The ubiquitin-proteasome system (UPS) is most widely known for its role in intracellular protein degradation; however, in the decades since its discovery, ubiquitination has been associated with the regulation of a wide variety of cellular processes. The addition of ubiquitin tags, either as single moieties or as polyubiquitin chains, has been shown not only to mediate degradation by the proteasome and the lysosome, but also to modulate protein function, localization, and endocytosis. The UPS plays a particularly important role in neurons, where local synthesis and degradation work to balance synaptic protein levels at synapses distant from the cell body. In recent years, the UPS has come under increasing scrutiny in neurons, as elements of the UPS have been found to regulate such diverse neuronal functions as synaptic strength, homeostatic plasticity, axon guidance, and neurite outgrowth. Here we focus on recent advances detailing the roles of the UPS in regulating the morphogenesis of axons, dendrites, and dendritic spines, with an emphasis on E3 ubiquitin ligases and their identified regulatory targets. 1. Introduction Ever since the ubiquitin proteasome system (UPS) was first characterized in the mid-20th century as the primary mediator of regulated protein degradation, its role in neurons has come under ever increasing scrutiny. Due to the large distances separating many synapses from the soma, local protein synthesis and degradation are particularly important to neuronal development and function. The diverse neuronal processes subject to regulation by the UPS range from long-term potentiation and homeostatic plasticity to acute regulation of neurotransmitter release. Several comprehensive reviews have been published on the importance of the UPS in synaptic plasticity [1, 2], intracellular trafficking [3, 4], and disease states [5, 6]; this paper will focus on the UPS-dependent regulation of neuronal morphogenesis. 2. The Ubiquitin Proteasome System Ubiquitin, aptly named for its intracellular omnipresence, is a small 76 residue protein which may be tagged onto target proteins as single moieties or polyubiquitin chains (Figure 1). Ubiquitination most famously serves to regulate protein degradation via the action of the ubiquitin proteasome system. In addition, ubiquitination has been shown to regulate a diverse array of cellular processes, including endocytosis, DNA repair, cell division, and protein trafficking [7, 8]. Ubiquitin is initially charged in an ATP-dependent manner by an E1 activating enzyme and then transferred to an E2 ubiquitin
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