Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease

摘要 肺中不受控制的细胞因子风暴导致有害作用，如中性粒细胞流入、毛细血管炎、炎症和炎症。 渗漏、组织水肿和器官衰竭常表现为肺炎引起的急性肺损伤（ALI）。 溶血磷脂酸受体1（LPA 1）是促炎性G蛋白偶联受体，其诱导促炎性细胞因子的产生。 通过Gα介导的信号传导和与内毒素受体CD 14相互作用释放炎性细胞因子。 LPA 1与肺部炎症性疾病的发病机制有关。击倒或抑制 LPA 1减弱内毒素或博来霉素诱导的肺损伤和脓毒症。我们发现LPA 1的稳定性 在泛素-溶酶体系统中调节。泛素特异性蛋白酶11（USP 11）去泛素化， 稳定LPA 1，从而促进LPA 1调节的促炎作用。USP 11的敲除降低了 LPA 1稳定性和减弱LPA和LPS诱导的肺部炎症。这是第一个证明 LPA 1的不稳定性降低了肺部炎症，而去泛素化酶有助于 肺损伤的发病机制。我们已经开发了一种小阻断肽（LDPep）来中断相互作用 在LPA 1和USP 11之间，它特异性地降低LPA 1蛋白水平，而不改变其他蛋白的表达。 LPA受体和USP 11靶蛋白。LDPep后处理减轻内毒素诱导的肺损伤， 败血症休克该项目将探索一种新的治疗方法，用于治疗炎症性疾病， 急性肺损伤和败血症。这些研究的执行将为在生物医学领域取得重大的机械进展奠定基础。 严重感染期间促炎反应的分子调节。这些研究的结果可以 作为进一步开发使LPA 1不稳定的药理学试剂的基础， 炎性疾病如肺损伤和脓毒症的严重程度。

Abstract An uncontrolled cytokine storm in lungs leads to detrimental effects such as neutrophil influx, capillary leakage, tissue edema, and organ failure often manifested as pneumonia-induced acute lung injury (ALI). Lysophosphatidic acid receptor 1 (LPA1) is a pro-inflammatory G protein coupled receptor, which induces pro- inflammatory cytokine release through Gα-mediated signaling and interaction with endotoxin receptor, CD14. LPA1 has been implicated in the pathogenesis of lung inflammatory disorders. Knockdown or inhibition of LPA1 attenuates endotoxin- or bleomycin-induced lung injury and sepsis. We discovered that LPA1 stability is regulated in the ubiquitin-lysosome system. Ubiquitin-specific protease 11 (USP11) deubiquitinates and stabilizes LPA1, thus promoting LPA1-modulated pro-inflammatory effects. Knockdown of USP11 reduces LPA1 stability and attenuates both LPA- and LPS-induced lung inflammation. This is the first to demonstrate that destabilizing LPA1 reduces lung inflammation, and deubiquitinating enzyme contributes to the pathogenesis of lung injury. We have developed a small blocking peptide (LDPep) to interrupt the interaction between LPA1 and USP11, which specifically reduces LPA1 protein level, without altering expression of other LPA receptors and USP11 target proteins. LDPep post-treatment lessens endotoxin-induced lung injury and sepsis shock. This project will explore a novel therapeutic approach for treating inflammatory disorders like ALI and sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance in the molecular regulation of pro-inflammatory responses during severe infection. Results from these studies can serve as the basis for further development of pharmacologic agents that destabilize LPA1, thereby reducing severity of inflammatory diseases such as lung injury and sepsis.