ABSTRACT

U b iqu itin is a h igh ly conserved eukaryotic protein that is synthesized as a fusion protein precursor, either to itself, or to one of two ribosomal proteins.1 Accordingly, an endopeptidase is required to cleave the fusion precursors to release free ubiquitin. The ubiquitin thus produced can be covalently attached to other proteins by a highly specific and regulated process (for recent reviews see refs. 2,3 and Chapters by Dohmen and Ciechanover et al). Such ub iqu itinated proteins are targeted for specific fates and/or localizations in the cell, such as degradation by the 26S proteasome (reviewed in refs. 2,4), or for plasma membrane proteins, inter­ nalization via endocytosis and transport to the vacuole/lysosome for degradation inde­ pendently of the 26S proteasome.5 Most biochemical processes are reversible reactions, and ubiquitination is no exception. Both the linear ubiquitin precursor proteins, and the posttranslationally formed, “isopeptide” ubiquitin conjugates, can be cleaved by members of a large family of enzymes that are encompassed by the term “deubiquitinating enzymes” (DUBs). In many ways, ubiqui­ tination is very much akin to phosphorylation, a process reversible by phosphatases, and in this analogy, DUBs are the “phosphatases” of the ubiquitin pathway.6 Ubiquitination and phosphorylation may serve similar functions,

to modify the activity, structure, or localization of a protein, and are often linked events. DUBs have been the subject of recent reviews,6,7 and the reader is referred to these reviews for further background and alternate viewpoints. This chapter will concentrate on developments in the past few years.