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  • Protein deubiquitination is becoming increasingly


    Protein deubiquitination is becoming increasingly instrumental in understanding the complexities of the Ub system. Adding to this complexity is the discovery of bacterial effectors with DUB activity that have structurally adapted themselves to interfere with the eukaryotic Ub system (Pruneda et al., 2016). As more and more DUBs are being discovered, it has become imperative to characterize both their selectivity toward Ub and Ub-like modifiers and their preference toward specific types of Ub–Ub lysine linkages.
    DUB regulation: background and overview Conjugation of ubiquitin and ubiquitin-like molecules (Ubl) (Box 1) to lysines of target proteins represents a major type of PTM that regulates countless processes in eukaryotes [1]. These modifications are catalyzed by an enzymatic cascade involving E1 activating enzymes, E2 conjugating enzymes, and E3 ligases (Box 2). Many different types of Ub/Ubl modification exist, because targets can be monoubiquitylated or modified with a variety of polyubiquitin chains (Box 3) that can each have different signaling outcomes. Ubiquitin signals have profound cellular effects and, therefore, conjugation events are kept in check by ubiquitin deconjugation. This function is performed by a specialized class of isopeptidases called DUBs, which hydrolyze the isopeptide bond between ubiquitin and the target proteins 2, 3. Five different DUB families have been identified: ubiquitin C-terminal hydrolase (UCH), ubiquitin specific protease (USP), ovarian tumor (OTU), Machado-Joseph disease (MJD); and Jab1/Mpn/Mov34 (JAMM) (Box 4). All of these are cysteine isopeptidases except the JAMM family members, which have metallo-isopeptidase activity [3]. Due to their critical role in cellular functions, deregulation of Adriamycin of the ubiquitin system is important in cancer, infectious, and neurological diseases 4, 5, 6. Hence, there is an increasing interest in targeting these molecules pharmaceutically. Given that E2 conjugating enzymes and most E3 ligases lack distinct catalytic clefts, approaches to therapeutic intervention currently focus on DUBs [7]. In the cell, the activity of degrading enzymes is carefully controlled. This has long been known for peptidases, the distant cousins of DUBs, which are tightly regulated not only through production as inactive enzymes (zymogens), but also through proteinaceous inhibitors and elaborate activation cascades to prevent aberrant proteolysis [8]. This tight control is essential, because unscheduled activation can be disastrous for the cell. It is gradually becoming clear that this is also true for DUB isopeptidases. The need to regulate DUB activity can be explained by the large number of ubiquitin conjugates in cells. Without proper regulation, DUBs could unspecifically hydrolyze any ubiquitin conjugate that they encounter, potentially deregulating cellular physiology. The general roles of DUBs and their target and chain specificity have been discussed elsewhere 3, 9, 10. Here, we discuss the emerging themes in regulation of DUBs at the protein level. We distinguish different ‘layers’ of DUB regulation and describe how they affect activity (Figure 1). After examination of the individual layers, we analyze how these different mechanisms can cooperate. Although our list of examples is not exhaustive (Table 1), it provides a good basis for discussing the different layers of DUB regulation.
    Cellular and target recruitment In Figure 1, we present a simplified classification of the different layers of DUB regulation. The first layer we discuss is that of DUB recruitment factors. Guiding the almost 100 DUBs encoded in the human genome to their relevant substrates and pathways is crucial for cellular physiology because it insulates DUBs from unwanted interactions and the cell from spurious activity. It can be mediated by distinct regions within the enzyme or by external factors: For instance, the Ubl domain of ubiquitin-specific protease 14 (USP14) recruits it to the proteasome, where its activity is increased 500-fold [11]. The endosomal protein signal transducing adaptor molecule (STAM) recruits the DUBs AMSH (associated molecule with an Src3 homology domain of STAM) and USP8 to the endosome pathway by interacting with an SRC homology 3 (SH3)-binding motif or MIT domain (microtubule interacting and transport), respectively 12, 13.