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<p>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.</p> Graphical Abstract <p>This schematic illustrates the dual role of the immunoproteasome in inflammation. Under protective conditions (left), acute or viral lung insults trigger transient Th1 responses and M1 macrophage polarization, promoting antiviral immunity and proinflammatory defense. These mechanisms are facilitated by immunoproteasome-mediated antigen processing and cytokine production. In contrast, chronic lung disease (right panel) shifts the immune landscape toward sustained Th2 activation, M2 macrophage polarization, and progressive airway remodeling. In this setting, elevated immunoproteasome activity—particularly through the LMP7 (β5i) subunit—amplifies pathogenic Th2 responses by enhancing T cell survival, boosting cytokine output (IL-4, IL-5, IL-13), and reinforcing M2 polarization. This underscores the therapeutic paradox of immunoproteasome targeting in lung disease: while inhibition may offer anti-inflammatory benefits, it also poses potential risks to immune surveillance and host defense.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • Jiaxing Miao,
  • Nargis Shaheen,
  • Yutong Zhao,
  • Jing Zhao

摘要

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.

Graphical Abstract

This schematic illustrates the dual role of the immunoproteasome in inflammation. Under protective conditions (left), acute or viral lung insults trigger transient Th1 responses and M1 macrophage polarization, promoting antiviral immunity and proinflammatory defense. These mechanisms are facilitated by immunoproteasome-mediated antigen processing and cytokine production. In contrast, chronic lung disease (right panel) shifts the immune landscape toward sustained Th2 activation, M2 macrophage polarization, and progressive airway remodeling. In this setting, elevated immunoproteasome activity—particularly through the LMP7 (β5i) subunit—amplifies pathogenic Th2 responses by enhancing T cell survival, boosting cytokine output (IL-4, IL-5, IL-13), and reinforcing M2 polarization. This underscores the therapeutic paradox of immunoproteasome targeting in lung disease: while inhibition may offer anti-inflammatory benefits, it also poses potential risks to immune surveillance and host defense.