Novel function for gluconeogenic enzyme, FBP1, in T cell activation and expansion

Abstract During an immune response, naïve T lymphocytes undergo rapid clonal expansion and must reprogram their metabolism to meet high energetic biosynthetic demands. The sudden increase in metabolic activity associated with a proliferative burst generates reactive oxygen species (ROS) increasing intracellular oxidative stress, which can disrupt homeostasis or trigger cell death, unless properly regulated. Our studies show that constitutively active isoform of gluconeogenic enzyme, fructose 1,6-bisphosphatase 1 (FBP1), facilitates re-entry glucose carbons into the pentose phosphate pathway ensure sustained production NADPH for redox lipid synthesis stimulated cells as they transition phase growth, is essential unperturbed effective response. Wildtype (wt) FBP1, catalyzes hydrolysis fructose-1,6 bisphosphate irreversible reaction, has C-terminal catalytic domain inhibitory N-terminal regulatory domain. We demonstrate short FBP1 representing induced human within 24 hours co-stimulation. isoform, FBP1-CD, product alternatively spliced transcript resistant inhibitors suppress wt harbors FBP1-CD levels enzyme are significantly reduced 5 days post-stimulation, correlating positively proliferation inversely ROS apoptosis cells. In addition new insights regulation, our reveal broader role regulating offer rational explanation suppression solid tumors. Supported by grant from NIH (R21 AI168777)