In the last decade, SUMOylation has emerged as an essential post-translational modification in eukaryotes. In plants, the biological role of SUMO (small ubiquitin-related modifier) has been studied through genetic approaches that together with recent biochemical studies suggest that the plant SUMOylation system has a high degree of complexity. The present review summarizes our current knowledge on the SUMOylation system in Arabidopsis, focusing on the mechanistic properties of the machinery components identified.

Introduction

The covalent attachment of SUMO (small ubiquitin-related modifier) to target proteins constitutes a mechanism of protein regulation and modulates many biological processes in eukaryotes. SUMO belongs to the ubiquitin-like protein family (Ubl), which comprises proteins that share the same tertiary structure and conjugation mechanism as ubiquitin. SUMO is synthesized as a precursor that is processed at its C-terminal tail by the specific ULPs (ubiquitin-like proteases), releasing a SUMO mature form with a Gly-Gly motif at its C-terminus. SUMO activation is a two-step and ATP-dependent reaction catalysed by the heterodimeric E1 activating enzyme, SAE (SUMO-activating enzyme) 1/SAE2. Activation starts with the production of a SUMO-adenylate intermediate that is subsequently transferred to the E1 active cysteine residue. Next, SUMO is transferred to the E2 conjugating enzyme active cysteine residue via a transesterification reaction. In a third reaction, SUMO is covalently attached to the target substrate through an isopeptide linkage between the SUMO C-terminal glycine residue and the ε-amino group of the target lysine residue in the substrate. Although there are variations, the target lysine residue is usually located within the consensus site ΨKXE (Ψ is a large hydrophobic amino acid, K is the modified lysine residue, X is any amino acid and E is a glutamate residue). This final step is facilitated by E3 ligase enzymes that interact both with SUMO charged E2 and with the substrate. SUMOylation is a reversible modification and SUMO excision from the substrate is catalysed by the same class of cysteine proteases involved in the maturation step. Initial studies on SUMOylation were focused on the identification of the SUMO machinery members and target proteins [1,2]. In the recent years, major effort has been put towards the characterization of the molecular mechanisms that control SUMO conjugation, which have revealed the existence of critical protein–protein interactions [38].

In plants, homology studies have identified SUMO machinery members and most of the Arabidopsis orthologues have been biochemically validated [914]. Although many genetic studies have established a role for SUMOylation in defence, abiotic stress responses, hormone signalling and flowering control, and SUMOylation has been shown to be essential during seed development, much less is known about the molecular mechanisms through which SUMO regulates those biological processes. This review summarizes our current knowledge of the Arabidopsis SUMOylation system, focusing on characterization of the machinery and the small number of identified targets.

The SUMO pathway and its components

Arabidopsis genome data mining identified genes coding for SUMO, large and small subunits of the E1 activating enzyme [AtSAE2 (where At is Arabidopsis thaliana) and AtSAE1], E2 conjugating enzyme [AtSCE (SUMO-conjugating enzyme)], E3 ligase and ULP homologues, confirming that the whole pathway is conserved in Arabidopsis (Table 1). When compared with the yeast and mammalian systems, the identification of a larger number of genes codifying for complete sequences of putative SUMO and ULP orthologues, namely 9 and 13 genes respectively, was remarkable [10,15]. Gene duplication seems to have been a frequent phenomenon for the SUMO and ULP, although the non-detectable gene expression for most paralogues suggests that the SUMOylation system may have evolved to bring about a reduction in the number of functional members. In addition, the Arabidopsis genome contains two copies of the E1 activating enzyme small subunit, AtSAE1a and AtSAE1b, which is surprising since AtSAE1 contributes to E1 activity to a minor degree and, apparently, it does not establish any contact with SUMO during activation [3]. Conservation analysis of the AtSAE1a/b primary and tertiary structures did not reveal the presence of any domain that could suggest a functional specialization (J. Seguí and L.M. Lois, unpublished work) and the only residue that contacts ATP in the adenylation domain, Arg16, is conserved in both isoforms. On the contrary, there is a single copy of the E1 large subunit AtSAE2, which comprises the three functional domains: adenylation, catalytic cysteine residue and UFD (ubiquitin-fold domain), and a C-terminal tail proposed to be responsible for nuclear localization [16]. The E2 conjugating enzyme is also encoded by a single gene, AtSCE1, and two E3 ligases of the RING (really interesting new gene)-type SIZ/PIAS [protein inhibitor of activated STAT (signal transducer and activator of transcription)] family have been identified, AtSIZ1 and AtHPY2 (high ploidy2). The RanBP2 (Ran-binding protein 2)-type SUMO E3 ligase identified in mammals is apparently not conserved in Arabidopsis, similarly to what has been described for yeast [17].

