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.
Pneumonia is a major cause of morbidity and mortality among Veterans and evidence suggest that patients die from overwhelming inflammation in the lung. This inflammation is caused from the release of proteins, called cytokines. This application studies a new pathway by which cytokines are produced in pneumonia. Execution of these studies will provide a significantly new conceptual advance in understanding how pneumonia occurs. Importantly, this application outlines new drug interventions that set the stage for use of novel therapies for this potentially fatal condition.
|Evankovich, John; Lear, Travis; Mckelvey, Alison et al. (2017) Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation. FASEB J 31:3894-3903|
|Han, SeungHye; Jerome, Jacob A; Gregory, Alyssa D et al. (2017) Cigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination. Respir Res 18:2|
|Lendermon, Elizabeth A; Coon, Tiffany A; Bednash, Joseph S et al. (2017) Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respir Res 18:131|
|Londino, James D; Gulick, Dexter L; Lear, Travis B et al. (2017) Post-translational modification of the interferon-gamma receptor alters its stability and signaling. Biochem J 474:3543-3557|
|Bednash, Joseph S; Weathington, Nathaniel; Londino, James et al. (2017) Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity. Nat Commun 8:15203|
|Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51|
|Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64|
|Liu, Yuan; Mallampalli, Rama K (2016) Small molecule therapeutics targeting F-box proteins in cancer. Semin Cancer Biol 36:105-19|
|Bednash, Joseph S; Mallampalli, Rama K (2016) Regulation of inflammasomes by ubiquitination. Cell Mol Immunol 13:722-728|
|Krzysiak, Troy C; Chen, Bill B; Lear, Travis et al. (2016) Crystal structure and interaction studies of the human FBxo3 ApaG domain. FEBS J 283:2091-101|
Showing the most recent 10 out of 50 publications