Breaking It Down: The Ubiquitin Proteasome System in Neuronal Morphogenesis

Hindawi Publishing Corporation Neural Plasticity Volume 2013, Article ID 196848, 10 pages http://dx.doi.org/10.1155/2013/196848 Review Article Breaking It Down: The Ubiquitin Proteasome System in Neuronal Morphogenesis Andrew M. Hamilton and Karen Zito Center for Neuroscience, University of California Davis, 1544 Newton Court, Davis, CA 95618, USA Correspondence should be addressed to Andrew M. Hamilton; Received 12 October 2012; Accepted 31 December 2012 Academic Editor: Michel Baudry Copyright © 2013 A. M. Hamilton and K. Zito. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 longterm 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 UPSdependent 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 conjugating enzyme. The Ub-E2 interacts with an E3 ubiquitin ligase, and this Ub-E2-E3 complex attaches the activated ubiquitin to a specific target through the carboxy-terminal glycine of ubiquitin. Additional ubiquitin ligands may then be bound to the previously attached ubiquitin moieties through one of 7 internal lysine residues on the ubiquitin itself. Multiple rounds of ubiquitination may result in a polyubiquitin chain, whose functional consequence depends on its three-dimensional structure, as conferred by the internal lysines used to link the chain together [8]. While any of the 7 ubiquitin lysines (K6, K11, K27, K29, K33, K48, or K63) may, in theory, be used to create a polyubiquitin chain, the results of K-48 and K-63 chains have been the best 2 Neural Plasticity ATP AMP + PPi E1 E1 Ub Ub Ub E1 E2 E2 E3 E2 Ub E3 Ub Ub E2 Ub DUB Ub Ub Ub Ub Ub Branched poly-Ub regulation of protein activity Ub Ub Ub Ub Ub Ub Ub Ub K48 poly-Ub proteasomal degradation K63 poly-Ub endocytosis; lysosomal degradation Ub Mono/multi-Ub endocytosis; gene expression; regulation of protein activity Figure 1: Ubiquitination and ubiquitin-mediated trafficking. Ubiquitin (Ub) is activated in an ATP-dependent manner by an E1, passed to an E2 ubiquitin conjugase, and finally transferred to a target protein by an E2/E3 ubiquitin ligase complex. Following monoubiquitination, the addition of further ubiquitin moieties occurs at specific lysine residues and results in one of a variety of polyubiquitin chains, each possessing a unique set of known consequences for protein regulation and trafficking. The ubiquitination state of a protein is regulated both via the addition of ubiquitin and also via the removal of single moieties or chains by deubiquitinases (DUBs). characterized [7, 9]. K-48 polyubiquitination directs proteins to the 26S proteasome, a massive proteolytic complex, where proteins are broken down into small oligopeptides and recycled. K-63 polyubiquitination, on the other hand, directs the endocytosis and lysosomal degradation of membrane proteins. Other forms of mono- or polyubiquitination have been shown to regulate protein processing, activity, or localization, rather than destruction [3, 8]. While all cells make extensive use of the UPS, neurons have developed the remarkable ability to rapidly regulate the proteasome in response to changes in synaptic activity. Not only is the proteasome necessary for activity-dependent regulation of key synaptic proteins such as scaffolding proteins and neurotransmitter receptors [10–13], direct pharmacological stimulation or inhibition of neural activity alters proteasomal localization [14–16] and activity level [15, 17] in a matter of minutes. Furthermore, activity-dependent changes in proteasomal degradation occur in what appears to be a highly specific manner [10], suggesting precise regulatory mechanisms for targeting of individual synaptic proteins by the UPS. The intricacy of UPS regulation in neurons has engendered intense interest in how ubiquitination and protein degradation contribute to neuronal development and function. This paper focuses on the role of the UPS in neuronal morphogenesis, particularly in the development of axons, dendrites, and dendritic spines. 3. Regulation of Axonal Growth and Guidance by the UPS One of the vital steps in the establishment of neural circuits, the growth and guidance of axons, has been shown to be regulated by the UPS in a number of model organisms. The best characterized targets of ubiquitination and proteasomal degradation in axons comprise proteins involved in regulating the (...truncated)