Bidirectional glutamine transport enables B-cell activation and transformation 3034

Abstract Description Comparing proteome changes during B-cell activation and transformation, we found strong induction of SLC7A5, which simultaneously mediates leucine uptake and glutamine export. However, the significance of glutamine export is unknown. Slc7a5 deletion in transformed B cells, but not primary resting B-cells, resulted in accumulated intracellular glutamine, impaired cell fitness, and prolonged survival of transplant recipients. Interestingly, glutamine deprivation, and pharmacological glutamine sequestration, partially rescued cell fitness, suggesting imbalanced amino acid pool due to abnormal accumulation of glutamine likely impedes B-cell activation and transformation. Isotope tracing of (15N)2-glutamine showed increased nitrogen flux from glutamine to purine synthesis upon Slc7a5 deletion, at the expense of glutathione, NAD+, and glucosamine synthesis. Chemogenomic screen with a selective SLC7A5 inhibitor revealed that deletion of genes involved in nucleotide metabolism led to synthetic lethality, whereas deletion of genes involved in protein translation rescued growth inhibition. Moreover, Slc7a5-deficient cells were more resistant to rapamycin and CHX treatment. Our findings suggest that bidirectional glutamine transport balances amino acid pool, which enables rapid protein synthesis and cell proliferation of activated and malignant B-cells. This is consistent with marked upregulation of SLC7A5 on plasma cells, which rely on massive protein synthesis for antibody secretion. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)