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发挥作用，是一种与败血症损伤有关的高度有效的细胞因子。IL-33/ST2L轴在炎症信号中似乎是不可或缺的，因为阻断ST2L受体可以显着减轻全身炎症。因此，有选择地调节ST2L的可用性的手法可能会减轻脓毒症的严重程度。然而，到目前为止，对ST2L表达的分子调控知之甚少。在研究细菌败血症的过程中，我们发现了一种新的孤儿蛋白FBXL19(F-box Protein 19，SCFFBXL19)，它特异性地针对磷酸化的ST2L进行泛素化和降解。我们已发表的和初步的工作还表明，ST2L被糖原合成酶激酶(GSK3？)磷酸化，IL-33/ST2L轴的激活诱导PARP和PKC的裂解，从而促进细胞凋亡。此外，FBXL19介导的ST2L处理减轻了IL-33/ST2L诱导的促炎信号和细胞凋亡，并减轻了脓毒症小鼠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脓毒症相关损伤中ST2L降解的分子标志。我们将通过执行两个特定的目标来验证这一假说：(1)研究GSK3促进ST2L降解和调节IL-33/ST2L信号的机制；(2)研究FBXL19及其配体促进ST2L泛素化和降解从而减轻感染性肺损伤的机制。这些研究将为脓毒症中一种相对较新的受体(ST2L)的分子调控奠定重要的机制进展。这些研究的结果旨在作为开发新型IL-33/ST2L途径小分子抑制剂的策略的基础，以减轻脓毒症引起的器官损伤的严重程度。

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.