Dynamic regulation of inflammatory TRAF proteins by FBXL2 and FBXO3. TNF receptor associated factor (TRAF) proteins have variable signaling effects and act to mediate inflammatory cell activation when active. SCFFBXL2 binds TRAFs, facilitating their ubiquitination under normal circumstances. In inflammatory disease, FBXO3 is upregulated, and leads to ubiquitination of FBXL2 by SCFFBXO3, with elimination of FBXL2 by the UPS. TRAF accumulation directly correlates with FBXO3 levels, with activation of many inflammatory pathways. The FBXO3 inhibitor BC-1215 prevents FBXL2 degradation, restoring TRAF disposal, and blunting inflammation.