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Originally published In Press as doi:10.1074/jbc.R400021200 on September 24, 2004

J. Biol. Chem., Vol. 279, Issue 52, 53899-53902, December 24, 2004
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Regulation and Function of SUMO Modification*

Roland S. Hilgarth{ddagger}, Lynea A. Murphy{ddagger}§, Hollie S. Skaggs{ddagger}§, Donald C. Wilkerson{ddagger}, Hongyan Xing{ddagger}, and Kevin D. Sarge{ddagger}

From the {ddagger}Department of Molecular and Cellular Biochemistry and §Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536


   INTRODUCTION
TOP
 INTRODUCTION
Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
 REFERENCES
 
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 I{kappa}B, 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 Conjugation and Deconjugation
TOP
 INTRODUCTION
 Enzymology and Regulation of...
Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
 REFERENCES
 
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 SUMO-1 (3, 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 {psi}KXE (where {psi} 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).



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  		FIG. 1.
The SUMO conjugation pathway. SUMO is cleaved into its mature form by the SUMO protease Ulp1. After this step it is activated in an ATP-dependent manner by conjugation to the Uba2 subunit of the E1-activating heterodimer Aos1/Uba2. Following activation SUMO is transferred to the E2-conjugating enzyme Ubc9. In the final step SUMO is transferred in a ligation reaction to substrate proteins forming an isopeptide bond between the terminal glycine on SUMO and the {epsilon}-amino group of a lysine in the target protein to be modified. This ligation reaction is aided by SUMO ligase E3 proteins (E3), which can directly interact with target proteins or the E2 enzyme.

 
The final step of sumoylation involves ligation of SUMO to the target protein. Until recently there was speculation as to whether SUMO ligation to target proteins involved E3 ligase-like proteins such as are required for ubiquitination. However, it is now clear that such E3 ligases do exist for the SUMO-1 modification pathway and that they play important roles in modulating the efficiency of SUMO attachment to target proteins (2). As with the ubiquitin system, SUMO E3 proteins are defined by three characteristics: binding to the substrate protein either directly or indirectly, binding to the E2 conjugation enzyme, and the ability to stimulate transfer of the modifier to the substrate or to another modifier in the case of modifier chain formation. Three different general types of SUMO E3 ligases have been described (11–16). The first E3 group comprises the PIAS family of proteins. In yeast only two E3 proteins have been identified (Siz1 and Siz2) which have sequence similarity to mammalian PIAS proteins, of which at least five members have SUMO E3 activity (11, 12, 14, 17). These proteins share a common RING finger-like structure and bind directly to the Ubc9 E2 enzyme and some SUMO protein targets. This RING finger motif has also been identified in some of the ubiquitin E3 ligases (18). A second type of SUMO E3 protein found in mammalian systems is RanBP2, which is part of the nuclear pore complex (15). RanBP2 differs from the PIAS proteins in that it does not have a RING finger domain or homology to ubiquitin E3 proteins. However, it interacts with Ubc9 although not the sumoylation target protein (15). The final E3 protein type (Pc2) belongs to the Poly-comb protein family and stimulates sumoylation of C terminus binding protein (16). In some cases sumoylation can exist in the form of polymeric chains because the SUMO-1 paralogs SUMO-2 and SUMO-3 have internal SUMO modification consensus sites that allow the formation of polymeric SUMO chains on modified proteins (19). Other post-translational modifications can regulate the SUMO modification of a protein. For example, phosphorylation negatively regulates the sumoylation of several substrate proteins, including c-Jun, promyelocytic leukemia (PML), and I{kappa}B{alpha}, (2, 3). Phosphorylation can also act positively, as in the case of the transcription factor HSF1 where sumoylation is stimulated by phosphorylation of serine residues near the SUMO modification site (20, 21).

