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

这项拟议的研究涉及调节组织衰老、炎症和 新陈代谢放松管制。蛋白酶体种群在很大程度上从标准的蛋白酶体转移到 炎症状态下的免疫蛋白酶体。免疫蛋白酶体不同于标准蛋白酶体 在20年代的核心有三个催化亚基。它有明显的加工动力学和切割偏好，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。它在高脂饮食小鼠的肝脏和患者的肝活检组织中的表达显著增加。 有慢性活动性肝炎或肝硬变。病理组织中免疫蛋白酶体水平显著升高。 人肝细胞与炎症组织病理分级直接相关。这个 免疫蛋白酶体在衰老的小鼠和大鼠组织中高度诱导。它的长时间存在会导致 慢性炎症和组织损伤，并可能对蛋白质的稳定性产生破坏性影响，许多 其中是抗炎因子或动态平衡因子，否则是稳定的。我们的研究是基于 主要概念是免疫蛋白酶体在炎症特异性降解中发挥主要作用 蛋白质。降解可能导致代谢重新编程和糖酵解和 氧化磷酸化，改变细胞的新陈代谢，以适应炎症条件。长的- 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作用 疾病。它与炎症密切相关，它的免疫调节方面，它的动态性质， 其在免疫细胞、衰老组织和高脂饮食小鼠组织中的高表达均指向 免疫蛋白酶体在炎症性代谢性疾病中发挥关键作用的可能性。这个 这项拟议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进行能量代谢。尽管发现了近三个 几十年前，除了在产生抗原肽方面的作用外，它的具体功能在很大程度上仍不清楚。 我们已经确定了线粒体生物发生和代谢的几个调节因子，这些调控因子通过 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 消化参与代谢动态平衡的蛋白质。尽管我们不排除 重新编程可能在压力反应的早期阶段起到保护作用，我们假设它过度， 长时间的存在会扰乱代谢动态平衡。这笔赠款将重点放在与11S相关的 免疫蛋白酶体，炎症过程中蛋白酶体的主要类型。我们将追求三个具体的目标 目标。首先，我们将用小鼠来确定免疫蛋白酶体是如何干扰线粒体代谢的。 和细胞模型。其次，我们将确定PA28Alpha相关免疫蛋白酶体在肝脏中的作用 新陈代谢。第三，我们将确定调节11S免疫蛋白酶体功能的分子因素。

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.