Table 1
Expressed Arabidopsis SUMO machinery members

Reported phenotypes of single and double mutants are indicated (NR, not reported). LD, long days; SD, short days.

   Mutant phenotype  
   Growth   
 Name Accession number Single mutant Double mutant Flowering Subcellular localization 
SUMO AtSUMO1 At4g26840 Normal  NR Cytoplasmic/nuclear [9,15
 AtSUMO2 At5g55160 Normal Lethal(atsumo1 atsumo2NR Cytoplasmic/nuclear [9,15
 AtSUMO3 At5g55170 NR  NR NR 
 AtSUMO5 At2g32765 NR  NR NR 
E1 AtSAE2 At2g21470 Lethal  NR NR 
 AtSAE1a At4g24940 Normal  NR NR 
 AtSAE1b At5g50580 NR  NR NR 
E2 AtSCE1 At3g57870 Lethal  NR Cytoplasmic/nuclear [9
E3 AtSIZ1 At5g60410 Dwarf  LD and SD [28Nuclear/nuclear foci [11
 AtHPY2 At3g15150 Dwarf  Nr Nuclear [26
ULP AtULP1a At3g06910 NR  NR NR 
 AtULP1c (OST2) At1g10570 Normal  LD and SD [25Nuclear/nuclear foci [25
 AtULP1d (OST1) At1g60220 Normal Salt-sensitive (atulp1c atulp1d) [25LD and SD [25Nuclear [25
 AtESD4 At4g15880 Dwarf [10 LD and SD [10Nuclear envelope [10
   Mutant phenotype  
   Growth   
 Name Accession number Single mutant Double mutant Flowering Subcellular localization 
SUMO AtSUMO1 At4g26840 Normal  NR Cytoplasmic/nuclear [9,15
 AtSUMO2 At5g55160 Normal Lethal(atsumo1 atsumo2NR Cytoplasmic/nuclear [9,15
 AtSUMO3 At5g55170 NR  NR NR 
 AtSUMO5 At2g32765 NR  NR NR 
E1 AtSAE2 At2g21470 Lethal  NR NR 
 AtSAE1a At4g24940 Normal  NR NR 
 AtSAE1b At5g50580 NR  NR NR 
E2 AtSCE1 At3g57870 Lethal  NR Cytoplasmic/nuclear [9
E3 AtSIZ1 At5g60410 Dwarf  LD and SD [28Nuclear/nuclear foci [11
 AtHPY2 At3g15150 Dwarf  Nr Nuclear [26
ULP AtULP1a At3g06910 NR  NR NR 
 AtULP1c (OST2) At1g10570 Normal  LD and SD [25Nuclear/nuclear foci [25
 AtULP1d (OST1) At1g60220 Normal Salt-sensitive (atulp1c atulp1d) [25LD and SD [25Nuclear [25
 AtESD4 At4g15880 Dwarf [10 LD and SD [10Nuclear envelope [10

Whereas identity among the annotated SUMO (1–6) paralogues ranges between 29 and 83% and AtSAE1a and AtSAE1b isoforms are 80% identical, the lower conservation among ULP paralogues (12–44%, considering the characterized isoforms) makes it difficult to identify SUMO-specific proteases by homology studies. These differences are mainly the result of the high degree of divergence in the ULP N-terminal regulatory domain [8]. Even the two highly related Arabidopsis ULPs, AtULP1c and AtULP1d, show only 25% N-terminus sequence identity, whereas their catalytic domains are 70% identical. Given that biochemical studies have failed to identify specific Arabidopsis proteases competent to process AtSUMO3/5 isoforms (see the next section) [12,13,18], it is expected that new proteases are to be identified. In the present review, through a new search for predicted ULP homologues at the Arabidopsis annotated genome, six novel putative ULPs have been identified: three are expressed at significant levels and have associated ESTs (expressed sequence tags; At1g09730, At3g48480 and At4g33620), At5g45570 is poorly expressed but also has associated ESTs, and At2g12100 and At4g09280 are poorly expressed and do not have associated ESTs (Figure 1). The identification of At5g60190, which was also previously identified in a search for SUMO-specific proteases and proven to be a RUB1-specific protease [12], underlines the need for biochemical studies in order to identify bona fide SUMO-specific proteases.

