Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
Biochem Soc Trans. 2021 Feb 26;49(1):365-377. doi: 10.1042/BST20200694.
The accumulation of misfolded proteins is associated with numerous degenerative conditions, cancers and genetic diseases. These pathological imbalances in protein homeostasis (termed proteostasis), result from the improper triage and disposal of damaged and defective proteins from the cell. The ubiquitin-proteasome system is a key pathway for the molecular control of misfolded cytosolic proteins, co-opting a cascade of ubiquitin ligases to direct terminally damaged proteins to the proteasome via modification with chains of the small protein, ubiquitin. Despite the evidence for ubiquitination in this critical pathway, the precise complement of ubiquitin ligases and deubiquitinases that modulate this process remains under investigation. Whilst chaperones act as the first line of defence against protein misfolding, the ubiquitination machinery has a pivotal role in targeting terminally defunct cytosolic proteins for destruction. Recent work points to a complex assemblage of chaperones, ubiquitination machinery and subcellular quarantine as components of the cellular arsenal against proteinopathies. In this review, we examine the contribution of these pathways and cellular compartments to the maintenance of the cytosolic proteome. Here we will particularly focus on the ubiquitin code and the critical enzymes which regulate misfolded proteins in the cytosol, the molecular point of origin for many neurodegenerative and genetic diseases.
蛋白质错误折叠的积累与许多退行性疾病、癌症和遗传疾病有关。这些蛋白质平衡失调（称为蛋白质稳态）是由于细胞内受损和有缺陷的蛋白质的不当分类和处理而导致的。泛素-蛋白酶体系统是细胞溶质中错误折叠蛋白质分子控制的关键途径，通过用小蛋白泛素的链修饰，将终末受损的蛋白质募集到蛋白酶体。尽管在这个关键途径中存在泛素化的证据，但调节这个过程的确切的泛素连接酶和去泛素化酶的补体仍在研究中。虽然伴侣蛋白作为对抗蛋白质错误折叠的第一道防线，但泛素化机制在靶向终末失效的细胞质蛋白质进行破坏方面起着关键作用。最近的工作指出，伴侣蛋白、泛素化机制和亚细胞隔离是细胞对抗蛋白质病的武器库的组成部分。在这篇综述中，我们研究了这些途径和细胞区室对细胞质蛋白质组的维持的贡献。在这里，我们将特别关注泛素码和调节细胞质中错误折叠蛋白质的关键酶，这是许多神经退行性疾病和遗传疾病的分子起源点。