As with other post-translational modifications, SUMO groups can be removed from proteins in a reaction catalyzed by SUMO-specific proteases (2, 3). Some of these proteases have dual functionality in that they both process SUMO to its mature diglycine form and also cleave the isopeptide bond between SUMO and its target proteins (2). In yeast, two SUMO proteases have been identified, Ulpl and Ulp2/Smt4, both of which are specific for SUMO and display compartmentalization, with Ulp1 being present at the nuclear pore complex and Upl2/Smt4 being present in the nucleoplasm. In mammals, several SUMO proteases have been confirmed with the possibility of many more being present due to alternative splice variants (2). As with yeast, many of the mammalian SUMO proteases are localized to different cellular compartments, which may function to regulate the balance of protein sumoylation in these compartments.


   Sumoylation and Subcellular Localization
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
 REFERENCES
 
Depending on the target protein, sumoylation can occur in the cytoplasm or nucleus, and this modification is involved in regulating the subcellular localization of a number of substrate proteins. RanGAP1 was the first identified SUMO substrate and plays an important role in the regulation of transport of ribonucleoproteins and proteins across the NPC (22, 23). Unmodified RanGAP1 resides predominantly in the cytoplasm and upon conjugation with SUMO associates with the cytoplasmic fibers of the NPC (22, 24). SUMO modification directs RanGAP1 to the NPC by an interaction with RanBP2/Nup358, possibly mediated by sumoylation-induced formation of a binding interface for interaction of these two proteins (25). Analysis of nuclear localization signal mutants of a protein called Smad4, a factor with a major role in the TGF-{beta} signal transduction pathway, indicates that nuclear import of this protein is required for it to be sumoylated (26). Smad4 moves to the nucleus in response to TGF-{beta} stimulation, and immunofluorescence analysis of TGF-{beta}-induced cells that were SUMO-1 transfected demonstrated an increase in the nuclear localization of Smad4 (26).

Nuclei contain a number of distinct bodies that are defined, at least in part, by the proteins contained in them. For example, the PML and Sp100 proteins are major components of PML nuclear bodies (PML NBs), also called ND10. Sumoylation has been found to be required for the subcellular localization of some, but not all, proteins found in bodies such as ND10. For example, the sumoylated forms of PML and Sp100 are found exclusively in the nucleus (27). SUMO conjugation was determined to be essential for PML protein localization in ND10, whereas the targeting and accumulation of Sp100 in these bodies was not sumoylation-dependent (27, 28). This appears to be true for other SUMO substrates as well (p53, LEF1, Daxx, and SRF1) which will localize to ND10 even after mutation of their target lysine (3). Topors, a DNA topoisomerase I-binding protein, interacts with both Ubc9 and SUMO-1 leading to the formation of Topors nuclear speckles with close association to ND10, although sumoylation-deficient mutants were still able to localize to the nuclear speckles (29). SUMO modification also targets cellular localization of tumor suppressors TEL and Smad4, which in the case of TEL, a suspected tumor suppressor, leads to localization of this phospho-protein in TEL bodies, a cell cycle-dependent nuclear structure (30). Sumoylation appears to also be important for localization of the transcription factor HSF1 to nuclear bodies (31).

An exciting development in understanding both the subcellular sites of sumoylation and the role of this modification in regulating subcellular localization of proteins has been the discovery that components of the sumoylation machinery are localized at the nuclear pore complex (32, 33). This localization suggests that sumoylation of at least some proteins occurring as they enter the nucleus could be involved in nuclear import itself or perhaps retention of these proteins in the nucleus. For example, Nup358, a nuclear pore protein demonstrated to have SUMO E3 ligase activity, localizes predominantly to the cytoplasmic filaments of the NPC and regulates targeting of RanGAP1 to the NPC (2, 25). Other SUMO enzymes, Ubc9 and SENP2, have also been found to localize at the nuclear pore. Ubc9, the E2 conjugating enzyme for SUMO, localizes to the cytoplasmic and nucleoplasmic faces of the NPC as visualized by immunogold analysis of the nuclear envelope (32). Ubc9 interacts with Nup358 as well as RanGAP1/SUMO-1, and a model has been proposed in which these three proteins interact to form a stable trimeric complex (15, 32). This model is strengthened by the observation that RanGAP1 is protected from SENP2 (SUMO protease) degradation when found in this complex (15, 32). SENP2/Axam itself associates with the nucleoplasmic face of the NPC via its NH2-terminal domain (32, 34), and loss of this domain results in relocalization of this enyzme and increased capacity for deconjugation of substrates (34). SENP2 also associates with Nup153, a component of the nuclear basket in humans. Ulp1, the yeast homologue of the vertebrate SUMO isopeptidase SENP2, is required for progression through the cell cycle and also localizes to the NPC via the NH2-terminal domain, which appears to be necessary for localization as well as enzymatic specificity (35). Further establishing the connection between sumoylation and nuclear import are data showing that yeast Ulp1 and Ulp2 mutants, deficient in SUMO conjugation, display an impairment of classical nuclear localization signal-mediated protein import (36).

