哮喘中泛素-蛋白酶体系统：机制与治疗可能性
2025/10/11
摘要
泛素-蛋白酶体系统（Ubiquitin-Proteasome System，UPS）通过翻译后修饰调节蛋白质的稳定性和活性，在哮喘中起着至关重要的作用。本文综述了哮喘中42种UPS成分，包括1种E2泛素偶联酶、27种E3泛素连接酶、8种去泛素化酶（DUB）、1种双功能（E3和DUB）酶和5种26S蛋白酶体成分。我们的分析集中在四个关键的病理特征，包括气道炎症、高反应性、粘液高分泌和重塑。我们鉴定了25对E3连接酶－底物对和7对dub －底物对，详细介绍了它们的泛素化和去泛素化机制。此外，一项文献综述结合GWAS数据显示，9个UPS基因中的20个单核苷酸多态性（SNP）与哮喘易感性相关。治疗性评估突出了24个可用药的UPS靶点。此外，我们强调了24种UPS相关化合物，其中10种已确定与哮喘相关，14种显示出未开发的潜力。新兴的治疗策略，如PROTACs和纳米疫苗，显示出很大的潜力。总的来说，这些发现为UPS介导的哮喘机制和遗传学提供了新的见解，并突出了其作为治疗靶点的潜力，为未来的研究和临床应用铺平了道路。
The Ubiquitin-Proteasome System in Asthma: Mechanisms and Therapeutic Possibilities
Shuangyu He, Siqi Wen, Zhen Wang, Yonggang Qu, Chongyu Xu, Danni Li, Jiapeng Hu
Abstract
The ubiquitin-proteasome system (UPS) plays a crucial role in asthma by regulating protein stability And activity through post-translational modifications. This review provides a comprehensive Analysis of 42 UPS components in asthma, including one E2 ubiquitin-conjugating enzyme, 27 E3 ubiquitin ligases, eight deubiquitinating enzymes (DUBs), one dual-function (both E3 and DUB) enzyme, And five components of the 26S proteasome. Our Analysis focuses on four key pathological features, including airway inflammation, hyperresponsiveness, mucus hypersecretion, And remodeling. We identify 25 E3 ligase-substrate pairs and seven DUB-substrate pairs, detailing their ubiquitination and deubiquitination mechanisms. Additionally, a Literature review combined with GWAS data reveals 20 single-nucleotide polymorphisms (SNPs) across nine UPS Genes associated with asthma susceptibility. Therapeutic evaluations highlight 24 druggable UPS targets. Furthermore, we underscore 24 UPS-related compounds, with ten having established relevance to asthma And 14 exhibiting untapped potential. Emerging treatment strategies such as PROTACs and nanovaccines show promising potential. Overall, these findings provide new insights into UPS-mediated mechanisms and genetics in asthma and highlight its potential as a therapeutic target, paving the way for future research and clinical applications.
泛素-蛋白酶体系统（Ubiquitin-Proteasome System，UPS）通过翻译后修饰调节蛋白质的稳定性和活性，在哮喘中起着至关重要的作用。本文综述了哮喘中42种UPS成分，包括1种E2泛素偶联酶、27种E3泛素连接酶、8种去泛素化酶（DUB）、1种双功能（E3和DUB）酶和5种26S蛋白酶体成分。我们的分析集中在四个关键的病理特征，包括气道炎症、高反应性、粘液高分泌和重塑。我们鉴定了25对E3连接酶－底物对和7对dub －底物对，详细介绍了它们的泛素化和去泛素化机制。此外，一项文献综述结合GWAS数据显示，9个UPS基因中的20个单核苷酸多态性（SNP）与哮喘易感性相关。治疗性评估突出了24个可用药的UPS靶点。此外，我们强调了24种UPS相关化合物，其中10种已确定与哮喘相关，14种显示出未开发的潜力。新兴的治疗策略，如PROTACs和纳米疫苗，显示出很大的潜力。总的来说，这些发现为UPS介导的哮喘机制和遗传学提供了新的见解，并突出了其作为治疗靶点的潜力，为未来的研究和临床应用铺平了道路。
（中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校）
（Clin Rev Allergy Immunol. 2025 Sep 11;68(1):86. doi: 10.1007/s12016-025-09081-y.）
The Ubiquitin-Proteasome System in Asthma: Mechanisms and Therapeutic Possibilities
Shuangyu He, Siqi Wen, Zhen Wang, Yonggang Qu, Chongyu Xu, Danni Li, Jiapeng Hu
Abstract
The ubiquitin-proteasome system (UPS) plays a crucial role in asthma by regulating protein stability And activity through post-translational modifications. This review provides a comprehensive Analysis of 42 UPS components in asthma, including one E2 ubiquitin-conjugating enzyme, 27 E3 ubiquitin ligases, eight deubiquitinating enzymes (DUBs), one dual-function (both E3 and DUB) enzyme, And five components of the 26S proteasome. Our Analysis focuses on four key pathological features, including airway inflammation, hyperresponsiveness, mucus hypersecretion, And remodeling. We identify 25 E3 ligase-substrate pairs and seven DUB-substrate pairs, detailing their ubiquitination and deubiquitination mechanisms. Additionally, a Literature review combined with GWAS data reveals 20 single-nucleotide polymorphisms (SNPs) across nine UPS Genes associated with asthma susceptibility. Therapeutic evaluations highlight 24 druggable UPS targets. Furthermore, we underscore 24 UPS-related compounds, with ten having established relevance to asthma And 14 exhibiting untapped potential. Emerging treatment strategies such as PROTACs and nanovaccines show promising potential. Overall, these findings provide new insights into UPS-mediated mechanisms and genetics in asthma and highlight its potential as a therapeutic target, paving the way for future research and clinical applications.
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