One clinical hallmark of patients with severe pneumonia or sepsis-induced lung injury is a robust acute inflammatory host response triggered by the invading pathogens. Here, the innate immunity system is activated to secrete large amounts of pro-inflammatory cytokines (i.e. a cytokine storm) after invading pathogens activate receptors on immune effector cells (T-cells, macrophages, etc.). The TRAF family of adaptors molecules are pivotal and highly conserved proteins that link external surface signals (e.g. via Toll receptors) to cytokine release via NF-kB dependent signaling. Thus, maneuvers designed to selectively modulate the availability of TRAF family proteins might lessen the severity of sepsis. However, to date, very little is known regarding the molecular regulation of the TRAF family at the level of protein stability. In the process of studying bacterial sepsis, we discovere that an orphan ubiquitin E3 ligase subunit, termed FBXO3, is activated and sufficient to ubiquitinate and mediate proteasomal degradation of another relatively new ubiquitin E3 ligase subunit, termed FBXL2. Further, we discovered that FBXL2 is anti-inflammatory as it targets the TRAF family of proteins for their disposal in epithelia and monocytes. Thus, our preliminary work demonstrates that P. aeruginosa, via activation of FBXO3, results in FBXL2 ubiquitination and degradation resulting in increased immunoreactive TRAFs, increased cytokine production, and impaired lung stability. These data led to our novel hypothesis that P. aeruginosa induced cytokine release involves FBXO3 mediated ubiquitination and degradation of FBXL2, which in turn increases levels of TRAF proteins which are pro-inflammatory. We will determine if an orphan ubiquitin E3 ligase subunit, FBXO3, coordinates with GSK3b to trigger ubiquitination dependent degradation of FBXL2, which in turn activates TRAF proteins to stimulate cytokine release (Aim 1). We will also determine if mutation or inhibition of FBXO3 will attenuate bacterial-induced acute lung injury (Aim 2). This proposal provides a new model of innate immunity as it relates to cytokine signaling. Execution of these studies will lay the foundation fo a significant mechanistic advance regarding the molecular regulation of the innate immune response during severe bacterial infection. Results from these studies are intended to serve as the basis for strategies directed at the development of highly selective novel small molecule inhibitors of FBXO3 to lessen the severity of bacterial or sepsis-induced acute lung injury.
One clinical hallmark of patients with severe pneumonia or sepsis-induced lung injury is a robust acute inflammatory host response triggered by invading pathogens. This study identifies novel molecular mechanisms involving the TRAF family of adaptor molecules that control cytokine expression. Execution of these studies will serve as the basis for strategies directed at the development of highly selective novel small molecule inhibitors that lessen the severity of bacterial or sepsis-induced acute lung injury.
|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|
|Lear, Travis; Dunn, Sarah R; McKelvey, Alison C et al. (2017) RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling. Am J Physiol Cell Physiol 313:C584-C592|
|Chakraborty, Krishnendu; Raundhal, Mahesh; Chen, Bill B et al. (2017) The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun 8:13944|
|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|
|Lear, Travis; McKelvey, Alison C; Rajbhandari, Shristi et al. (2016) Ubiquitin E3 ligase FIEL1 regulates fibrotic lung injury through SUMO-E3 ligase PIAS4. J Exp Med 213:1029-46|
|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|
|Chiarchiaro, Jared; Chen, Bill B; Gibson, Kevin F (2016) New molecular targets for the treatment of sarcoidosis. Curr Opin Pulm Med 22:515-21|
|Buland, Justin R; Wasserloos, Karla J; Tyurin, Vladimir A et al. (2016) Biosynthesis of oxidized lipid mediators via lipoprotein-associated phospholipase A2 hydrolysis of extracellular cardiolipin induces endothelial toxicity. Am J Physiol Lung Cell Mol Physiol 311:L303-16|
|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|
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