Sumoylation is most often implicated in promoting localization of proteins to the nucleus and in some cases to nuclear bodies. However, there is evidence that SUMO modification could also function to regulate nuclear export of some substrates. For example, nuclear sumoylation of Dictyostelium Mek1 is responsible for its movement to the cytoplasm (37), and mutation of lysine 99 of the TEL protein leads to increased levels of this protein in the nucleus, suggesting a possible role for sumoylation in its nuclear export (38). In addition, sumoylation of heterogeneous nuclear ribonucleoproteins M and C has been proposed to function as a regulator of conformational changes that may influence nucleocytoplasmic transport of these protein complexes (39).


   SUMO and Transcription Regulation
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
 REFERENCES
 
The sumoylation of transcription activators, repressors, coactivators, corepressors, and components of PML NBs is involved in the regulation of gene expression (3, 6, 8). The activities of many transcription factors are regulated by association with PML NBs, and assembly of PML NBs requires sumoylation of the PML protein (3, 7). Thus, alteration of PML sumoylation has broad effects on transcription (1, 7). For example, sumoylation of PML recruits corepressor Daxx to PML NBs, thereby relieving Daxx-mediated repression of these genes. Similarly, sumoylation of PML directs p53 to PML NBs and could then trigger some modification, such as acetylation and sumoylation, which stimulates the transcriptional activity of p53. Also, sumoylation of PML recruits another sumoylated nuclear body-associated protein, Sp100. Sumoylation of other transcription factors has also been found to regulate their localization, including Drosophila Dorsal, Bicoid, p73{alpha}, and Pdx1 (1). Similar to what is observed for PML, corepressor HIPK2 and repressor TEL and TEL-AML1 localize to nuclear dots in a SUMO-dependent manner. Whether sumoylation alters the repressive function of these transcription factors is unclear.

The sumoylation of transcription factors has been reported to have different effects on their activities in various pathways including those involving cytokines, WNT, steroid hormone, and AP-1 (3, 6, 8). In most cases, SUMO modification plays a negative role in transcription regulation. The transcription factors that are inhibited by SUMO modification include STAT1, catenin-TCF/LEF, c-Jun, Ah receptor nuclear translocator (ARNT), CEBP{alpha}, c-Myb, Sp3, IRF-1, SREBPs, SRF, Elk, AP1, AP2, androgen receptor (AR), glucocorticoid receptor (GR), and progesterone receptor (PR), as well as huntingtin (3, 6, 40). The {psi}KXE sumoylation site motifs of some factors such as GR, Sp3, c-Myb, C/EBP, and the SREBPs are located within an inhibitory or negative regulatory domain or the so-called "synergy control" motifs that can transrepress transcriptional activity. Mutation of sumoylation sites in transcription factors has been found to increase their transcriptional activity, for example, transcription factors Elk-1, Sp-3, SREBPs, STAT-1, SRF, c-Myb, C/EBPs, AR, p300, c-Jun, GR, and peroxisome proliferator-activated receptor {gamma} that may reflect a role for SUMO-1 modification as a negative regulator of transactivation domains (3, 6, 41). Consistent with this idea, overexpression of free SUMO-1 can suppress AP2 and AP2-mediated transcription (8). Direct evidence for repression of transcriptional activity by sumoylation is that fusion of SUMO to GAL4 drastically reduces its activity in reporter gene assays (42). Furthermore, SUMO is also able to inhibit transcription in trans as demonstrated by SUMO-dependent trans-repression of the VP-16 activation domain (43).

