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 and 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 a constitutively active isoform of gluconeogenic enzyme, fructose 1,6-bisphosphatase 1 (FBP1), facilitates re-entry of glucose carbons into the pentose phosphate pathway to ensure the sustained production of NADPH for redox homeostasis and lipid synthesis in stimulated T cells as they transition to a phase of rapid growth, and is essential for their unperturbed clonal expansion and for an effective immune response. Wildtype (wt) FBP1, which catalyzes hydrolysis of fructose-1,6 bisphosphate in an irreversible reaction, has a C-terminal catalytic domain and an inhibitory N-terminal regulatory domain. We demonstrate that a short isoform of FBP1 representing the catalytic domain is induced in human T cells within 24 hours of co-stimulation. The short isoform, FBP1-CD, is the product of an alternatively spliced transcript and is resistant to inhibitors that suppress activity of wt FBP1, which harbors the regulatory domain. FBP1-CD levels and enzyme activity are significantly reduced 5 days post-stimulation, correlating positively with proliferation and inversely with ROS and apoptosis in T cells. In addition to new insights into immune regulation, our studies reveal a broader role for FBP1 in regulating proliferative metabolism and offer a rational explanation for the suppression of FBP1 in solid tumors. Supported by grant from NIH (R21 AI168777)