Department of Physiology, National University of Singapore, Singapore.
Neurobiol Dis. 2011 Jul;43(1):9-16. doi: 10.1016/j.nbd.2010.08.001. Epub 2010 Aug 7.
The proteasome, which identifies and destroys unwanted proteins rapidly, plays a vital role in maintaining cellular protein homeostasis. Proteins that are destined for proteasome-mediated degradation are usually tagged with a chain of ubiquitin linked via lysine (K) 48 that targets them to the proteolytic machinery. However, when the proteasome becomes compromised in its function, it is attractive to think that the cell may switch to an alternative, non-proteolytic form of ubiquitination that could help divert cargo proteins away from an otherwise overloaded proteasome. Of the several types of ubiquitin chain topologies, K63-linked ubiquitination is the only one known to fulfil diverse proteasome-independent roles, including DNA repair, endocytosis and NFκB signaling. By virtue of its apparent dissociation from the proteasome, we have originally proposed that K63-linked ubiquitination may be involved in cargo diversion during proteasomal stress and accordingly, in the biogenesis of inclusion bodies associated with neurodegenerative diseases. Here, we provide an overview of this non-classic form of ubiquitin modification, and discuss current evidence and controversies surrounding our proposed role for K63 polyubiquitin as a key regulator of inclusion dynamics that is relevant to neurodegeneration. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."
蛋白酶体通过识别和快速降解不需要的蛋白质，在维持细胞蛋白质平衡中起着至关重要的作用。通常，那些注定要被蛋白酶体介导降解的蛋白质会被一连串通过赖氨酸（K）48 连接的泛素标记，这些泛素将它们靶向到蛋白酶体的降解机制中。然而，当蛋白酶体的功能受损时，人们可能会认为细胞可能会切换到一种替代的、非蛋白水解的泛素化形式，这种形式可以帮助将货物蛋白从过载的蛋白酶体中转移出去。在几种泛素链拓扑结构中，只有 K63 连接的泛素化被认为具有多种独立于蛋白酶体的作用，包括 DNA 修复、内吞作用和 NFκB 信号转导。由于其明显与蛋白酶体解离，我们最初提出 K63 连接的泛素化可能参与蛋白酶体应激期间的货物转移，因此，参与与神经退行性疾病相关的包涵体的生物发生。在这里，我们概述了这种非经典形式的泛素修饰，并讨论了目前围绕我们提出的 K63 多泛素作为与神经退行性变相关的包涵体动力学的关键调节剂的作用的证据和争议。本文是题为“神经疾病中的自噬和蛋白质降解”的特刊的一部分。