The effects of SUMO on transcriptional activity may be complicated by the finding that a number of transcription co-factors, such as GRIP1, SRC-1, and histone deacetylases (HDAC) 1 and 4, are also sumoylated (1, 3, 6, 8). Sumoylation might be involved in modulating the functions of proteins as co-activators (GRIP1, SRC-1) or co-repressors (HDAC1, HDAC4) but is not essential (8). Several observations reveal that the PIAS/SUMO system may modulate the assembly of coactivator or corepressor complexes that regulate transcription (40). Other findings indicate further links between the SUMO system and class I and class II HDACs that mediate transcription repression. For example, sumoylation of p300 can mediate repression of gene activity by recruitment of the corepressor HDAC6 (44). The AR, which interacts with the corepressor SMRT, is part of a larger HDAC1-containing complex (45). Mutation of the sumoylation site in AR abrogates SMRT binding, suggesting that sumoylation is required for the association of SMRT and class 1 HDACs. Similar data show that histone H4 sumoylation mediates transcriptional repression through recruitment of HDAC1 and HP1 (46). However, sumoylation of methyl-transferase 3a (Dnmt3a) disrupts its ability to interact with HDAC1/2, which abolishes its capacity to repress transcription (47). Regarding other possible mechanisms by which sumoylation could mediate effects on transcription factors/co-factors, examples where sumoylation has been found to regulate ubiquitination of proteins such as NF{kappa}B inhibitor I{kappa}B{alpha}, PCNA, Smad4, and Mdm2, either directly by competition for the modified lysine or indirectly, leaves open the possibility that some effects of sumoylation could be mediated via control of protein levels in general or turnover of specific subpopulations of a protein in a cell (3, 6, 48).

Although sumoylation of most transcription factors results in repression, SUMO modification appears to have positive effects on transcriptional activation by the heat shock factors HSF1 and HSF2 and the {beta}-catenin-activated factor Tcf-4. Sumoylation of HSF1 and HSF2, which is stress-induced in the case of HSF1 but can be observed for HSF2 present in non-stressed cells, is correlated with their localization to PML NBs (31, 49). For both HSFs, in vitro sumoylation leads to increased DNA-binding activity, but in the case of HSF1, mutation of the sumoylation site did not appear to block stress-induced DNA-binding activity in cells (21, 31, 49). One possibility is that, because of the critical importance of inducing heat shock protein expression in response to cellular stress, cells may have evolved multiple independent pathways for activating HSF1 DNA binding, of which sumoylation is only one. Tcf-4-dependent transcription is activated by coexpression of {beta}-catenin and PIASy, and this activation is reduced when Tcf-4 lacks SUMO attachment sites, suggesting that sumoylation activates Tcf-4 (50). A protein called DJ-1, originally identified as a Myc-interacting protein, positively regulates AR activity and also appears to be modified by SUMO, and mutation of the acceptor lysine destroys the capacity of DJ-1 to positively regulate AR activity (13).


   Role of SUMO in Genomic Integrity and Chromosomes
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
SUMO and Viral Proteins
 Perspectives
 REFERENCES
 
