Role of Protein Ubiquitination in Sepsis

蛋白质泛素化在脓毒症中的作用

• 批准号: 9551775
• 负责人: JIAN ZHANG
• 金额: $ 28.74万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9551775
• 关键词: Role; Protein; Ubiquitination; Sepsis

Project Summary Sepsis with its complications is a major challenge in contemporary medicine. Approximately 250,000 cases of sepsis lead to fatalities in the USA annually at huge costs for the healthcare system. Depending on the standards of medical care, the worldwide mortality rates in septic humans range from 30% to 70% with an aggregate mortality rate of ~50%. NLRP3 is a key component of the macromolecular signaling complex called the inflammasome that promotes caspase 1-dependent production of IL-1β pro-inflammatory cytokine involved in the development of sepsis. Although the factors leading to NLRP3 inflammasome activation have been extensively studied, the mechanisms for negatively regulating the activation of the NLRP3 inflammasome, and thus, controlling sepsis, are not known. We found that NLRP3 is inhibited by ubiquitination by Cbl-b, an E3 ubiquitin ligase. The significance of this finding is demonstrated by the observation that that lipopolysaccharide (LPS) injection or cecal ligation and puncture (CLP) induces a significant mortality in Cblb-/- mice compared to wild-type (WT) controls, and this increased mortality in Cblb-/- mice induced by LPS is blocked by an IL-1 receptor antagonist or by introducing NLRP3 deficiency. Therefore, our central hypothesis is that during sepsis, Cbl-b is autoubiquitinated/activated and ubiquitinates NLRP3, which in turn inhibits NLRP3 and attenuates NLRP3-mediated innate responses. We propose to determine 1) how Cbl-b regulates NLRP3 inflammasome activation; 2) whether and how Cbl-b controls non-canonical NLRP3 inflammasome in vivo using CLP-induced sepsis and LPS-induced septic shock as the study models. Understanding the role of Cbl-b in regulating the NLRP3 inflammasome-mediated signaling pathway will provide novel insights and therapeutic strategies to combat sepsis.

项目摘要 败血症具有并发症是当代医学的主要挑战。大约25万例 败血症每年导致美国死亡人数，医疗系统的巨额成本。取决于 医疗标准，化粪池的全球死亡率在30％至70％不等 总死亡率约为50％。 NLRP3是大分子信号传导复合物的关键组成部分 促进caspase 1依赖性产生IL-1β促炎性细胞因子的炎性体 在败血症的发展中。尽管导致NLRP3炎性体激活的因素已经 广泛研究的是负面控制NLRP3炎症体的激活的机制， 因此，尚不清楚控制败血症。我们发现NLRP3被CBL-B泛素化抑制了E3 泛素连接酶。这一发现的意义证明了那种脂多糖的观察结果 （LPS）注射或盲肠结扎和穿刺（CLP）与CBLB - / - 小鼠相比诱导了显着的死亡率 野生型（WT）对照，并且LPS诱导的CBLB - / - 小鼠的死亡率增加被IL-1阻断 受体拮抗剂或引入NLRP3缺乏症。因此，我们的中心假设是在败血症期间 CBL-B是自义/激活和泛素化的NLRP3，进而抑制NLRP3并减弱 NLRP3介导的先天反应。我们建议确定1）CBL-B如何调节NLRP3炎症体 激活; 2）使用CLP诱导 败血症和LPS引起的败血性休克作为研究模型。了解CBL-B在调节 NLRP3炎性介导的信号通路将为新颖的见解和治疗策略提供 战斗败血症。