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，许多研究为突触可塑性和记忆形成中泛素-蛋白酶体系统介导的蛋白质降解提供了强有力的支持。在该系统中，靶底物通过涉及数百种不同连接酶的一系列酶促反应被小蛋白泛素共价修饰。虽然一些底物将仅获得一个泛素，但大多数底物会以多个泛素修饰为标志，这些修饰在特定的赖氨酸位点或先前泛素的 N 端蛋氨酸连接在一起，形成多聚泛素链。目标蛋白至少有 8 条已知的连锁特异性多聚泛素链，其中许多独立于蛋白酶体，并且这些链在性质上可以是同质的、混合的或分支的，所有这些都会导致目标底物的不同功能结果和命运。然而，由于焦点仍然集中在蛋白质降解上，关于这些不同泛素链在大脑中的作用仍有很多未知，特别是在依赖于活动和学习的突触可塑性期间。在这里，我们回顾了泛素链的不同类型和功能，并总结了表明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，并推测了理解活动和学习依赖性突触可塑性中的连锁特异性泛素修饰的未来方向和影响。