Madhukar Geet, Haque Md Azizul, Khan Shawez, Kim Jong-Joo
Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA.
Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Biochem Pharmacol. 2025 Jun;236:116875. doi: 10.1016/j.bcp.2025.116875. Epub 2025 Mar 20.
Ubiquitination is a vital post-translational modification that regulates protein stability and various cellular processes through the addition of ubiquitin molecules. Central to this process are E3 ubiquitin ligases, which determine the specificity of ubiquitination by coordinating the attachment of ubiquitin to target proteins, influencing their degradation, localization, and activity. E3 ubiquitin ligases are involved in numerous cellular pathways, including DNA repair, cell proliferation, and immune responses. Dysregulation of E3 ubiquitin ligases is often associated with cancer, contributing to tumor progression and resistance to therapies. The development of targeted protein degraders, such as proteolysis-targeting chimeras (PROTACs), represents a significant advancement in drug discovery, leveraging the specificity of E3 ubiquitin ligases to selectively eliminate pathogenic proteins. However, challenges remain in translating this knowledge into effective therapies, including issues related to tissue-specific targeting and off-target effects. The limitations also include a limited understanding of ligase-substrate interactions that includes both the identification of novel E3 ligases and their substrates, as well as understanding the dynamic, context-dependent nature of these interactions, which can vary across tissue types or disease states This review emphasizes the therapeutic potential of E3 ubiquitin ligases, exploring their diverse roles in disease, their contribution to targeted degradation strategies while highlighting the need for further research to overcome current limitations and enhance therapeutic efficacy.
泛素化是一种重要的翻译后修饰，通过添加泛素分子来调节蛋白质稳定性和各种细胞过程。E3泛素连接酶是这一过程的核心，它们通过协调泛素与靶蛋白的连接来决定泛素化的特异性，影响靶蛋白的降解、定位和活性。E3泛素连接酶参与众多细胞途径，包括DNA修复、细胞增殖和免疫反应。E3泛素连接酶的失调常与癌症相关，促进肿瘤进展和对治疗的抗性。靶向蛋白降解剂的开发，如蛋白酶靶向嵌合体（PROTACs），代表了药物发现的重大进展，利用E3泛素连接酶的特异性来选择性消除致病蛋白。然而，将这一知识转化为有效疗法仍存在挑战，包括与组织特异性靶向和脱靶效应相关的问题。这些局限性还包括对连接酶-底物相互作用的理解有限，这既包括新型E3连接酶及其底物的鉴定，也包括理解这些相互作用的动态、依赖于上下文的性质，这种性质在不同组织类型或疾病状态下可能会有所不同。本综述强调了E3泛素连接酶的治疗潜力，探讨了它们在疾病中的多种作用、它们对靶向降解策略的贡献，同时强调了进一步研究以克服当前局限性并提高治疗效果的必要性。
