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Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism

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Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism biomolecules Review Not So Slim Anymore—Evidence for the Role of SUMO in the Regulation of Lipid Metabolism Amir Sapir Department of Biology and the Environment, Faculty of Natural Sciences, University of Haifa–Oranim, Tivon 36006, Israel; [email protected]; Tel.: +972-495-396-15 Received: 2 June 2020; Accepted: 3 August 2020; Published: 6 August 2020 Abstract: One of the basic building blocks of all life forms are lipids—biomolecules that dissolve in nonpolar organic solvents but not in water. Lipids have numerous structural, metabolic, and regulative functions in health and disease; thus, complex networks of enzymes coordinate the different compositions and functions of lipids with the physiology of the organism. One type of control on the activity of those enzymes is the conjugation of the Small Ubiquitin-like Modifier (SUMO) that in recent years has been identified as a critical regulator of many biological processes. In this review, I summarize the current knowledge about the role of SUMO in the regulation of lipid metabolism. In particular, I discuss (i) the role of SUMO in lipid metabolism of fungi and invertebrates; (ii) the function of SUMO as a regulator of lipid metabolism in mammals with emphasis on the two most well-characterized cases of SUMO regulation of lipid homeostasis. These include the effect of SUMO on the activity of two groups of master regulators of lipid metabolism—the Sterol Regulatory Element Binding Protein (SERBP) proteins and the family of nuclear receptors—and (iii) the role of SUMO as a regulator of lipid metabolism in arteriosclerosis, nonalcoholic fatty liver, cholestasis, and other lipid-related human diseases. Keywords: SUMO; SUMO proteases; lipid metabolism; nuclear receptors; SREBPs; fatty acid metabolism; metabolism of cholesterol; steroid hormones 1. The Core Regulatory Circuit of SUMO A growing number of studies show the importance of Small Ubiquitin-like Modifier (SUMO) as a regulator of numerous cellular processes in health and disease [1,2]. Within the many types of posttranscriptional modifications of proteins (PTMs), SUMO belongs to the superfamily of ubiquitin-like modifiers that have essential functions in eukaryotes. These functions include regulation of the cell cycle [3]; transcriptional and posttranscriptional control on mRNA levels [4]; DNA damage repair [5]; regulation of signal transduction [6]; and, indirectly, protein degradation [7]. The SUMO family members are short polypeptides of about 100 amino acids that are covalently conjugated to specific lysines in the sequence of their target substrates. SUMO conjugation relies on the coordinated sequential activity of several enzymes: E1 (SUMO-activating); E2 (the SUMO-specific conjugating enzyme Ubc9); and, in some cases, E3 (SUMO ligase, e.g., the PIAS1-4 proteins) [8] (Figure1). The final step of the cascade is the attachment of SUMO to a specific lysine residue on the substrate undergoing SUMOylation (SUMO conjugation to its protein substrate). However, in contrast to ubiquitin, SUMO proteins do not directly target proteins for degradation but rather alter substrate localization, solubility, or conformation. SUMOylation is a highly regulated and reversible process due to the activity of both positive and negative regulators of SUMO conjugation [9]. One group of proteins that plays a key role in the regulation of SUMOylation are the SUMO proteases SENPs/ULPs (SENtrin-specific Proteases/Ubiquitin-Like Proteases) [10]. Although some SENPs/ULPs play a role in Biomolecules 2020, 10, 1154; doi:10.3390/biom10081154 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x 2 of 20 Biomolecules 2020, 10, 1154 2 of 20 in the maturation of SUMO before its conjugation, the most common function of these proteases is thethe cleavage maturation of ofSUMO SUMO from before its its target conjugation, (de-SUMOylation) the most common in a functionprocess ofcounteracting these proteases SUMO is the conjugation.cleavage of SUMO from its target (de-SUMOylation) in a process counteracting SUMO conjugation. FigureFigure 1. 