Emerging role of the immunoproteasome as a druggable target in lung inflammatory diseases

The ubiquitin-proteasome system is the primary system that mediates protein turn over through proteolytic activities in the 20S proteasome that catalyzes peptide hydrolysis. It is crucial for maintaining protein homeostasis and regulates many cellular processes including DNA repair, cell proliferation, and inflammatory responses. Immunoproteasome, a special class of proteasome with three distinct catalytic subunits β1i (LMP2), β2i (MECL-1), and β5i (LMP7), is induced in most cells in response to various stimuli. The subunits replacement alters proteasomal cleavage preference and enhances the generation of major histocompatibility complex I (MHC I) antigenic peptides. Immunoproteasome is involved in pathogenesis of inflammatory diseases by regulating T cells differentiation, macrophages polarization, proinflammatory cytokine production, and management of oxidative stress. In this review, we will discuss the impact of immunoproteasome dysfunctions in pulmonary diseases, such as asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). Selective inhibition of immunoproteasome has the potential to serve as a therapeutic tool to address these significant health challenges. This review underscores the substantial role of the immunoproteasome in mediating the progression of various human lung diseases and highlights its potential as a therapeutic target, offering promising avenues for intervention in response to these health challenges.