Meray Robin K, Lansbury Peter T
Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, Cambridge, Massachusetts 02139, USA.
J Biol Chem. 2007 Apr 6;282(14):10567-75. doi: 10.1074/jbc.M611153200. Epub 2007 Jan 26.
Deubiquitinating enzymes (DUBs) are negative regulators of protein ubiquitination and play an important role in ubiquitin-dependent processes. Recent studies have found that diverse cellular mechanisms are employed to control the activity of DUBs. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a highly expressed neuronal DUB linked to Parkinson disease; however, little is known about its specific functions or modes of regulation. Here, we demonstrate that UCH-L1 is post-translationally modified by monoubiquitin in cells, at lysine residues near the active site. This modification restricts enzyme activity by preventing binding to ubiquitinated targets, and permanent monoubiquitination, as mimicked by a ubiquitin-UCH-L1 fusion, inhibits UCH-L1 in its capacity to increase free ubiquitin levels in cells. Interestingly, UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, thereby regulating the lifetime of this modification. Our results illustrate monoubiquitination as a reversible regulatory mechanism for DUB activity involving auto-deubiquitination.
去泛素化酶（DUBs）是蛋白质泛素化的负调控因子，在泛素依赖性过程中发挥重要作用。最近的研究发现，多种细胞机制被用于控制DUBs的活性。泛素C末端水解酶-L1（UCH-L1）是一种与帕金森病相关的高表达神经元DUB；然而，对其具体功能或调控模式知之甚少。在这里，我们证明UCH-L1在细胞中在活性位点附近的赖氨酸残基处被单泛素进行翻译后修饰。这种修饰通过阻止与泛素化靶标的结合来限制酶活性，并且如泛素-UCH-L1融合所模拟的永久性单泛素化抑制UCH-L1增加细胞中游离泛素水平的能力。有趣的是，UCH-L1以分子内方式催化自身的去泛素化，从而调节这种修饰的寿命。我们的结果表明单泛素化是一种涉及自去泛素化的DUB活性的可逆调控机制。
