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Modification in Reverse: the SUMO Proteases

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Modification in Reverse: the SUMO Proteases Review TRENDS in Biochemical Sciences Vol.32 No.6 Modification in reverse: the SUMO proteases Debaditya Mukhopadhyay and Mary Dasso Laboratory of Gene Regulation and Development, National Institute of Child Health and Development, National Institutes of Health, Building 18, Room 106, Bethesda, MD 20892, USA SUMOs (small ubiquitin-like modifiers) are enzymatic mechanisms and the determinants of their ubiquitin-related proteins that become covalently con- specificity show many distinct features, which will be jugated to cellular target proteins that are involved in a the major topic of this review. variety of processes. Frequently, this modification has a key role in regulating the activities of those targets and, SUMO paralogs and pathway fundamentals thus, their cellular functions. SUMO conjugation is a Budding yeast express one SUMO protein (Smt3p), whereas highly dynamic process that can be rapidly reversed mammalian cells usually express three SUMO paralogs by the action of members of the Ubl (ubiquitin-like (SUMO-1, SUMO-2 and SUMO-3) [1]. Mature SUMO-1 protein)-specific protease (Ulp) family. The same family is 45% identical to SUMO-2 and SUMO-3, whereas of enzymes is also responsible for maturation of newly SUMO-2 and SUMO-3 are 95% identical to each other. synthesized SUMOs prior to their initial conjugation. The tails cleaved from each paralog are distinct. SUMO-2 Recent advances in structural, biochemical and cell bio- and SUMO-3 have sometimes been used interchangeably in logical analysis of Ulp/SENPs reveal their high degree of the literature. Here, we will refer to the isoform having two specificity towards SUMO paralogs, in addition to dis- amino acids (Val-Tyr) after the di-glycine motif as SUMO-2 crimination between processing, deconjugation and and that with 11 amino acids (Val-Pro-Ser-Ser-Leu-Ala-Gly- chain-editing reactions. The dissimilar sub-nuclear local- His-Ser-Phe) as SUMO-3. Where they cannot be distin- ization patterns of Ulp/SENPs and phenotypes of Ulp/ guished, SUMO-2 and SUMO-3 will be collectively referred SENP mutants further indicate that different Ulp/SENPs to as SUMO-2/3. An additional human SUMO paralog have distinct and non-redundant roles. (SUMO-4), which most-closely resembles SUMO-2 and SUMO-3, has been reported [8]. SUMO-4 is probably not Introduction conjugated under physiological conditions, so its biological SUMO (small ubiquitin-like modifier) modulates many role is unclear [9]. processes such as nuclear transport, transcription replica- SUMO conjugation occurs through a cascade of tion, recombination and chromosome segregation [1]. Like reactions that are performed by an activating enzyme ubiquitin, SUMOs are synthesized as propeptides that (E1), a conjugating enzyme (E2) and, usually, a SUMO require cleavage to reveal C-terminal di-glycine motifs ligase (E3) [1]. SUMO E1 and E2 enzymes resemble their prior to conjugation (Figure 1). Conjugation results in ubiquitin counterparts. Mammalian paralogs all become formation of an isopeptide bond between the SUMO C conjugated using the same E1 and E2 enzymes [1]. Never- terminus and an e-amino group of a lysine within the theless, there are important differences between paralogs. target protein. Enzymes responsible for SUMO processing First, individual targets show different conjugation pat- and deconjugation are called Ubl (ubiquitin-like protein)- terns: some targets are modified exclusively by SUMO-1 in specific proteases (Ulp) in yeast [2] and Sentrin-specific vivo [10], other targets are conjugated to SUMO-2/3, or proteases (SENP) in mammals [3]. Ulp/SENPs directly readily conjugated with all paralogs [11,12]. Second, the regulate the pools of free, conjugatable SUMO protein concentrations of both total and free SUMO-2/3 are higher and the half-life of conjugated species. than those of SUMO-1 [10]. Third, SUMO-1 and SUMO-2/3 Budding yeast has two Ulp/SENPs, humans have six show different in vivo dynamics [13] and responses to and Arabidopsis has seven [4,5] (Box 1). Although it is physiological stresses such as heat shock [10,13]. Finally, possible that novel Ulp/SENPs remain to be discovered, SUMO-2 and SUMO-3, like Smt3p, can form chains in vitro particularly in metazoans, the modest number of Ulp/ and in vivo, primarily through a conserved acceptor lysine SENPs seems striking by comparison to the number of (Lys15 in Smt3p, Lys11 in SUMO-2 or SUMO-3) [14–16].It enzymes in the ubiquitin pathway: there are >100 deubi- is not yet known whether individual SUMO moieties func- quitylating enzymes (DUBs) in higher eukaryotes [6] but tion distinguishably from SUMO chains in the same way only one ubiquitin polypeptide to process or deconjugate that single ubiquitin moieties and structurally distinct [7]. As an understanding of the biochemical properties polyubiquitin chains represent intracellular signals that of Ulp/SENPs emerges, it has become clear that their are functionally distinct from each other [7]. However, there is evidence that SUMO-2/3 chain formation might Corresponding author: Dasso, M. ([email protected]). be crucial for in vivo regulation of some targets [17,18]. Available online 17 May 2007. SUMO-1 does not have an acceptor lysine at the equivalent www.sciencedirect.com 0968-0004/$ – see front matter ß 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibs.2007.05.002 Review TRENDS in Biochemical Sciences Vol.32 No.6 287 Figure 1. SUMO paralogs and Ulp/SENP catalyzed reactions. (a) The primary sequences of the single budding yeast SUMO protein, Smt3, are aligned with human SUMO- 1–4, to show features that are essential for their function. An essential di-glycine motif (red) is revealed by processing before conjugation. Sequences removed through the processing reaction are shown in blue. Conserved lysine residues within Smt3, SUMO-2 and SUMO-3 are the major sites of chain linkage and are shown in purple. A residue in SUMO-4 (Pro90) that prevents its processing and deconjugation by Ulp/SENPs is shown in green. (b) A schematic representation of reactions catalyzed by Ulp/SENPs. The processing reaction (broken black box) involves cleavage of a peptide bond within the SUMO pro-peptide to reveal the C-terminal di-glycine motif. Processing requires Ulp/SENPs to directly recognize newly translated SUMOs as substrates. SUMO deconjugation (broken red box) requires cleavage of the amide bond between the C terminus of the mature SUMO and the e-amine group of the target lysine within the substrate. In principle, recognition in this reaction could involve both SUMO proteins and binding surfaces contributed by the substrate. There is currently little evidence for the importance of the latter. Chain editing (solid red box) is chemically identical to deconjugation, although it is distinguished by cleavage of one or more SUMOs from a poly-SUMO chain rather than from another cellular target substrate. Enzymes of the Ulp2 sub-family are important for this reaction, and a feature(s) of the SUMO chain is likely to contribute towards substrate recognition. E1, E2 and E3 are the activating, conjugating and SUMO ligase enzymes of the conjugation pathway, respectively. For more details about this pathway, see Ref. [1]. site, although it can form chains in vitro [19] using Lys7, showed that Ulp1p bears no substantial relationship to Lys16 and Lys17 [20]. DUBs but is related to adenoviral proteases [2,21]. Sequence comparisons further predicted a 200 amino Identification of Ulp/SENPs acid protease fold, which defines this group of enzymes Li and Hochstrasser [2] used an elegant sib-selection (C48 cysteine proteases), and showed that they diverged strategy to isolate SUMO proteases: they assayed cleavage from DUBs early in evolution [2,22,23]. C48 family mem- of a model Smt3p substrate within extracts made from bers exist in all eukaryotic species examined. Database pools of bacterial transformants expressing multiple yeast searches found one other family member in budding yeast proteins. Pools with cleavage activity were subdivided to (Ulp2p) [24] and seven related proteins in humans, which isolate individual cDNAs encoding Smt3p proteases. Using were named SENPs [3]. SENPs were originally designated this approach, they found a previously uncharacterized 72- purely on the basis of sequences found through database kDa protein, which they named Ulp1p. Sequence analysis searches. It was later discovered that the closely related SENP3 and SENP4 sequences corresponded to the same protein; as a result, there is a discontinuity within Box 1. SUMO proteases in plants the SENP nomenclature. Many mammalian Ulp/SENPs In plants, sumoylation has been implicated in abiotic stress have been given alternative names owing to their discovery response, pathogen defense, abscisic acid signaling and flower through multiple means (Table 1). It should also be noted induction [5]. Arabidopsis thaliana has eight genes that encode complete SUMO proteins [5]. Database searches using the Ulp1p that one Ulp/SENP family member, SENP8 – also known conserved domain as the search parameter yield >100 hits in the as deneddylase 1 – does not act on SUMOs. Instead, it acts Arabidopsis genome. These sequences include a family of 97 on another ubiquitin-like protein, Nedd8 [25,26]. potentially functional genes and apparent pseudogenes that arose Ulp1p and Ulp2p are not redundant. Ulp1p is encoded through selfish gene trans-duplication [68]. Currently, it seems that by an essential gene [2]. Over-expression of processed there are only eight Ulp/SENP proteases expressed in Arabidopsis [5] (Figure 2), one of which is Nedd8-specific [4]. Notably, plant Smt3p weakly rescues Dulp1 cells, but full-length Smt3p SENPs display SUMO paralog specificity [4,69], and at least one of does not [2], indicating that Ulp1p has an important role in these enzymes localizes to the nuclear envelope [70], indicating Smt3p maturation. Interestingly, mutants with decreased conservation of Ulp/SENP function between the plant and animal levels of Ulp1p activity have pronounced defects in main- kingdoms.
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