Metabolic and non-metabolic roles of PHGDH and their impact on T cell function

Cell-intrinsic metabolism underpins T cell differentiation and function. Metabolic enzymes can, however, also engage in non-metabolic (moonlighting) roles – which creates potential for functional incompatibilities. For the rate limiting enzyme in serine synthesis, PHGDH, we here describe a paradigm of such an incompatibility, demonstrating how, and at what price, metabolic function is traded off to block moonlighting during CD8+ T cell differentiation.
Complete serine restriction of CD8+ T cells triggered an extensive stress response orchestrated by a coordination of p53 and Myc – highlighting the importance of serine for T cells. Surprisingly therefore, PHGDH was only expressed in naïve but not memory CD8+ T cells, causing memory-selective serine auxotrophy and immunodeficiency in serine deplete hosts. Silencing of PHGDH was, however, a requirement for a normal naïve to memory transition to occur and, more broadly, a hallmark of differentiation across immune and non-immune cell lineages. Specific mutations in PHGDH, such as R163Q, are linked to differentiation-abnormalities and yet the R163Q variant showed near-normal enzymatic activity. This triggered a search for PHGDH moonlighting features, which identified PHGDH as RNA-binding protein (RBP) with affinity for cell-fate determining transcripts.
Our data establish a trade-off between metabolic activity and moonlighting of PHGDH in differentiating T cells, highlighting the integrated evolution of complex cellular processes and expanding the conceptual framework when interpreting cellular metabolic phenotypes.