biostudies-literatureLear TBNIAMSNHLBINIDDK NIH HHSNHLBI NIH HHSNHBLINIAMS NIH HHSNIDDK129110https://www.ebi.ac.uk/biostudies/studies/S-EPMC6795399biostudies-literatureUnknown4(19)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 moleculeJCI insightKIAA0317 regulates pulmonary inflammation through SOCS2 degradation.PMC6795399R01 DK119627DK119627R35 HL139860P01 HL114453HL144820HL139860HL143843HL142777HL133184AR060780P50 AR060780F31 HL143843T32 HL007563R01 HL133184K08 HL144820R01 HL142777Burton CLRajbhandari SDunn SRMcKelvey ACShlomchik MJEvankovich JWGingras SLafyatis RChen BBLockwood KCValenzi EGordon RLondino JDLiu YJurczak MJZhang YCoon TALear TBMcVerry BJfalseKIAA0317 regulates pulmonary inflammation through SOCS2 degradation.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 molecule2019-01-01T00:00:00Z2019 Oct2026-04-15T23:16:57.632Z2019-11-07T08:04:43ZS-EPMC67953993157831210.1172/jci.insight.129110