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.

Keywords: brain; glia; neurodegeneration; neuron; protease; proteasome; synapse; ubiquitin.

Figure 1

Summary of the UPP. Through the coordinated action of E1/E2/E3, Ub is conjugated to a substrate destined for proteasomal degradation. Ub-binding proteins that are part of the 19S or that associate with it reversibly (not depicted) bind poly-Ub on the substrate, which is subsequently deubiquitinated, unfolded and degraded. Poly-Ub is then processed into mono-Ub which re-enters the cycle.

Figure 2

Mammalian DUBs. Mammalian DUBs categorized by similarities at the protease domain. Highlighted are DUBs involved in the nervous system. With the exception of JAMM proteases, which are zinc-dependent metallo-proteases, the rest are cysteine proteases.

Figure 3

Roles of DUBs in Ub homeostasis. Diagrammatic summary of the various functions of DUBs in Ub homeostasis. Newly produced Ub is C-terminally fused to other proteins, such as other Ub molecules, and must be cleaved by DUBs in order for its terminal glycine residue to be exposed for isopeptide bond formation. Once conjugated to a substrate protein, poly-Ub chains can be edited, or can be completely removed. Poly-Ub chains that are unanchored are processed into single Ub and re-enter the Ub conjugation cycle.

Figure 4

Summary of DUBs involved in various steps of the UPP. Summary of the various steps of substrate ubiquitination and degradation during which specific DUBs involved in the UPP are reported to function. UCHL1 maintains a pool of mono-Ub for conjugation by removing additional amino acids present in newly translated Ub, or by processing accidental thiol or amine modifications formed during Ub reactions. Once a substrate has been ubiquitinated, DUBs such as USP7, USP9X and under some circumstances, ataxin-3 can deubiquitinate and rescue it from proteasomal degradation. Ataxin-3 has also been reported to enhance the degradation of a few substrates by editing poly-Ub chains for better recognition by and access to the proteasome. Once at the proteasome, premature deubiquitination of substrates by USP14 can prevent degradation. If a proteasome-bound substrate has been committed to degradation and is being unfolded, deubiquitination by PSMD14, UCHL5, and USP14 recycles Ub.