An optimal ubiquitin-proteasome pathway in the nervous system: the role of deubiquitinating enzymes

Abstract

The Ubiquitin-Proteasome Pathway (UPP), which is critical for normal function in the nervous system and is implicated in various neurological diseases, requires the small modifier protein ubiquitin to accomplish its duty of selectively degrading short-lived, abnormal or misfolded proteins. Over the past decade, a large class of proteases collectively known as deubiquitinating enzymes (DUBs) has increasingly gained attention in all manners related to ubiquitin. By cleaving ubiquitin from another protein, DUBs ensure that the UPP functions properly. DUBs accomplish this task by processing newly translated ubiquitin so that it can be used for conjugation to substrate proteins, by regulating the “where, when, and why” of UPP substrate ubiquitination and subsequent degradation, and by recycling ubiquitin for re-use by the UPP. Because of the reliance of the UPP on DUB activities, it is not surprising that these proteases play important roles in the normal activities of the nervous system and in neurodegenerative diseases. In this review, we summarize recent advances in understanding the functions of DUBs in the nervous system. We focus on their role in the UPP, and make the argument that understanding the UPP from the perspective of DUBs can yield new insight into diseases that result from anomalous intra-cellular processes or inter-cellular networks. Lastly, we discuss the relevance of DUBs as therapeutic options for disorders of the nervous system.

USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila

“…Through the coordinated action of these proteins, a ubiquitin molecule is conjugated most commonly to a lysine residue of a substrate protein through an isopeptide bond. Because ubiquitin itself has seven lysine residues, which are available for isopeptide bond formation, and because ubiquitin moieties can also be connected "head to tail," ubiquitin chains of different conformations are generated (2,3). Different chains impart specific outcomes on the fate of the protein to which they are conjugated.…”

“…2 DUBs are divided into five families, based on similarity in their catalytic domains: ubiquitin-specific proteases, ubiquitin C-terminal hydrolases, Machado-Joseph disease proteins, otubain proteases, and the JAB1/MPN/Mov34 metalloenzymes. Nearly 100 genes encoding DUBs have been identified in humans, but the functions of many of them remain to be discovered (3,(7)(8)(9)(10).…”

“…These and other findings place USP5 at the proteasome: before a protein is degraded by the proteasome, the ubiquitin chain signaling its degradation is removed en bloc by another DUB, RPN11/POH1, leaving unanchored polyubiquitin. USP5 processes this unanchored chain to yield monoubiquitin (3,10). Thus, this DUB is thought of as a ubiquitin recycler, helping to maintain a monoubiquitin pool for reutilization (7,15,16).…”

Defensive roles of Sdu1, a PPPDE superfamily member with ubiquitin C-terminal hydrolase activity, against thermal stress in Schizosaccharomyces pombe

“…These findings demonstrate that UCH L1 activity is involved in polyubiquitin accumulation, proteasome inhibition, and disease aggravation in experimental models of membranous nephropathy (Meyer-Schwesinger et al, 2011). UCH L3, expressed in various tissues, is involved in learning and working memory in mice, and related with muscular and retinal degeneration, potentially due to oxidative stress (Ristic et al, 2014). UCH L3 enhances osteoblast differentiation through the stabilization of Smad1 signaling in murine skeletal muscle C2C12 myoblasts .…”

“…It was also suggested to be an epithelial-to-mesenchymal transition regulator in prostate cells and a potential target for preventing metastatic prostate cancer (Song et al, 2014). UCH37 reversibly associates with the 19S component of the proteasome and deubiquinates proteasome substrates, and regulates transforming growth factor-β signaling in non-neural tissue (Wicks et al, 2005;Ristic et al, 2014). UCH37 is a major DUB associated with Schizosaccharomyces pombe 26S proteasome, but its disruption does not interfere with cell viability without showing obvious signs of impaired ubiquitin-dependent proteolysis (Stone et al, 2004).…”