Non-canonical ubiquitin-based signals for proteasomal degradation

Abstract

Commentary 539Introduction Ubiquitylation [also known as ubiquitination, as coined by the discoverers of this modification with regard to its connection to proteolysis (Wilkinson, 2005)] is a three-step enzymatic reaction that is carried out by several enzymes: the ubiquitin-activating enzyme (E1), a ubiquitin carrier protein (E2; also known as ubiquitin-conjugating enzyme, UBC) and a ubiquitin-protein ligase (E3). An additional component of the ubiquitylation machinery has been described. This E4 enzyme is involved in elongation of short ubiquitin chains (Koegl et al., 1999). However, the requirement for an E4 activity appears to be limited to a small subset of substrates. Ubiquitylation-dependent proteasomal degradation is involved in the regulation of numerous cellular processes, including cell cycle progression, apoptosis, DNA repair, the maintenance of cellular quality control, autophagy, the regulation of transcription and receptor-mediated endocytosis (Mayer et al., 2005;Mayer et al., 2006;Mayer et al., 2008). In general, modification by ubiquitin serves as a recognition element in trans, whereby different downstream effectors bind to the ubiquitin-modified protein to affect its fate and/or function. In the case of proteasomal degradation, the ubiquitylated protein is recognized by the 26S proteasome and subsequently degraded (Dikic et al., 2009;Su and Lau, 2009).The widely accepted canonical signal for proteasomal degradation is a polyubiquitin chain that is anchored to the -NH 2 group of a lysine residue(s) in the substrate by an isopeptide bond and is assembled through the formation of isopeptide bonds between the C-terminal residue of one ubiquitin moiety (glycine 76) and lysine 48 of the previously conjugated ubiquitin moiety (Chau et al., 1989). Recent studies have reported, however, that other types of ubiquitin chains can also be recognized by the proteasome (Figs 1, 2). These include an ester-based linkage that connects ubiquitin to a threonine or serine residue in the substrate, and a thiolester-based linkage whereby ubiquitin is bound to a cysteine residue in the substrate (McDowell et al., 2010;Tait et al., 2007;Vosper et al., 2009). Ubiquitin can also be conjugated to the -NH 2 group of the N-terminal residue of the substrate. Instead of using lysine 48 for the linkage, polyubiquitin chains can also be assembled through one of the six additional lysine residues in the molecule. Such homogenous chains based on, for example, lysine 63 (Saeki et al., 2009), or heterogeneous chains in which different ubiquitinubiquitin linkages are found, have also been reported to target proteins for proteasomal degradation. Linear chains, in which the ubiquitin links are attached to one another 'head-to-tail', and heterologous chains, in which the links are made of ubiquitin and a ubiquitin-like protein, such as small ubiquitin-like modifier (SUMO), have additionally been shown to target proteins for proteasomal degradation. Surprisingly, it has been demonstrated that the proteasome does not necessarily have ...

Post-translational add-ons mark the path in exosomal protein sorting

“…M1, K6, K11, K27 and K29 could be involved in proteasomal degradation of target proteins [21,30,33,86]. Moreover, a new conjugation factor, named E4, participates in the generation of efficient poly-ubiquitinated-linked chains under stress conditions to direct modified proteins to the proteasome, demonstrating the existence of an E4-dependent multi-ubiquitination pathway for degradation [88] (Fig.…”

“…K48-linked chains require at least four ubiquitin units to attach to the target protein to enable recognition by the 26S proteasome [86,87]. In particular, the proteasome subunit S5a/Rpn10 contains an ubiquitin-interacting motif (UIM) in the hydrophobic patch of its C-t region, which enables recognition of this specific poly-ubiquitin chain.…”

Lysine Residues Are Not Required for Proteasome-Mediated Proteolysis of the Auxin/Indole Acidic Acid Protein IAA1

“…Non-Lys ubiquitination was first described on mammalian major histocompatibility complex class I a-chain (Cadwell and Coscoy, 2005) and has been subsequently found on other proteins from metazoans and yeast (Wang et al, 2007(Wang et al, , 2012Ishikura et al, 2010;Shimizu et al, 2010;Domingues and Ryoo, 2012;Kravtsova-Ivantsiv and Ciechanover, 2012;Boban et al, 2015). Such alternativesite ubiquitination involves Ser and/or Thr hydroxyl groups as oxyesters and Cys sulfhydryl groups as thioesters (for review, see Kravtsova-Ivantsiv and Ciechanover, 2012). Given that these studies are with yeast and mammalian proteins, the extent of non-Lys specificity for plant UPS substrates is unknown.…”

Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer

“…Ubiquitin possesses a total of 7 inner lysine residues (lysines 6, 11, 27, 29, 33, 48, and 63); all of them behave as a potential attachment site for another ubiquitin moiety, resulting in different subsets of ubiquitin chains (1). Polyubiquitin chains might also be heterogeneous with two or more ubiquitin moieties linked to distinct internal lysine residues (2). Irrespective of the type of ubiquitin chains, the process of ubiquitination is carried out by the sequential action of three types of enzymes: an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase.…”