Regulation of proteolysis by deubiquiting enzyme in lung inflammatory disease

肺部炎症疾病中去泛素化酶对蛋白水解的调节

• 批准号: 9237362
• 负责人: Yutong Zhao
• 金额: $ 37.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237362
• 关键词: Acids; Acute Lung Injury; Aftercare; Anti-inflammatory; Ants; Attenuated; Back; Bacterial Infections; Binding; Biological; Bleomycin; Blood capillaries; CD14 gene; Cell surface; Cells; Complex; Data; Deubiquitinating Enzyme; Development; Disease; Edema; Endotoxins; Enzymes; Epithelium; Etiology; Extravasation; Focal Infection; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Infection; Inflammatory; Inflammatory Response; Injury; Interruption; Ions; LTB4R gene; Life; Link; Lipopolysaccharides; Lung; Lung Inflammation; Lung diseases; Lysophosphatidic Acid Receptors; Lysosomes; Mediating; Modeling; Mole the mammal; Molecular; Morbidity - disease rate; Organ failure; Pathogenesis; Pathway interactions; Peptides; Pharmacology; Phosphorylation; Play; Pneumonia; Proteins; Pseudomonas aeruginosa; Recycling; Regulation; Regulation of Proteolysis; Research; Role; Scheme; Sepsis; Severities; Shock; Signal Transduction; System; Testing; Tissues; Ubiquitin; Ubiquitination; Up-Regulation; Virulent; base; capillary; clinical care; cytokine; endotoxin receptor; improved; inflammatory lung disease; knock-down; lung injury; mortality; neutrophil; novel; novel therapeutic intervention; novel therapeutics; pathogen; receptor; response; small molecule; ubiquitin isopeptidase; ubiquitin-specific protease

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.

抽象的 肺部不受控制的细胞因子风暴会导致有害影响，例如中性粒细胞流入、毛细血管 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 (LPA1) 是一种促炎 G 蛋白偶联受体，可诱导促炎症反应 通过 Gα 介导的信号传导以及与内毒素受体 CD14 的相互作用来释放炎症细胞因子。 LPA1 与肺部炎症性疾病的发病机制有关。击倒或抑制 LPA1 可减轻内毒素或博莱霉素引起的肺损伤和败血症。我们发现LPA1的稳定性是 在泛素-溶酶体系统中受到调节。泛素特异性蛋白酶 11 (USP11) 去泛素化并 稳定 LPA1，从而促进 LPA1 调节的促炎作用。 USP11 的击倒减少 LPA1 稳定性并减轻 LPA 和 LPS 诱导的肺部炎症。这是第一个演示的 破坏 LPA1 的稳定性可减少肺部炎症，而去泛素化酶有助于 肺损伤的发病机制。我们开发了一种小阻断肽（LDPep）来中断相互作用 LPA1 和 USP11 之间，特异性降低 LPA1 蛋白水平，而不改变其他蛋白的表达 LPA 受体和 USP11 靶蛋白。 LDPep 后处理可减轻内毒素引起的肺损伤 败血症休克。该项目将探索一种治疗炎症性疾病的新方法，例如 ALI 和败血症。这些研究的执行将为机械领域的重大进展奠定基础 严重感染期间促炎症反应的分子调节。这些研究的结果可以 作为进一步开发破坏 LPA1 稳定性的药物的基础，从而减少 肺损伤和败血症等炎症性疾病的严重程度。