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

描述（由申请人提供）：IL-33通过其受体ST2L起作用，是一种与脓毒性损伤有关的高效细胞因子。IL-33/ST2L轴在炎症信号传导中是不可或缺的，因为ST2L受体的阻断可显著减轻全身性炎症。因此，选择性调节ST2L可用性的策略可能会减轻败血症的严重程度。然而，迄今为止，关于ST2L表达的分子调控知之甚少。在研究细菌性脓毒症的过程中，我们发现一种新的孤儿蛋白FBXL19 （F-box protein 19, SCFFBXL19）特异性靶向磷酸化的ST2L泛素化和降解。我们发表的和初步的研究也表明，ST2L被糖原合成酶激酶（GSK3¿）磷酸化，并且IL-33/ST2L轴的激活诱导PARP和PKC¿的切割，从而促进细胞凋亡。此外，FBXL19介导的ST2L处理可以减弱IL-33/ST2L诱导的促炎信号和细胞凋亡，并减轻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，即GSK3驱动的ST2L磷酸化是F-box蛋白介导的泛素化和ST2L降解在败血症相关损伤中的分子特征。我们将通过两个具体目的来验证这一假设：(1)研究GSK3¿促进ST2L降解和调节IL-33/ST2L信号传导的机制；(2)研究FBXL19及其配体促进ST2L泛素化和降解从而减轻脓毒性肺损伤的机制。这些研究将为一种相对较新的受体（ST2L）参与脓毒症的分子调控的重大机制进展奠定基础。这些研究的结果旨在为开发IL-33/ST2L通路的新型小分子抑制剂以减轻脓毒症诱导的器官损伤的严重程度提供策略基础。

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.