The 11S-associated immunoproteasome in mitochondrial function and metabolic disorders

线粒体功能和代谢紊乱中的 11S 相关免疫蛋白酶体

• 批准号: 10681643
• 负责人: Do-Hyung Kim
• 金额: $ 40.79万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681643
• 关键词: Address; Aging; Anti-Inflammatory Agents; Autoimmune Diseases; Binding Proteins; Biochemical; Biogenesis; Catalytic Domain; Cell Culture Techniques; Cell model; Cells; Chronic; Chronic Active Hepatitis; Cirrhosis; Complex; Degradation Pathway; Diabetes Mellitus; Digestion; Disease; Energy Metabolism; Fatty Liver; Genes; Genetic Polymorphism; Glycolysis; Goals; Grant; Hepatic; Hepatocyte; High Fat Diet; Histopathologic Grade; Homeostasis; Human; Immune; Immunologics; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Knockout Mice; Lipodystrophy; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Modeling; Molecular; Mus; Mutation; Nature; Nutritional status; Obesity; Oxidative Phosphorylation; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Play; Population; Proteins; Proteomics; Rare Diseases; Rattus; Regulation; Respiration; Role; Signal Transduction; Systems Biology; Tissues; Ubiquitination; Work; aged; biological adaptation to stress; diet-induced obesity; experience; fatty acid oxidation; human disease; interest; liver biopsy; liver inflammation; liver metabolism; mitochondrial metabolism; mouse model; multicatalytic endopeptidase complex; preference; protein degradation; recruit; screening; therapeutic target

This proposed study concerns the proteolytic machinery that regulates tissue aging, inflammation, and metabolic deregulation. The proteasome population is largely shifted from the standard proteasome to the immunoproteasome under inflammation. The immunoproteasome is different from the standard proteasome in the 20S core three catalytic subunits. It has distinct processing kinetics and cleavage preferences, and associates with the 11S regulatory complex to perform ATP- and ubiquitination-independent degradation of proteins. Its expression is highly increased in high fat diet mouse liver and in liver biopsies from patients who have chronic active hepatitis or cirrhosis. The immunoproteasome level is highly increased in pathological hepatocytes from human in direct correlation with the histopathological grade of inflammation. The immunoproteasome is highly induced in aged mouse and rat tissues. Its prolonged presence can cause chronic inflammation and tissue damages and can have devastating effects on the stability of proteins, many of which are anti-inflammatory factors or homeostatic factors otherwise stable. Our study is based on the overarching concept that the immunoproteasome plays the major role in inflammation-specific degradation of proteins. The degradation may cause metabolic reprogramming and the transition between glycolysis and oxidative phosphorylation, shifting the cellular metabolism that fits in the inflammatory conditions. The long- term goal of our study is to understand the functions of the immunoproteasome in inflammatory metabolic diseases. Its strong relevance with inflammation, its immunological aspect of regulation, its dynamic nature, and its high expression in immune cells and aged tissues and high fat diet mouse tissues all point toward the possibility that the immunoproteasome might play crucial roles in inflammatory metabolic diseases. The objective of this proposed study is to define the mechanisms by which the immunoproteasome regulates energy metabolism via the selective digestion of key metabolic regulators. Despite its discovery nearly three decades ago, its specific function remains largely unknown other than its role in producing antigenic peptides. We have identified several regulators of the mitochondrial biogenesis and metabolism under the control by the immunoproteasome. We hypothesize that the immunoproteasome induces metabolic reprogramming by digestion of proteins involved in metabolic homeostasis. Although we do not exclude the possibility that the reprogramming might be protective in early stages of stress response, we hypothesize that its excessive, prolonged presence disturbs metabolic homeostasis. This grant will focus on the 11S-associated immunoproteasome, the major type of the proteasome during inflammation. We will pursue three specific aims. First, we will determine how the immunoproteasome perturbs mitochondrial metabolism using mouse and cellular models. Second, we will define the role of PA28alpha-associated immunoproteasome in hepatic metabolism. Third, we will identify the molecular factors that mediate 11S-immunoproteasome functions.

这项拟议的研究涉及调节组织衰老、炎症和炎症的蛋白水解机制。 代谢失调。蛋白酶体群体很大程度上从标准蛋白酶体转移到了 炎症下的免疫蛋白酶体。免疫蛋白酶体与标准蛋白酶体不同 在20S核心三个催化亚基中。它具有独特的加工动力学和裂解偏好，并且 与 11S 调节复合体结合，执行不依赖于 ATP 和泛素化的降解 蛋白质。它的表达在高脂肪饮食小鼠肝脏和来自以下患者的肝活检中高度增加： 患有慢性活动性肝炎或肝硬化。病理状态下免疫蛋白酶体水平显着升高 来自人类的肝细胞与炎症的组织病理学分级直接相关。这 免疫蛋白酶体在老年小鼠和大鼠组织中被高度诱导。它的长期存在会导致 慢性炎症和组织损伤，并对蛋白质的稳定性产生破坏性影响，许多 其中是抗炎因子或稳定的稳态因子。我们的研究基于 总体概念是免疫蛋白酶体在炎症特异性降解中起主要作用 蛋白质。降解可能导致代谢重编程以及糖酵解和糖酵解之间的转变 氧化磷酸化，改变适合炎症条件的细胞代谢。长- 我们研究的长期目标是了解免疫蛋白酶体在炎症代谢中的功能 疾病。它与炎症、其免疫学方面的调节、其动态性质密切相关， 它在免疫细胞和衰老组织以及高脂肪饮食小鼠组织中的高表达都表明 免疫蛋白酶体可能在炎症代谢疾病中发挥重要作用。这 这项研究的目的是确定免疫蛋白酶体调节的机制 通过选择性消化关键代谢调节剂来调节能量代谢。尽管发现了近三 几十年前，除了其在产生抗原肽中的作用之外，其具体功能仍然很大程度上未知。 我们已经确定了线粒体生物发生和代谢的几个调节因子 免疫蛋白酶体。我们假设免疫蛋白酶体通过以下方式诱导代谢重编程： 参与代谢稳态的蛋白质的消化。虽然我们不排除这种可能性 重编程可能在应激反应的早期阶段具有保护作用，我们假设其过度， 长时间存在会扰乱代谢稳态。这笔赠款将重点关注 11S 相关项目 免疫蛋白酶体，炎症过程中蛋白酶体的主要类型。我们将采取三项具体行动 目标。首先，我们将使用小鼠确定免疫蛋白酶体如何扰乱线粒体代谢 和细胞模型。其次，我们将定义 PA28α 相关免疫蛋白酶体在肝损伤中的作用。 代谢。第三，我们将确定介导 11S-免疫蛋白酶体功能的分子因素。