Current landscape of the immunoproteasome: implications for disease and therapy
Zifeng Zou, Yanglin Hao, Zetong Tao, Weicong Ye, Zilong Luo, Xiaohan Li, Ran Li, Kexiao Zheng, Jiahong Xia, Chao‐Yu Guo, Xi Zhang, Jie Wu
Abstract
The immunoproteasome, an inflammation-induced proteasome variant, coordinates proteostasis and adaptive immunity by replacing constitutive subunits (β1, β2, β5) with inducible counterparts (β1i, β2i, β5i). This specialization enhances antigen processing for MHC class I presentation and oxidative protein clearance. Beyond immune regulation, it critically contributes to cardiovascular, respiratory, neurodegenerative, autoimmune, retinal, and oncological pathologies through mechanisms involving NF-κB activation, mitochondrial dysfunction, and inflammatory polarization. While β5i-specific inhibitors (e.g., ONX 0914) show therapeutic potential in preclinical models by mitigating proteotoxicity and inflammation, the immunoproteasome's dual roles-cytoprotective or pathogenic-are context-dependent, necessitating precise targeting strategies. This review synthesizes recent advances in immunoproteasome biology, disease mechanisms, and therapeutic prospects, while highlighting unresolved questions on subunit specificity and microenvironmental regulation.