Since its discovery, sumoylation has held an important role in cell biology that extends into fields such as chromosome cohesion and kinetochore assembly. During mitosis, the proper distribution of chromosomes into replicated cells is a highly ordered and complex process that is dependent upon the proper timing of sister chromatid assembly and separation. Misregulation of this process was one of the first phenotypes described in SUMO-1 (Smt3/Pmt3) mutants in yeast, characterized by aberrant mitosis and defects in chromosomal segregation (51, 52). Other components of the sumoylation machinery, such as the E2 conjugating enzyme and SUMO isopeptidases, have also been shown to be important for this process. For example, the SUMO-1 isopeptidase in budding yeast (Smt4) acts as a key regulator of centromeric chromatid cohesion (53). The same study also suggested that the yeast homologue of topoisomerase II (Top2) was the SUMO-1 substrate important for this process, because topoisomerase II mutants lacking SUMO-1 modifications sites can rescue defects in the isopeptidase mutants (53). In support of this idea, topoisomerase II was found to be the major high molecular weight, chromatin-dependent sumoylated protein in mitotic Xenopus extracts (54). Interestingly, this effect does not appear to be mediated via sumoylation-induced changes in topoisomerase II activity, because a dominant negative mutation in the Ubc9 (SUMO E2 conjugation enzyme) prevented sister chromatid cohesion at the metaphase to anaphase transition but did not alter topoisomerase II activity (54). Sumoylation of other proteins such as the Psds5 protein has also been implicated in sister chromatid cohesion. In the case of Psds5, which is a non-essential regulator of cohesion maintenance in yeast, results suggest that the desumoylation of this protein promotes sister chromatid dissolution by rendering the cohesin complex, which acts as the molecular glue between sister chromatids, accessible to other factors that promote dissolution (55).

The role of SUMO-1 in mitotic chromosome structure is not limited to the cohesive properties of centromeres, as sumoylation has also been implicated in the maintenance and recruitment of proteins to the kinetochore, the protein complex that forms at the centromere and recruits microtubules for anaphase separation. In Saccharomyces cerevisiae, SUMO-1 has been shown to be a suppressor of a temperature-sensitive MIF2 (yeast homologue of CENP-C), a protein which links {alpha}-satellite-containing centromeric DNA to the proteins of the inner kinetochore plate (56). Interestingly, neither CENP-C nor MIF2 is sumoylated, and thus the role of sumoylation is thought to be indirect (57). In addition to modifying several central kinetochore/centromere proteins, sumoylation is also thought to target various proteins to this region during mitosis for reasons which remain unclear. For example, during mitosis SUMO-1 targets RanGAP1 to the mitotic spindles and kinetochores, and at the kinetochores specifically, RanBP2/Nup358 colocalizes specifically at the kinetochore (58).

In addition to the apparent role of sumoylation in chromosome maintenance and kinetochore assembly/disassembly, the sumoylation modification of a number of critical tumor suppressor and repair proteins implicated SUMO-1 as an integral player in maintaining genomic stability. p53 and Mdm2 are both targets of sumoylation, which has functional effects on the activities of these proteins (3, 6, 7, 48). Evidence indicates that components of the Wnt signaling cascade (e.g. axin, {beta}-catenin, LEF/Tcf-4) are also targets of sumoylation, which may regulate the system at multiple vertical and horizontal steps (3, 6, 7). Although sumoylation apparently affects cell cycle and developmental proteins, the integrity of DNA itself may also rely on the sumoylation status of various proteins, particularly those involved in DNA repair. Both UBL1 (SUMO-1) and UBE2I (Ubc9) have been identified to interact with RAD51/52, proteins well known for their role in homologous recombination and repairing double-stranded breaks in cells (59, 60). Sumoylation has also been implicated in the repair of the DNA damage mediated by topoisomerase II (61, 62), which is of clinical relevance because topoisomerase is a target of numerous anti-cancer therapies. More recent evidence suggests that the Rad6 postreplicative repair pathway is apparently sumoylation-dependent, particularly with respect to PCNA, the activity of which varies by which molecular tag (e.g. SUMO-1 or ubiquitin) it carries (63, 64). The balance between sumoylation and ubiquitination of PCNA, which determines which specific repair pathway the cell utilizes, illustrates the critical role of sumoylation in this important cell function.


