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Abstract
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.
Authors
Travis B. Lear, Alison C. McKelvey, John W. Evankovich, Shristi Rajbhandari, Tiffany A. Coon, Sarah R. Dunn, James D. Londino, Bryan J. McVerry, Yingze Zhang, Eleanor Valenzi, Christine L. Burton, Rachael Gordon, Sebastien Gingras, Karina C. Lockwood, Michael J. Jurczak, Robert Lafyatis, Mark J. Shlomchik, Yuan Liu, Bill B. Chen
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