Abstract
Abstract TRAF3 is an adaptor protein that negatively regulates signaling through CD40 and BAFF receptor in B lymphocytes. B cells isolated from B cell conditional TRAF3-/- mice display a remarkable pro-survival phenotype compared to wild type B cells, but the mechanism for this abnormal survival is poorly understood. We find that CREB protein expression and activity - but not mRNA - were increased in TRAF3-/- B cells. Inhibition of activity of CREB and its co-activator molecule CBP attenuated the survival of TRAF3-/- B cells. Immune precipitation revealed that TRAF3 associated with both CREB and CBP preferentially in the nucleus in B cells. The TRAF-C domain was identified as necessary and sufficient for TRAF3 nuclear localization. The human TRAF3 mutant LP1 isolated from a myeloma tumor and lacking a TRAF-C domain, failed to localize to the nucleus or associate with CREB. Guided by results of microarray analysis, we found that the proteins Glut1 and Hexokinase II, two CREB targets important for glucose metabolism, were elevated in TRAF3-/- B cells and associated with enhanced glucose uptake and broad metabolic reprogramming in Seahorse extracellular flux analysis. We are currently investigating the importance of TRAF3-regulated metabolic changes to B cell survival.
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