Intracellular protein degradation is a tightly regulated process that in many cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major route by which cells not only remove normal proteins at the appropriate time but also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This has led to a major impetus to identify constituents of the pathway. The key components that regulate substrate ubiquitylation are the ubiquitin-protein ligases. Ligases come in many forms, from single proteins to very large multiprotein complexes. Specificity of targeting can be modulated by the requirement for post-translational modifications such as phosphorylation, hydroxylation or oxidation of the substrate and, in some cases, the ligase itself. The requirement for substrate modification prior to ubiquitylation allows the same ligase to target different substrates within the same cell at different times. Abnormal intracellular protein processing is a common feature of many human diseases including neurodegenerative diseases and cancer. It may not represent the causative factor that initiates the disease process but may be a downstream regulator of the toxic effect. These abnormalities often arise from the loss of a key protein-protein interaction. As a consequence, mutated proteins can have very different half-lives from their normal counterparts. This can affect the levels of their activity and/or lead to the formation of protein aggregates (inclusion bodies/aggresomes). In this review, we aim to highlight examples of diseases where abnormal protein ubiquitylation is proposed to be a key regulator of the disease process. The recent success of the proteasome inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma suggests that the modulation of individual ubiquitin-protein ligase activities with synthetic agents may represent a novel approach that has enormous potential for the treatment of a wide range of diseases.

译文

:细胞内蛋白质降解是一个严格调控的过程,在许多情况下是由蛋白质泛素化控制的。遍在蛋白途径是细胞不仅在适当的时间去除正常蛋白而且在正常或突变的细胞质和膜蛋白中异常折叠的主要途径。这导致了确定该途径成分的主要动力。调节底物泛素化的关键成分是泛素蛋白连接酶。从单个蛋白到非常大的多蛋白复合物,甘氨酸有多种形式。靶向的特异性可以通过翻译后修饰的要求来调节,例如底物的磷酸化,羟基化或氧化,在某些情况下还可以是连接酶本身。在泛素化之前对底物进行修饰的要求允许相同的连接酶在不同时间靶向同一细胞内的不同底物。细胞内蛋白质加工异常是许多人类疾病(包括神经退行性疾病和癌症)的普遍特征。它可能不代表引发疾病过程的病因,但可能是毒性作用的下游调节剂。这些异常通常是由于关键蛋白质与蛋白质相互作用的丧失而引起的。结果,突变的蛋白质的半衰期可能与其正常的半衰期截然不同。这可能会影响其活性水平和/或导致蛋白质聚集体(包涵体/聚集体)的形成。在这篇综述中,我们旨在突出疾病的例子,其中异常蛋白质泛素化被认为是疾病过程的关键调节因子。蛋白酶体抑制剂Bortezomib(PS-341)在治疗复发性难治性骨髓瘤方面的最新成功表明,合成剂对单个泛素蛋白连接酶活性的调节可能代表了一种新颖的方法,具有广泛的治疗潜力。疾病。

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