School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
Fralin Biomedical Research Institute, Translational Biology, Medicine and Health, Virginia Polytechnic Institute and State University, Roanoke, VA, USA.
Neurobiol Learn Mem. 2020 Oct;174:107286. doi: 10.1016/j.nlm.2020.107286. Epub 2020 Aug 1.
Over the last 20 years, a number of studies have provided strong support for protein degradation mediated by the ubiquitin-proteasome system in synaptic plasticity and memory formation. In this system, target substrates become covalently modified by the small protein ubiquitin through a series of enzymatic reactions involving hundreds of different ligases. While some substrates will acquire only a single ubiquitin, most will be marked by multiple ubiquitin modifications, which link together at specific lysine sites or the N-terminal methionine on the previous ubiquitin to form a polyubiquitin chain. There are at least eight known linkage-specific polyubiquitin chains a target protein can acquire, many of which are independent of the proteasome, and these chains can be homogenous, mixed, or branched in nature, all of which result in different functional outcomes and fates for the target substrate. However, as the focus has remained on protein degradation, much remains unknown about the role of these diverse ubiquitin chains in the brain, particularly during activity- and learning-dependent synaptic plasticity. Here, we review the different types and functions of ubiquitin chains and summarize evidence suggesting a role for these diverse ubiquitin modifications in synaptic plasticity and memory formation. We conclude by discussing how technological limitations have limited our ability to identify and elucidate the role of different ubiquitin chains in the brain and speculate on the future directions and implications of understanding linkage-specific ubiquitin modifications in activity- and learning-dependent synaptic plasticity.
在过去的 20 年中，许多研究为泛素-蛋白酶体系统介导的突触可塑性和记忆形成中的蛋白质降解提供了强有力的支持。在这个系统中，靶底物通过涉及数百种不同连接酶的一系列酶反应被共价修饰小蛋白泛素。虽然一些底物只会获得一个单一的泛素，但大多数底物将被多个泛素修饰标记，这些修饰在特定赖氨酸位点或前一个泛素的 N-末端甲硫氨酸处连接在一起，形成多泛素链。靶蛋白可以获得至少八种已知的连接特异性多泛素链，其中许多与蛋白酶体无关，这些链可以是同质的、混合的或分支的，所有这些都会导致靶底物的不同功能结果和命运。然而，由于研究重点一直放在蛋白质降解上，对于这些不同的泛素链在大脑中的作用，尤其是在活动和学习依赖性突触可塑性方面，仍有许多未知。在这里，我们回顾了不同类型和功能的泛素链，并总结了这些不同泛素修饰在突触可塑性和记忆形成中的作用的证据。最后，我们讨论了技术限制如何限制了我们识别和阐明不同泛素链在大脑中的作用的能力，并推测了在活动和学习依赖性突触可塑性中理解连接特异性泛素修饰的未来方向和影响。
