    • Cellular Metabolism
    • Epigenetics

    Background:

    • Regulatory CD4 T cells (Tregs) are crucial for immune homeostasis and are influenced by metabolic reprogramming.
    • Glycolytic enzymes represent potential targets for immune modulation therapies.
    • Phosphoglycerate mutase (PGAM) is identified as a key enzyme in Treg differentiation and function.

    Purpose of the Study:

    • To investigate the role of glycolytic enzymes, specifically PGAM, in regulating Treg differentiation and suppressive functions.
    • To elucidate the metabolic pathways linking PGAM activity, serine synthesis, one-carbon metabolism, and Treg function.
    • To explore the therapeutic potential of targeting PGAM and associated metabolic pathways for autoimmune diseases.

    Main Methods:

    • Pharmacologic and genetic inhibition of PGAM in Tregs.
    • Analysis of Treg differentiation, suppressive function, and Th17-like cell induction.
    • Investigation of the role of 3-phosphoglycerate (3PG) in de novo serine synthesis.
    • In vivo studies using murine models of multiple sclerosis and autoimmune colitis, including dietary interventions (serine/glycine-free diet) and metabolic pathway inhibition.

    Main Results:

    • PGAM was overexpressed in Tregs and associated with a highly suppressive phenotype.
    • PGAM inhibition reduced Treg differentiation and suppressive function, promoting a pro-inflammatory Th17-like state.
    • PGAM's regulatory role was linked to serine synthesis from its substrate 3PG; blocking this pathway or adding exogenous serine reversed PGAM inhibition effects.
    • Altering serine levels in vivo attenuated autoimmunity in a multiple sclerosis model.
    • Serine limits Treg polarization via one-carbon metabolism and epigenetic methylation; inhibiting this pathway enhanced Treg function in autoimmune models.

    Conclusions:

    • PGAM plays a critical regulatory role in Treg differentiation and suppressive function.
    • A metabolic axis exists between glycolysis, serine synthesis, one-carbon metabolism, and Treg epigenetic regulation.
    • Targeting PGAM and related metabolic pathways offers a novel strategy for immune modulation in autoimmune diseases.

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