SUMOylation and De-SUMOylation: Wrestling with Life's Processes

Abstract

The small ubiquitin-like modifier (SUMO) is a ubiquitinlike protein that covalently modifies a large number of cellular proteins. SUMO modification has emerged as an important regulatory mechanism for protein function and localization. SUMOylation is a dynamic process that is mediated by activating (E1), conjugating (E2), and ligating (E3) enzymes and readily reversed by a family of ubiquitin-like protein-specific proteases (Ulp) in yeast and sentrin/SUMO-specific proteases (SENP) in human. This review will focus on the de-SUMOylating enzymes with special attention to their biological function.Many biochemical pathways are reversible to create an on and off state that is essential for biological regulation. A reversible system allows for quick termination of a biological response that has to be precisely controlled. The SUMO 2 modification pathway is an example of a reversible system that is controlled by a series of on and off enzymes ( Fig. 1) (1). In contrast to the much more complex ubiquitin pathway (2), SUMOylation utilizes only a single conjugating enzyme, Ubc9 (3), and a limited number of ligases (4 -6). This simplicity also manifests in the off step because there are only two SUMO-deconjugating enzymes in yeast and six in human. One may assume that these limited numbers of on and off enzymes would sufficient to regulate only be a small number of substrates and biological pathways. However, the number of SUMO substrates continues to expand, and the varieties of systems that are known to be regulated by SUMO also proliferate quickly. Here, I will review only the enzymes that are involved in the de-SUMOylation pathways to provide insights into how these limited numbers of proteases are able to regulate a diverse array of biological responses. Localization and Enzymatic Activity of SUMO-specific ProteasesSUMO-specific proteases are C48 cysteine proteases that possess a conserved catalytic domain characterized by the catalytic triad (histidine, aspartate, and cysteine) and a conserved glutamine residue required for the formation of the oxyanion hole in the active site (7). Members of the C48 cysteine protease family have N-and C-terminal sequences that differ from each other. Homologs of these proteases are present in plant, yeast, and mammalian cells. In this review, I will focus on the two yeast ubiquitin-like protein-specific proteases (Ulp) and the six human sentrin/SUMO-specific proteases (SENP) ( Table 1).Yeast has a single SUMO-like modifier, Smt3, and two Smt3-specific proteases, Ulp1 and Ulp2. Both Smt3 and Ulp2 (Smt4) were identified from the same screen as suppressors of the Mif2 (a centromeric protein) mutation (8). Ulp1 is a protein of 621 amino acids that contains the catalytic domain at the C terminus and an N-terminal domain that attaches this protease to the nuclear pore (7). Ulp1 possesses the C-terminal hydrolase activity required for removing C-terminal amino acids from Smt3 to reveal the diglycine residues important for conjugation to Smt3 substrates. Ulp1 also has the isopeptidase activ...

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

“…S mall ubiquitin-related modifier (SUMO) proteins can be conjugated onto specific lysine residues of a wide variety of proteins, creating branched peptides 1,2 . Proteinconjugated SUMO binds SUMO-interacting motifs, inducing conformational changes and stabilizing intra-or intermolecular interactions 3 .…”

SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop

“…It can be reversed by a family of Sentrin/SUMO-specific proteases (SENPs) (Hay, 2007;Yeh, 2009). Mounting evidence demonstrates that SENP family members play crucial roles in determining the protein SUMOylation status and activity (Cheng et al, 2007;Hay, 2007;Yeh, 2009). We previously reported that SENP1 is involved in hypoxia signaling, angiogenesis, T and B cell development, and mitochondrial biogenesis via de-SUMOylation of distinct targets (Cheng et al, 2007;Cai et al, 2012;Van Nguyen et al, 2012).…”

“…SUMOylation is catalyzed by activating enzyme (E1), conjugating enzyme (E2), as well as ligating enzyme (E3). It can be reversed by a family of Sentrin/SUMO-specific proteases (SENPs) (Hay, 2007;Yeh, 2009). Mounting evidence demonstrates that SENP family members play crucial roles in determining the protein SUMOylation status and activity (Cheng et al, 2007;Hay, 2007;Yeh, 2009).…”

Small Ubiquitin-like Modifier (SUMO) Protein-specific Protease 1 De-SUMOylates Sharp-1 Protein and Controls Adipocyte Differentiation

“…SUMO modification has now emerged as an important regulatory mechanism in many signaling pathways through alteration of the function of target proteins (9,11,12). SUMOylation is catalyzed by activating (E1), conjugating (E2), and ligating (E3) enzymes.…”

“…SUMO (also called Sentrin) is a novel ubiquitin-like protein that can covalently modify a large number of proteins (9,10). SUMO modification has now emerged as an important regulatory mechanism in many signaling pathways through alteration of the function of target proteins (9,11,12).…”