Molecular regulation of immunoproteasome assembly in inflammatory diseases

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Severe bacterial infections are a major cause of global mortality and morbidity. An aberrant host response to infection leads to destructive inflammation and extensive tissue damage, resulting in organ dysfunction and multi- organ failure. An increasing incidence of gram-negative bacteria (GNB) resistance to antibiotics has been associated with increased mortality and significant public health problems in the world over last two decades. Uncontrollable inflammation is a critical feature of GNB pneumonia-induced acute respiratory distress syndrome (ARDS), a devastating complication of severe sepsis. Since there are no specific treatment available, current research focuses on identifying new drug targets to diminish pro-inflammatory responses. Dysfunction of protein homeostasis in immune system has been known to contribute to the pathogenesis of systemic inflammation. Protein degradation is mainly controlled by the proteasome. Recently, a specific subgroup of the proteasome called the immunoproteasome has been identified to play a critical role in inflammatory responses including antigen presentation. In the preliminary study, we found that endotoxin increases immunoproteasome structural assembly; however, the molecular regulation of immunoproteasome structural assembly and its role in the pathogenesis of ARDS have not been revealed. We hypothesize that deubiquitinase USP14 determines immunoproteasome structural assembly, and that inhibition of the immunoproteasome diminishes NLPR3 inflammasome activation and GNB-induced inflammation. We will determine molecular mechanisms by which USP14 activation regulates LPS-induced immunoproteasome structural assembly. Next, we will determine the mechanisms underlying how the phosphorylation of USP14 by PKCδ promotes immunoproteasome structural assembly and severity of GNB-induced lung injury and sepsis. We will use state-of the art molecular approaches, human samples, and preclinical animal models. The data will lay the foundation for a significant mechanistic advancement regarding the molecular regulation of the pro-inflammatory responses through the modulation of the inducible immunoproteasome structural assembly, which are implicated in the pathogenesis of acute bacterial infection.