   SUMO and Viral Proteins
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
Perspectives
 REFERENCES
 
Two major-immediate-early (MIE) proteins critical for propagation of the human cytomegalovirus and herpesvirus, IE1 (IE1-p72 or IE72) and IE2 (IE2-p86 or IE86), have been found to be sumoylated. In the case of the IE1 protein, which is known to interact with PML, blocking this modification does not disrupt targeting of this protein to ND10 nuclear bodies nor does it affect ND10 organization, suggesting that sumoylation is not a prerequisite for the derepressive activities of IE1 (65, 66). However, IE1 does modulate the sumoylation of PML and is important for effects on nuclear body dynamics (67). Targeting of IE2 to ND10 is not affected by mutations of its target lysine residues, but sumoylation appears to be critical for IE2-mediated transactivation (68). Recent studies have also shown that PIAS1 can increase the levels of IE2 sumoylation which leads to enhanced IE2-mediated transactivation (69). The BZLF1 (Z) protein of Epstein-Barr virus (EBV) is SUMO-1-modified at lysine 12 within the transactivation domain, and results suggest that BZLF1 sumoylation decreases PML SUMO modification by competing for limiting amounts of free SUMO protein (70). The immediate early protein E1 of bovine papillomavirus was found to interact both in vivo and in vitro with Ubc9 using a yeast two-hybrid screen and to be sumoylated at lysine residue 514 (71). Mutations within E1 that prevent SUMO-1 modification do not affect intracellular stability but do disrupt nuclear import and accumulation leading to the decreased ability of E1 to replicate the viral genome (71, 72).

A number of adenoviral proteins important for viral replication have also been shown to be sumoylated. Adenoviral E1B is modified at SUMO-1 at lysine 104, which is important for the ability of this protein to transform primary cells and inhibit p53-mediated transactivation, and also appears to mediate E1B localization to the nucleus (73). Expression of adenoviral Gam1 leads to a global reduction in sumoylation including the reduced sumoylation of HDAC1, dispersal of PML-containing nuclear bodies, and delocalization of SUMO-1 (74). The adenovirus E1A protein has been shown to physically interact with the SUMO E2 Ubc9 protein although no clear role has been identified (75). In addition, yeast two-hybrid analysis indicated that the geminivirus TYLCSV protein Rep interacts with a Ubc9 homologue from Nicotiana benthamiana (NbSCE1), but it is not clear if Rep is a substrate for sumoylation (76).


   Perspectives
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
REFERENCES
 
Investigation of the regulation and function of SUMO modification of proteins is an exciting and rapidly growing field. The recent use of broad proteomics approaches to identify large numbers of new putative sumoylated proteins will only add to the already rapid pace of advance (77–81). Key areas requiring further investigation include understanding the underlying molecular and biochemical mechanisms by which this modification plays its critical roles in regulating subcellular localization, transcription, chromosome function, and genomic integrity, to name a few, and to understand how sumoylation leads to different effects in different proteins. Further investigation of the mechanisms and function of nuclear pore-associated sumoylation, including identification of additional proteins that are sumoylated at this cellular site, should also yield interesting new results and better understanding of the role of this important protein modification.


   FOOTNOTES
 
* This minireview will be reprinted in the 2004 Minireview Compendium, which will be available in January, 2005. Back

To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, University of Kentucky, 800 Rose St., Lexington, KY 40536. Tel.: 859-323-5777; E-mail: kdsarge{at}uky.edu.

1 The abbreviations used are: SUMO, small ubiquitin-like modifier; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase; PIAS, protein inhibitors of activated STATs; STAT, signal transducer and activator of transcription; PML, promyelocytic leukemia; NPC, nuclear pore complex; TGF-{beta}, transforming growth factor {beta}; NB, nuclear body; AR, androgen receptor; GR, glucocorticoid receptor; PR, progesterone receptor; C/EBP, CCAAT enhancer-binding protein; SREBP, sterol regulatory element-binding protein; SRF, serum response factor; HDAC, histone deacetylase; PCNA, proliferating cell nuclear antigen; EBV, Epstein-Barr virus; HSF, heat shock factor; TCF, T-cell factor; LEF, lymphoid enhancer factor. Back



   REFERENCES
TOP
 INTRODUCTION
 Enzymology and Regulation of...
 Sumoylation and Subcellular...
 SUMO and Transcription...
 Role of SUMO in...
 SUMO and Viral Proteins
 Perspectives
 REFERENCES
 

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