Phylogenetic relationship of ULP proteins

Figure 1
Phylogenetic relationship of ULP proteins

The Arabidopsis genome database at NCBI and the Arabidopsis Information Resource (TAIR) were searched using human SENP1 (SUMO1/sentrin-specific peptidase 1) and Arabidopsis ESD4 catalytic domain sequences. The sequences retrieved were aligned, including all human and yeast ULP isoforms (protein multiple alignment software MUSCLE [34]). Sequences annotated as pseudogenes, duplicated annotations and sequences with non-conserved active-site residues (ScULP1: His514, Asp531, Gln574 and Cys580 [35]) were removed from the alignment. Asterisks indicate sequences with a D531N substitution. Phylogenetic analysis was performed with the TreeTop-Phylogenetic Tree Prediction software (http://www.genebee.msu.su/) and PhyloDraw was used for tree representation (http://pearl.cs.pusan.ac.kr/phylodraw/). Maximum expression levels (arbitrary units) considering all developmental stages, as determined in Genevestigator database (https://www.genevestigator.com/gv/index.jsp), are indicated below the accession number or name. Annotations with non-detectable expression levels are crossed out and those with assigned ESTs are in bold. Among the latter, those that have not been biochemically characterized are shown in italics. At, Arabidopsis thaliana; Hs, Homo sapiens; Sc, Saccharomyces cerevisiae.

Figure 1
Phylogenetic relationship of ULP proteins

The Arabidopsis genome database at NCBI and the Arabidopsis Information Resource (TAIR) were searched using human SENP1 (SUMO1/sentrin-specific peptidase 1) and Arabidopsis ESD4 catalytic domain sequences. The sequences retrieved were aligned, including all human and yeast ULP isoforms (protein multiple alignment software MUSCLE [34]). Sequences annotated as pseudogenes, duplicated annotations and sequences with non-conserved active-site residues (ScULP1: His514, Asp531, Gln574 and Cys580 [35]) were removed from the alignment. Asterisks indicate sequences with a D531N substitution. Phylogenetic analysis was performed with the TreeTop-Phylogenetic Tree Prediction software (http://www.genebee.msu.su/) and PhyloDraw was used for tree representation (http://pearl.cs.pusan.ac.kr/phylodraw/). Maximum expression levels (arbitrary units) considering all developmental stages, as determined in Genevestigator database (https://www.genevestigator.com/gv/index.jsp), are indicated below the accession number or name. Annotations with non-detectable expression levels are crossed out and those with assigned ESTs are in bold. Among the latter, those that have not been biochemically characterized are shown in italics. At, Arabidopsis thaliana; Hs, Homo sapiens; Sc, Saccharomyces cerevisiae.

