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

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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.