Pheumonia is a leading cause of death among Veterans. A hallmark of pheumonia is acute lung injury resulting from a profound release of host cell cytokines. The tumor necrosis factor receptor associated factor (TRAF) proteins are critical in mediating cytokines responses, but little is known regarding their molecular regulation. Here we show that a ubiquitin E3 ligase subunit, termed F box protein FBXL2, serves as a sentinel inhibitor that mediates disposal of TRAF proteins to impair cytokines secretion in pro-inflammatory cells. Further, we discovered that a relatively new protein, termed F box protein FBX03, targets FBXL2 for degradation thereby stimulating cytokine release. FBX03 harbors a bacterial-like molecular signature that led to the development of a potent anti-inflammatory agent, BC1215. A loss-of-function naturally occurring FBX03 mutation was also identified in human subjects that lack ability to robustly express cytokines. Thus, in this proposal, we will test the hypothesis that antagonism or mutation of FBX03 results in reduced severity of acute lung injury from pneumonia by preserving levels of FBXL2, which in turn mediates degradation of TRAF proteins that are pro-inflammatory. To Evaluate this hypothesis,we will determine if during experimental pneumonia FBXO3 stimulates cytokine release by stabilizing TRAF proteins via degradation of the TRAF inhibitor, FBXL2 (Aim 1), determine if a novel small molecule FBXO3 antagonist, BC1215, lessens severity of acute lung injury during experimental pneumonia (Aim 2), and determine if a naturally occurring FBXO3 point mutation reduces severity of acute lung injury during pneumonia in hospitalized Veterans (Aim 3). In summary, this application unveils a new molecular model of innate immunity as it relates to cytokine signaling. Execution of these studies will lay the groundwork for a fundamental conceptual advance in the pathobiology of inflammation that sets the stage for a new translational initiative in Veterans with pneumonia.