Ciechanover Aaron, Iwai Kazuhiro
Department of Biochemistry, and the Rappaport Family Institute for Research in the Medical Sciences, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
IUBMB Life. 2004 Apr;56(4):193-201. doi: 10.1080/1521654042000223616.
In the ubiquitin system, a target substrate is modified by ubiquitin or a ubiquitin-like protein. This modification remodels the surface of the target proteins, affecting, among other properties, their stability, interactions with other proteins, activity, and subcellular localization. At least 10 different modifiers have been described in mammalian cells and conjugation of each modifier to its target may result in a different biological effect. In many cases proteins are modified by multiple moieties of ubiquitin that generate a branched polyubiquitin chain. For most proteins, this modification leads to their degradation by the 26S proteasome. Yet, dependent on the character of the internal linkage between the ubiquitin moieties, it can also lead to activation of transcriptional regulators. Modification by a single moiety of ubiquitin can target proteins for degradation in the lysosome/vacuole. Conjugation of ubiquitin or ubiquitin-like proteins can serve a variety of non-proteolytic functions, such as activation of enzymes, modulation of membrane dynamics, or routing of the tagged proteins to their sub-cellular destination. Ubiquitination of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that targets, in a specific manner, thousands of cellular proteins. It is carried out by a modular cascade of enzymes with high specificity towards defined structural motifs in the target proteins. It has emerged as a critically important post-translational modification that plays major roles in regulating a broad array of basic cellular processes, such as cell division, differentiation, signal transduction, trafficking, and quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many diseases, certain malignancies, neurodegenerative disorders and pathologies of the inflammatory and immune response among them. Understanding of the underlying mechanisms involved is important for the development of novel, mechanism-based drugs.
在泛素系统中，靶底物会被泛素或类泛素蛋白修饰。这种修饰重塑了靶蛋白的表面，除其他特性外，还会影响其稳定性、与其他蛋白的相互作用、活性以及亚细胞定位。在哺乳动物细胞中已描述了至少10种不同的修饰因子，每种修饰因子与其靶标的结合可能会产生不同的生物学效应。在许多情况下，蛋白质会被多个泛素部分修饰，从而形成分支多聚泛素链。对于大多数蛋白质而言，这种修饰会导致它们被26S蛋白酶体降解。然而，取决于泛素部分之间内部连接的性质，它也可能导致转录调节因子的激活。单个泛素部分的修饰可将蛋白质靶向溶酶体/液泡进行降解。泛素或类泛素蛋白的结合可发挥多种非蛋白水解功能，例如酶的激活、膜动力学的调节或标记蛋白向其亚细胞目的地的转运。细胞蛋白的泛素化是一个高度复杂、受时间控制且严格调控的过程，它以特定方式靶向数千种细胞蛋白。它由一系列对靶蛋白中特定结构基序具有高度特异性的酶组成的模块化级联反应来执行。它已成为一种至关重要的翻译后修饰，在调节广泛的基本细胞过程中发挥着主要作用，如细胞分裂、分化、信号转导、运输和质量控制。毫不奇怪，该系统的异常与许多疾病的发病机制有关，其中包括某些恶性肿瘤、神经退行性疾病以及炎症和免疫反应的病理学。了解其中的潜在机制对于开发新型的基于机制的药物很重要。
