Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Mol Cell. 2011 Aug 19;43(4):599-612. doi: 10.1016/j.molcel.2011.05.036.
The mechanisms by which ubiquitin ligases are regulated remain poorly understood. Here we describe a series of molecular events that coordinately regulate CHIP, a neuroprotective E3 implicated in protein quality control. Through their opposing activities, the initiator E2, Ube2w, and the specialized deubiquitinating enzyme (DUB), ataxin-3, participate in initiating, regulating, and terminating the CHIP ubiquitination cycle. Monoubiquitination of CHIP by Ube2w stabilizes the interaction between CHIP and ataxin-3, which through its DUB activity limits the length of chains attached to CHIP substrates. Upon completion of substrate ubiquitination, ataxin-3 deubiquitinates CHIP, effectively terminating the reaction. Our results suggest that functional pairing of E3s with ataxin-3 or similar DUBs represents an important point of regulation in ubiquitin-dependent protein quality control. In addition, the results shed light on disease pathogenesis in SCA3, a neurodegenerative disorder caused by polyglutamine expansion in ataxin-3.
泛素连接酶的调控机制仍知之甚少。本文描述了一系列协调调控 CHIP 的分子事件，CHIP 是一种神经保护 E3，参与蛋白质质量控制。通过它们相反的活性，起始 E2、Ube2w 和特异性去泛素化酶（DUB）ataxin-3 参与启动、调节和终止 CHIP 的泛素化循环。Ube2w 对 CHIP 的单泛素化稳定了 CHIP 和 ataxin-3 之间的相互作用，ataxin-3 通过其 DUB 活性限制了连接到 CHIP 底物上的链的长度。在完成底物泛素化后，ataxin-3 去泛素化 CHIP，有效地终止反应。我们的结果表明，E3 与 ataxin-3 或类似 DUB 的功能配对代表了泛素依赖性蛋白质质量控制中的一个重要调控点。此外，这些结果揭示了 SCA3 的发病机制，SCA3 是一种神经退行性疾病，由 ataxin-3 中的多聚谷氨酰胺扩展引起。
