Regulation of the IL-33 receptor, ST2L, by Protein Stability in Septic Injury

脓毒性损伤中蛋白质稳定性对 IL-33 受体 ST2L 的调节

• 批准号: 8851660
• 负责人: Yutong Zhao
• 金额: $ 37.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8851660
• 关键词: Acute; Acute Lung Injury; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Behavior; Binding; Chronic; Complex; Cytokine Receptors; Data; Development; Endotoxins; Exhibits; F Box Domain; F-Box Proteins; Family; Genes; Glycogen Synthase Kinases; Health; Immunology; Inflammation; Inflammatory; Injury; Knockout Mice; Ligands; Ligation; Lysosomes; Mediating; Medicine; Modeling; Molecular; Molecular Profiling; Mus; Nature; Organ; Orphan; Pathway interactions; Patients; Phosphorylation; Process; Proteins; Publishing; Pulmonary Inflammation; Regulation; Respiratory Failure; Scheme; Sepsis; Septic Shock; Severities; Signal Transduction; Surface; System; Testing; Therapeutic; Therapeutic Intervention; Ubiquitination; Work; base; cell injury; cytokine; design; inhibitor/antagonist; lung injury; multicatalytic endopeptidase complex; neutralizing antibody; novel; novel strategies; receptor; septic; small molecule; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): IL-33, acting via its receptor, ST2L, is a highly potent cytokine implicated in septic injury. The IL-33/ST2L axis appears indispensable in inflammatory signaling as blockade of the ST2L receptor significantly attenuates systemic inflammation. Thus, maneuvers designed to selectively modulate availability of ST2L might lessen the severity of sepsis. However, to date, very little is known regarding the molecular regulation of ST2L expression. In the process of studying bacterial sepsis, we discovered that a new orphan protein, FBXL19 (F-box protein 19, SCFFBXL19), specifically targets phosphorylated ST2L for its ubiquitination and degradation. Our published and preliminary works also shows that ST2L is phosphorylated by glycogen synthase kinase (GSK3¿), and that activation of the IL-33/ST2L axis induces cleavage of PARP and PKC¿ thereby promoting apoptosis. Further, FBXL19 mediated disposal of ST2L attenuates IL-33/ST2L-induced pro-inflammatory signaling, apoptosis, and lessens the severity of inflammatory organ injury in septic murine models. These data led to our novel hypothesis that GSK3¿-driven phosphorylation of ST2L serves as a molecular signature for F-box protein mediated ubiquitination and degradation of ST2L in sepsis-associated injury. We will test this hypothesis by executing two specific Aims: (1) To investigate the mechanisms by which GSK3¿ promotes ST2L degradation and regulates IL-33/ST2L signaling, and (2) To investigate the mechanisms by which FBXL19 and its ligand promotes ST2L ubiquitination and degradation thereby attenuating septic lung injury. These studies will lay the groundwork for a significant mechanistic advance with regard to the molecular regulation of a relatively new receptor (ST2L) involved in sepsis. Results from these studies are intended to serve as the basis for strategies directed at the development of novel small molecule inhibitors of the IL-33/ST2L pathway to lessen the severity of sepsis-induced organ injury.

描述（由申请人提供）：IL-33 通过其受体 ST2L 发挥作用，是一种与脓毒性损伤有关的高效细胞因子。IL-33/ST2L 轴似乎在炎症信号传导中不可或缺，因为 ST2L 受体的阻断可显着减轻全身炎症。因此，旨在选择性调节 ST2L 可用性的操作可能会减轻脓毒症的严重程度，但迄今为止，人们对 ST2L 的分子调节知之甚少。在研究细菌脓毒症的过程中，我们发现一种新的孤儿蛋白 FBXL19（F-box 蛋白 19，SCFFBXL19）专门针对磷酸化的 ST2L 进行泛素化和降解。被糖原合酶激酶 (GSK3¿) 磷酸化，IL-33/ST2L 轴的激活会诱导 PARP 和PKC??此外，FBXL19 介导的 ST2L 处理减弱了 IL-33/ST2L 诱导的促炎信号传导、细胞凋亡，并减轻了脓毒症小鼠模型中炎症器官损伤的严重程度。这些数据导致了我们的新假设：GSK3¿ ST2L 驱动的磷酸化是脓毒症相关损伤中 F-box 蛋白介导的 ST2L 泛素化和降解的分子特征，我们将通过执行两个特定目标来检验这一假设：(1) 研究 GSK3¿促进 ST2L 降解并调节 IL-33/ST2L 信号传导，以及 (2) 研究 FBXL19 及其配体促进 ST2L 泛素化和降解的机制，从而减轻脓毒性肺损伤。这些研究将为重大机制进展奠定基础。这些研究的结果旨在作为开发新型小分子策略的基础。 IL-33/ST2L 通路抑制剂可减轻脓毒症引起的器官损伤的严重程度。