Breaking it down: the ubiquitin proteasome system in neuronal morphogenesis

Abstract

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.

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).

Figure 2

The ubiquitin-proteasome system in regulation of neural morphogenesis. Known signaling cascades for ubiquitin-dependent regulation of the formation of axons (bottom right inset), dendrites (left inset), and dendritic spines (top right inset). Regulatory factors depicted outside of the insets represent signaling from the cell body, rather than local regulation. E3 ligases are depicted in bold; arrows represent positive regulation; bars represent inhibition or degradation.