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: 8499556
• 负责人: Yutong Zhao
• 金额: $ 35.8万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499556
• 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; Immunology; Inflammation; Inflammatory; Injury; Knockout Mice; Ligands; Ligation; Lysosomes; Mediating; Medicine; Modeling; Molecular; Molecular Profiling; Mus; Nature; Organ; Orphan; Pathway interactions; Patients; Phosphorylation; Pneumonia; Process; Proteins; Publishing; 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; public health relevance; 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（由适用提供）：通过其受体ST2L起作用的IL-33是在化粪池损伤中实施的高潜在细胞因子。 IL-33/ST2L轴在炎​​症信号传导中似乎是必不可少的，因为ST2L接收器的阻塞会显着减弱全身性炎症。这是为了选择性调节ST2L的可用性的操作可能会降低败血症的严重性。但是，迄今为止，关于ST2L表达的分子调节知之甚少。在研究细菌败血症的过程中，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用于其泛素化和降解。我们发表的和初步的作品还表明，ST2L被糖原合酶激酶（GSK3¿）磷酸化，并且IL-33/ST2L轴的激活会诱导PARP和PKC的裂解，从而促进凋亡。此外，FBXL19介导的ST2L处置减弱了IL-33/ST2L诱导的促炎信号传导，凋亡，并降低了化粪池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，即ST2L的GSK3驱动的磷酸化是F-box蛋白介导的sT2L在败血症相关损伤中介导的ST2L的泛素化和降解的分子特征。我们将通过执行两个具体目的来检验这一假设：（1）研究GSK3缺的机制促进ST2L降解并调节IL-33/ST2L信号传导，以及（2）研究FBXL19及其配体及其配体促进ST2L Ubiquitination and deveradation和Degrangation的机制。这些研究将为败血症所涉及的相对新受体（ST2L）的分子调节而进行重大的机械进步奠定基础。这些研究的结果旨在作为针对IL-33/ST2L途径的新型小分子抑制剂发展的策略的基础，以减轻败血症诱导的器官损伤的严重程度。