KIAA0317 regulates pulmonary inflammation through SOCS2 degradation
Autor: | James D. Londino, Travis Lear, Rachael A. Gordon, Karina C. Lockwood, Robert Lafyatis, Shristi Rajbhandari, Michael J. Jurczak, John Evankovich, Christine L. Burton, Tiffany A. Coon, Bill B. Chen, Alison C. McKelvey, Yingze Zhang, Mark J. Shlomchik, Eleanor Valenzi, Sarah R. Dunn, Yuan Liu, Bryan J. McVerry, Sebastien Gingras |
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Rok vydání: | 2019 |
Předmět: |
Adult
Male 0301 basic medicine Ubiquitin-Protein Ligases medicine.medical_treatment Suppressor of Cytokine Signaling Proteins Inflammation Proinflammatory cytokine Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Ubiquitin medicine Animals Humans Lung SOCS2 Aged Mice Knockout biology business.industry Pneumonia General Medicine Middle Aged Immunity Innate Ubiquitin ligase Mice Inbred C57BL Molecular Docking Simulation 030104 developmental biology medicine.anatomical_structure Cytokine 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines Female medicine.symptom Transcriptome business Research Article Protein Binding |
Zdroj: | JCI Insight. 4 |
ISSN: | 2379-3708 |
Popis: | Dysregulated proinflammatory cytokine release has been implicated in the pathogenesis of several life-threatening acute lung illnesses such as pneumonia, sepsis, and acute respiratory distress syndrome. Suppressors of cytokine signaling proteins, particularly SOCS2, have recently been described as antiinflammatory mediators. However, the regulation of SOCS2 protein has not been described. Here we describe a mechanism of SOCS2 regulation by the action of the ubiquitin E3 ligase KIAA0317. KIAA0317-mediated degradation of SOCS2 exacerbated inflammation in vitro, and depletion of KIAA0317 in vivo ameliorated pulmonary inflammation. KIAA0317-knockout mice exhibited resistance to LPS-induced pulmonary inflammation, while KIAA03017 reexpression mitigated this effect. We uncovered a small molecule inhibitor of KIAA0317 protein (BC-1365) that prevented SOCS2 degradation and attenuated LPS- and P. aeruginosa-induced lung inflammation in vivo. These studies show KIAA0317 to be a critical mediator of pulmonary inflammation through its degradation of SOCS2 and a potential candidate target for therapeutic inhibition. |
Databáze: | OpenAIRE |
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