Acute Respiratory Distress Syndrome (ARDS) affects almost a quarter million patients annually and has a mortality rate of over 40%. Its primary causes are pneumonia and sepsis. Central to the pathophysiology of this lung injury is a sustained immune response. With an exaggerated immune response, NF-?B mediated cytokine release leads to the devastating effects of pulmonary edema, multi-organ failure, and shock. Recently, we discovered a novel pathway for inflammation through protein ubiquitination, a universal mechanism whereby ubiquitin E3 ligases target proteins for degradation. We discovered that a pro-inflammatory, orphan HECT- domain ubiquitin (Ub) E3 ligase, termed KIAA0317, is activated after microbial infection. This E3 ligase ubiquitinates a potent anti-inflammatory protein termed SOCS2 (Suppressor of Cytokine Signaling 2), thereby marking it for degradation in the proteasome. SOCS2 not only suppresses the activation of signal transducers and activators of transcription (STATs), but also prevents NF-?B-dependent gene activation. Maneuvers designed to selectively modulate the abundance of SOCS2 might serve as a novel strategy for therapeutic intervention. However, to date, very little is known regarding the molecular regulation of SOCS2 at the level of protein stability. Our preliminary data suggest that (i) bacteria activates KIAA0317, which is sufficient to ubiquitinate and mediate the degradation of the inflammatory repressor SOCS2, (ii) KIAA0317 is a pro- inflammatory protein in vivo and in vitro, (iii) the kinase PKC? phosphorylates SOCS2, thereby creating a unique molecular signal for KIAA0317 targeting, and (iv) a novel small molecule inhibitor of KIAA0317, BC-1365, attenuates LPS and P. aeruginosa-induced cytokine secretion in vivo. These data led to our novel hypothesis that transcriptionally upregulated KIAA0317 specifically targets SOCS2 for ubiquitination and degradation, thus inducing inflammation and tissue injury. We will determine how KIAA0317 is regulated transcriptionally by bacterial pathogens and the molecular basis of how SOCS2 is targeted by KIAA0317, thereby upregulating NF-?B mediated inflammation. We will also determine whether KIAA0317 and its genetic variants can be used as novel biomarkers for inflammatory diseases (Aim 1). We will test KIAA0317 knockout mice in various experimental lung injury models to confirm that KIAA0317 is a druggable target. Further, we will design an optimal KIAA0317 antagonist using a quantitative structure-activity relationship (qSAR) based design and test its toxicity, target engagement, and anti-inflammatory activity both in vitro and in vivo (Aim 2). Last, this proposal unveils a new molecular model of lung injury as it relates to cytokine signaling. Our preliminary data have uncovered a novel protein, KIAA0317, which is linked to cytokine response through SOCS2 protein signaling. These studies will be the first to elucidate the enzymatic behavior of KIAA0317, which appears to activate the NF-?B-cytokine axis. Execution of these studies will lay the groundwork for a fundamental, paradigm-changing therapeutic advance for regulating innate immunity and treating inflammatory diseases that will ultimately set the stage for a new translational initiative.
One clinical hallmark of patients with ARDS is a robust acute inflammatory host response that is triggered by invading pathogens. This study identifies novel molecular mechanisms involving the KIAA0317/SOCS2 axis that control the inflammatory response and lung injury. Execution of these studies will serve as the basis for strategies directed at establishing novel biomarkers for ARDS and developing highly selective novel small molecule inhibitors that lessen the severity of 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; Chen, Bill B (2016) Therapeutic targets in fibrotic pathways. Cytokine 88:193-195 |
| McKelvey, Alison C; Lear, Travis B; Dunn, Sarah R et al. (2016) RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity. Elife 5: |
| 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 |
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