Current landscape of the immunoproteasome: implications for disease and therapy.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-08-25 DOI:10.1038/s41420-025-02698-0

Zifeng Zou, Yanglin Hao, Zetong Tao, Weicong Ye, Zilong Luo, Xiaohan Li, Ran Li, Kexiao Zheng, Jiahong Xia, Chao Guo, Xi Zhang, Jie Wu

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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.

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免疫蛋白酶体的现状：对疾病和治疗的影响。

免疫蛋白酶体是一种炎症诱导的蛋白酶体变体，通过用诱导的对应物（β1i, β2i, β5i）取代组成亚基（β1, β2, β5）来协调蛋白质稳态和适应性免疫。这种专门化增强了MHC I类递呈和氧化蛋白清除的抗原处理。除了免疫调节外，它还通过NF-κB激活、线粒体功能障碍和炎症极化等机制对心血管、呼吸、神经退行性、自身免疫、视网膜和肿瘤病理起重要作用。虽然β5i特异性抑制剂（如ONX 0914）通过减轻蛋白质毒性和炎症在临床前模型中显示出治疗潜力，但免疫蛋白酶体的双重作用-细胞保护或致病-依赖于环境，需要精确的靶向策略。本文综述了免疫蛋白酶体生物学、疾病机制和治疗前景的最新进展，同时强调了亚基特异性和微环境调节方面尚未解决的问题。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.