1. TheThe Small Small Ubiquitin-like Ubiquitin-like Modifier Modifier (SUMO) (SUMO) conjugation conjugation cycle: cycle: The Thenames names of the of enzymes the enzymes are basedare based on mammalian on mammalian nomenclature. nomenclature. After AfterSUMO SUMO cleavage cleavage (not shown), (not shown), SUMO SUMO is conjugated is conjugated to a heterodimericto a heterodimeric E1 ligase E1 ligasecomplex complex (SAE1/2). (SAE1 Next,/2). SUMO Next, is SUMO transferred is transferred to the E2 to ligase the E2(Ubc9). ligase Finally, (Ubc9). theFinally, SUMO-Ubc9 the SUMO-Ubc9 moleculemolecule forms a complex forms a complexwith an withE3 ligase an E3 (e.g., ligase PISA1–4) (e.g., PISA1–4) and with and the with target the protein.target protein. This complex This complex formation formation facilitates facilitates the transf theer transfer of SUMO of SUMO to a specific to a specific lysine lysine residue residue on the on sequencethe sequence of the of target the target protein. protein. Alternatively, Alternatively, SUMO SUMO conjugation conjugation to tothe the E2 E2 ligase, ligase, Ubc9, Ubc9, can can be be followed by the direct transfer of SUMO to the protein target independently of E3 ligase activity. followed by the direct transfer of SUMO to the protein target independently of E3 ligase activity. Substrates can be conjugated with a single SUMO (monoSUMOylation), with multiple SUMO peptides Substrates can be conjugated with a single SUMO (monoSUMOylation), with multiple SUMO on different lysine residues (multiSUMOylation), or with a chain of SUMO2/3 tags (polySUMOylation). peptides on different lysine residues (multiSUMOylation), or with a chain of SUMO2/3 tags SUMO-specific proteases (named SENtrin-specific Proteases (SENPs) in mammals and Ubiquitin-Like (polySUMOylation). SUMO-specific proteases (named SENtrin-specific Proteases (SENPs) in Proteases (ULPs) in nonmammalian organisms cleave SUMO from its protein substrate in order to mammals and Ubiquitin-Like Proteases (ULPs) in nonmammalian organisms cleave SUMO from its reverse SUMO conjugation and activity. protein substrate in order to reverse SUMO conjugation and activity. The human genome harbors genes for five SUMO proteins (SUMO1–5), which show some The human genome harbors genes for five SUMO proteins (SUMO1–5), which show some nonoverlapping functions [11]. Whereas the role of SUMO4 is still not well understood, several studies nonoverlapping functions [11]. Whereas the role of SUMO4 is still not well understood, several have shown that the main role of SUMO1 is to regulate processes in the context of normal physiology. studies have shown that the main role of SUMO1 is to regulate processes in the context of normal The activity of two additional SUMO proteins with an extremely high level of sequence similarity, physiology. The activity of two additional SUMO proteins with an extremely high level of sequence SUMO2 and SUMO3 (henceforth SUMO2/3), was initially attributed to the regulation of various stress similarity, SUMO2 and SUMO3 (henceforth SUMO2/3), was initially attributed to the regulation of responses similar to the proposed role of SUMO5 [12,13]. However, recent findings have suggested various stress responses similar to the proposed role of SUMO5 [12,13]. However, recent findings that SUMO2/3 proteins have functions, including the regulation of specific steps of the cell cycle [14], have suggested that SUMO2/3 proteins have functions, including the regulation of specific steps of that are unrelated to stress. Another difference between SUMO proteins in mammals is the potential to the cell cycle [14], that are unrelated to stress. Another difference between SUMO proteins in form a chain of modifiers. SUMO2/3 and 5 molecules can form chains on the targeted protein because mammals is the potential to form a chain of modifiers. SUMO2/3 and 5 molecules can form chains on they possess lysine residues near their amino termini, which serve as SUMO-acceptor sites. The lack of the targeted protein because they possess lysine residues near their amino termini, which serve as such lysines in the sequence of SUMO1 suggests that this form of SUMO is only mono-conjugated SUMO-acceptor sites. The lack of such lysines in the sequence of SUMO1 suggests that this form of to the target. The biological significance of mono- versus chain-conjugation is still an active area of SUMO is only mono-conjugated to the target. The biological significance of mono- versus chain- Biomolecules 2020, 10, x 3 of 20 Biomolecules 2020, 10, 1154 3 of 20 conjugation is still an active area of research [15]. The SUMO-conjugation pathway (E1 + E2 + E3) and SUMO-deconjugating enzymes (SENPs/ULPs) constitute the direct SUMO regulatory network, research [15]. The SUMO-conjugation pathway (E1 + E2 + E3) and SUMO-deconjugating enzymes which determines the level, pattern, and dynamics of SUMOylation of target proteins [15]. Other (SENPs/ULPs) constitute the direct SUMO regulatory network, which determines the level, pattern, PTM processes, like phosphorylation, acetylation, and ubiquitination, antagonize or enhance the and dynamics of SUMOylation of target proteins [15]. Other PTM processes, like phosphorylation, level of SUMO conjugation. In many cases, the cross-talk between different PTM processes is the acetylation, and ubiquitination, antagonize or enhance the level of SUMO conjugation. In many cases, mechanism by which SUMO manifests its activity on the target protein. the cross-talk between different
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