Department of Orthopedics, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Cell Infect Microbiol. 2022 Jul 22;12:905906. doi: 10.3389/fcimb.2022.905906. eCollection 2022.
E3 ubiquitin ligases determine the substrate specificity and catalyze the ubiquitination of lysine residues. HUWE1 is a catalytic HECT domain-containing giant E3 ligase that contains a substrate-binding ring structure, and mediates the ubiquitination of more than 40 diverse substrates. HUWE1 serves as a central node in cellular stress responses, cell growth and death, signal transduction, etc. The expanding atlas of HUWE1 substrates presents a major challenge for the potential therapeutic application of HUWE1 in a particular disease. In addition, HUWE1 has been demonstrated to play contradictory roles in certain aspects of tumor progression in either an oncogenic or a tumor-suppressive manner. We recently defined novel roles of HUWE1 in promoting the activation of multiple inflammasomes. Inflammasome activation-mediated immune responses might lead to multifunctional effects on tumor therapy, inflammation, and autoimmune diseases. In this review, we summarize the known substrates and pleiotropic functions of HUWE1 in different types of cells and models, including its involvement in development, cancer, neuronal disorder and infectious disease. We also discuss the advances in cryo-EM-structural analysis for a functional-mechanistic understanding of HUWE1 in modulating the multitudinous diverse substrates, and introduce the possibility of revisiting the comprehensive roles of HUWE1 in multiple aspects within one microenvironment, which will shed light on the potential therapeutic application of targeting giant E3 ligases like HUWE1.
E3 泛素连接酶决定了底物特异性，并催化赖氨酸残基的泛素化。HUWE1 是一种含有催化 HECT 结构域的巨 E3 连接酶，它含有一个底物结合环结构，并介导超过 40 种不同底物的泛素化。HUWE1 作为细胞应激反应、细胞生长和死亡、信号转导等的中心节点。HUWE1 底物的扩展图谱对 HUWE1 在特定疾病中的潜在治疗应用提出了重大挑战。此外，HUWE1 已被证明在肿瘤进展的某些方面以致癌或肿瘤抑制的方式发挥矛盾的作用。我们最近定义了 HUWE1 在促进多种炎症小体激活中的新作用。炎症小体激活介导的免疫反应可能对肿瘤治疗、炎症和自身免疫性疾病产生多功能影响。在这篇综述中，我们总结了 HUWE1 在不同类型的细胞和模型中的已知底物和多效性功能，包括其在发育、癌症、神经紊乱和传染病中的参与。我们还讨论了冷冻电镜结构分析在功能机制理解方面的进展，以了解 HUWE1 调节众多不同底物的作用，并介绍了重新审视 HUWE1 在一个微环境中的多个方面的综合作用的可能性，这将为靶向 HUWE1 等巨 E3 连接酶的潜在治疗应用提供启示。
