A novel role for fructose 1,6-bisphosphatase in early T cell activation

Abstract

T cells reprogram their metabolism upon activation, switching to aerobic glycolysis and diverting glucose to biosynthetic pathways to acquire the necessary building blocks for supporting rapid expansion. The sudden increase in metabolic activity associated with a rapid proliferation generates reactive oxygen species (ROS), increasing intracellular oxidative stress that can disrupt intracellular homeostasis and lead to death. Here, we demonstrate that fructose 1,6-bisphosphatase (FBP1), a key metabolic enzyme that catalyzes an irreversible rate-limiting step in gluconeogenesis, is activated in stimulated T cells for a function unrelated to gluconeogenesis. We have identified a short isoform of FBP1 that is generated from the alternative splicing of FBP1 messenger RNA in stimulated T cells. We show that this isoform is enzymatically active and resistant to inhibition. We propose that the function of this novel isoform of FBP1 is to help maintain oxidative homeostasis in activated T cells by promoting the entry of glucose into the pentose phosphate pathway to increase the production of NADPH, the major reducing power in T cells, to avoid excessive reactive oxygen species buildup. The FBP1 gene has been widely reported to be suppressed or mutated in multiple cancers and FBP1 expression can inhibit growth and metastasis in those cancers. Thus, understanding the reason why FBP1 is differentially regulated in human T cells and cancer cells may have implications for developing a new potential prognostic predictor and a drug target that could be broadly applied to develop treatments for FBP1-deficient cancers.