Department of Human Genetics, Leiden University Medical Centre, 2333ZC Leiden, The Netherlands.
Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, U.K.
Biochem Soc Trans. 2024 Jun 26;52(3):1085-1098. doi: 10.1042/BST20230562.
In vivo, muscle and neuronal cells are post-mitotic, and their function is predominantly regulated by proteostasis, a multilayer molecular process that maintains a delicate balance of protein homeostasis. The ubiquitin-proteasome system (UPS) is a key regulator of proteostasis. A dysfunctional UPS is a hallmark of muscle ageing and is often impacted in neuromuscular disorders (NMDs). Malfunction of the UPS often results in aberrant protein accumulation which can lead to protein aggregation and/or mis-localization affecting its function. Deubiquitinating enzymes (DUBs) are key players in the UPS, controlling protein turnover and maintaining the free ubiquitin pool. Several mutations in DUB encoding genes are linked to human NMDs, such as ATXN3, OTUD7A, UCHL1 and USP14, whilst other NMDs are associated with dysregulation of DUB expression. USP5, USP9X and USP14 are implicated in synaptic transmission and remodeling at the neuromuscular junction. Mice lacking USP19 show increased maintenance of lean muscle mass. In this review, we highlight the involvement of DUBs in muscle physiology and NMDs, particularly in processes affecting muscle regeneration, degeneration and inflammation following muscle injury. DUBs have recently garnered much respect as promising drug targets, and their roles in muscle maturation, regeneration and degeneration may provide the framework for novel therapeutics to treat muscular disorders including NMDs, sarcopenia and cachexia.
在体内，肌肉和神经元细胞是有丝分裂后的，它们的功能主要受蛋白质稳态调节，这是一个多层次的分子过程，维持着蛋白质稳态的微妙平衡。泛素-蛋白酶体系统 (UPS) 是蛋白质稳态的主要调节剂。UPS 功能障碍是肌肉衰老的标志，并且经常受到神经肌肉疾病 (NMD) 的影响。UPS 的功能障碍通常会导致异常蛋白质积累，从而导致蛋白质聚集和/或错误定位，影响其功能。去泛素化酶 (DUBs) 是 UPS 的关键参与者，控制着蛋白质的周转和游离泛素池的维持。几个 DUB 编码基因的突变与人类 NMD 有关，例如 ATXN3、OTUD7A、UCHL1 和 USP14，而其他 NMD 与 DUB 表达的失调有关。USP5、USP9X 和 USP14 参与神经肌肉接头的突触传递和重塑。缺乏 USP19 的小鼠表现出维持瘦肌肉质量的能力增加。在这篇综述中，我们强调了 DUBs 在肌肉生理学和 NMD 中的作用，特别是在影响肌肉损伤后肌肉再生、退化和炎症的过程中的作用。DUBs 最近作为有前途的药物靶点备受关注，它们在肌肉成熟、再生和退化中的作用可能为治疗肌肉疾病（包括 NMD、肌肉减少症和恶病质）提供新的治疗框架。
