Regulation and Function of SUMO Modification

Abstract

Small ubiquitin-like modifier (SUMO) 1 is a protein of 97 amino acids that is structurally similar to ubiquitin and has been called by other names including Smt3p, Pmt2p, PIC-1, GMP1, Ubl1, and Sentrin (1). Like ubiquitin, SUMO has been found to be covalently attached to certain lysine residues of specific target proteins (2). In contrast to ubiquitination, however, sumoylation does not promote the degradation of proteins but instead alters a number of different functional parameters of proteins, depending on the protein substrate in question. These parameters include but are not limited to properties such as subcellular localization, protein partnering, and DNA-binding and/or transactivation functions of transcription factors (2-4). The contrast between the functional effects of ubiquitination and sumoylation is most striking in the case of IB, where sumoylation stabilizes the protein by modifying the same residue that is ubiquitinated, thereby directly competing with that pathway (5). This review will focus on the regulation of SUMO modification and its role in controlling the functional properties of proteins. The reader is also referred to other excellent reviews on this topic (2-4, 6 -8). Enzymology and Regulation of SUMO Conjugationand Deconjugation Three different ubiquitous SUMO-related proteins have been identified in mammalian cells, SUMO-1, SUMO-2, and SUMO-3, with SUMO-2 and SUMO-3 having greater sequence relatedness with each other than with 4). Recently a tissue-specific SUMO-4 has been identified in human kidney with homology to SUMO-2/3, which raises the possibility that some SUMO proteins could have tissue-dependent functions (9). SUMO modification occurs on the lysine in the consensus sequence ⌿KXE (where ⌿ represents a hydrophobic amino acid, and X represents any amino acid) (2, 3). The mechanism involved in maturation and transfer of SUMO to target substrates is very similar to that seen with ubiquitination and other ubiquitin-like proteins (3, 4). This process involves four enzymatic steps: maturation, activation, conjugation, and ligation ( Fig. 1). In the first step the SUMO protein is cleaved by SUMO-specific carboxyl-terminal hydrolase to produce a carboxyl-terminal diglycine motif. This process of maturation is identical with all three mammalian SUMO forms. After maturation, SUMO proteins are able to be utilized for conjugation to proteins. The SUMO-activating (E1) enzyme is a heterodimer consisting of Aos1 and Uba2 (also known as SAE1/SAE2 or Sua1/hUba2 in humans). Activation of SUMO by the E1 is an ATP-dependent process and results in the formation of a thioester bond between SUMO and the Uba2 subunit of the E1-activating enzyme. Activation is followed by transfer of SUMO from the E1 enzyme to a conserved cysteine in the conjugating (E2) enzyme, Ubc9. This single E2 enzyme identified so far for the sumoylation pathway contrasts with the multiple E2 enzymes involved in attaching ubiquitin to proteins (4, 10).The final step of sumoylation involves ligation of SUMO to the target protei...

Sumoylation induced by the Arf tumor suppressor: A p53-independent function

“…Mammalian transcription factors that control cell proliferation are sumoylated (23)(24)(25)32), and the effects of Gam1 on sumoylation can increase the activity of several such factors (38). Gam1 reduces the sumoylation of HDAC1 without affecting its enzymatic activity (43), but HDAC1 recruitment to promoters is enhanced when histone H4 is sumoylated (44).…”

“…Effects of sumoylation are highly diverse and can influence protein transport, modulation of gene expression (usually, but not always, down-regulation), ubiquitination, DNA repair, and centromeric chromatid cohesion (24,25,32,33). Here, we propose that the p53-independent tumor-suppressive effects of p19 Arf may be mediated by its ability to enhance sumoylation of a diverse group of protein targets.…”

“…Covalent addition of the small ubiquitin-like modifiers (SUMO-1, SUMO-2, and SUMO-3) to the -amino groups of certain lysine residues in protein substrates is carried out by a single E1 enzyme (the SUMO-1-activating enzyme 1͞2 heterodimer also known as Aos1͞Uba2) and a single E2 enzyme (Ubc9) in a process analogous to ubiquitination (23)(24)(25). Before conjugation, SUMO isoforms must be cleaved by a SUMO-specific protease to generate a C-terminal diglycine motif.…”

“…The E1 mediates SUMO transfer to a cysteine residue in Ubc9, after which one of several E3s can interact with both Ubc9 and protein substrates to accelerate the rate and magnitude of their sumoylation (26)(27)(28). Mammalian protein inhibitor of activated signal transducer and activator of transcription (PIAS) proteins appear to act as SUMO E3 ligases for LEF1, p53, and c-Jun, whereas the nucleoporin RanBP2 facilitates sumoylation of RanGAP1, Sp100, histone deacetylase (HDAC) 4, and Mdm2 (24,25,28). SUMO-specific proteases serve a dual role in the SUMO cascade, being required not only for initial SUMO processing but also for cleaving ligated SUMO from protein substrates (29)(30)(31).…”

BCL11A is a SUMOylated protein and recruits SUMO‐conjugation enzymes in its nuclear body

“…Conjugation of small ubiquitin-like modifier (SUMO), called SUMOylation, is considered to be involved in the broad range of the protein function; for example, subcellular distribution, DNA-binding and transcriptional activity (Seeler & Dejean 2001Verger et al 2003;Gill 2004;Hilgarth et al 2004;Falender et al 2005;Treuter & Gustafsson 2007). SUMO molecules are covalently conjugated to the lysine residue within a consensus amino acid sequence, ψKxE (ψ is a hydrophobic amino acid and x is any kind of residues), named the SUMO consensus motif (SCM).…”