Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells

Membrane phospholipids affect GLUT function in RBC but the role of their large intercellular S1P pool is unknown. We show that altering S1P content by intervening in its precursor uptake, synthesis and efflux had major impacts on RBC glucose uptake and glycolysis. We identified the mechanism as direct activation of PP2A by S1P leading to cell-surface GLUT reduction. This mechanism was highly dynamic as it responded to metabolic cues from the environment by regulating intracellular S1P and thereby glucose uptake, hence counteracting pathophysiological conditions such as diabetes. Accordingly, RBC from hyperglycemic mice and humans with diabetes had higher S1P, Sphk1 and PP2A activities, and lower cell-surface GLUTs. Proof of concept is provided by the resistance of RBC lacking the main S1P exporter MFSD2B to pathological HbA1c increases in hyperglycemia. This mechanism may also be functional in other insulin-independent tissues and could be pharmacologically exploited by existing S1P homeostasis-modifying drugs.