Similarities and differences among SUMO family members

The functional consequences of SUMO attachment are dependent on the nature of the target and involve intracellular localization, protein interactions, stability and activity regulation. At the molecular level, SUMO can mask a specific interaction surface with other molecules such as proteins or DNA, it can contribute as an additional interaction surface, or it can induce conformational changes that affect protein function. Considering that the SUMOylation outcome is achieved through the interaction with specific effectors, the attached SUMO isoform will determine the consequences of the modification. In addition, the target itself can confer specificity for the SUMO paralogue to be conjugated through a mechanism that involves non-covalent binding between the target and the modifier [19]. In Arabidopsis, expression has been reported for four SUMO paralogues (AtSUMO1/2, 3 and 5) that are not biologically redundant since double atsumo1/atsumo2 mutant plants are not viable, suggesting that AtSUMO3/5 do not have overlapping roles with AtSUMO1/2. This specialization among SUMO paralogues is not conserved in mammals, where SUMO2/3 can compensate for SUMO1 loss [20,21]. On the other hand, AtSUMO1/2 are highly conserved paralogues (83% identity) that can complement each other's deletion [22]. A recent study has determined that in planta constitutive expression of mature AtSUMO3/5 results in delayed growth and senescence-like symptoms [14]. On the other hand, similar studies that have constitutively expressed AtSUMO1/2 at high levels did not report any obvious plant growth defect [9,10,15], suggesting that a tight control of mature AtSUMO3/5 availability is critical for plant growth homoeostasis. Supporting this observation, data mining from the Genevestigator database [23] revealed that AtSUMO3/5 expression levels through plant development are 10-fold lower than AtSUMO1/2 levels on average (I. Teixeira and L.M. Lois, unpublished work). Assuming that these differences are conserved at the protein level, it is tempting to speculate that plants have developed mechanisms to maintain low levels of AtSUMO3/5 isoforms. One possible explanation for the AtSUMO3/5 deleterious effect could involve a competition with AtSUMO1/2 for conjugation. Alternatively, AtSUMO3/5 toxicity might be the result of interaction with effectors that, when in excess, are detrimental for plant development. In order to discriminate between both possibilities, it would be necessary to analyse the effect that increasing non-conjugable AtSUMO3/5 paralogue levels has on plant development.

ULPs contribute to maintaining mature SUMO pools by processing the immature form and releasing SUMO from its target. Studies addressing the characterization of the Arabidopsis ULP family have concluded that there is some specificity but also overlapping functions, similar to what has been described for the human orthologues [8,24]. Four Arabidopsis ULPs [AtULP1a, AtULP1c, AtULP1d and AtESD4 (early in short days 4)] have been characterized according to their capacity to process immature SUMO (peptidase) and excise it from modified substrates (isopeptidase). Interestingly, none of them showed any significant peptidase or isopeptidase activity towards AtSUMO5, and only AtULP1a displayed a very inefficient peptidase activity towards AtSUMO3 and non-detectable isopeptidase activity [12,13]. In our laboratory, we failed to detect endogenous AtSUMO3/5 peptidase activities in Arabidopsis total protein extracts, whereas AtSUMO1/2 peptidase activities were easily detectable, suggesting that AtSUMO3/5 might be processed at very low rates or under specific circumstances (J. Seguí and L.M. Lois, unpublished work). On the other hand, it has been proposed that the Xanthomonas campestris type III effector shows peptidase and isopeptidase activity towards AtSUMO1/2, and there is some controversy about its capacity to remove AtSUMO3 from a modified target [12,18]. In addition, AtULP1c, AtULP1d and AtESD4 show similar subcellular distribution at the nucleus, with some differences at the subnuclear level (Table 1). Genetic studies also support the existence of a ULP functional redundancy. Single atulp1c, atulp1d and atesd4 mutants and atulp1c/atulp1d double mutants have been shown to be viable, although the fact that atesd4 mutant plants display growth defects suggests that this protease may have a major role in vivo [10,25].

The two E3 ligases identified in Arabidopsis, AtSIZ1 and AtHPY2, also localize at the nucleus, but they do not seem to have complementary functions, since atsiz1 and athpy2 mutant plants display a severe dwarf phenotype [11,22,26]. According to the displayed growth defects, AtHPY2 has been proposed to function mainly in the meristem, whereas AtSIZ1 would have a more general role in plant development. Unfortunately, no results regarding epistasis between both genes have been reported, which would provide relevant information on the degree of specialization of both proteins. In vitro, both ligases are SUMOylated but only AtSIZ1 has been proven to facilitate SUMO conjugation to other substrates (Table 2).

Table 2
Biological processes affected in atsiz1 mutant plants

Modifications in other machinery components resulting in a similar phenotype are indicated and the proposed SUMO targets affected are shown. ABA, abscisic acid.

Biological process Mutant phenotype Machinery component with similar phenotype Proposed target Reference(s) 
ABA signalling Increased ABA response AtSCE1 co-suppression ABI5 [9,27
Flowering Early under long and short days esd4/ost1ost2 double mutant FLD [10,25,28
Abiotic stress Phosphate deficiency  PHR1 [11
 Heat and cold sensitivity  ICE1 [29,31
 Drought sensitivity   [32
Biotic stress Constitutive systemic acquired resistance   [33
Biological process Mutant phenotype Machinery component with similar phenotype Proposed target Reference(s) 
ABA signalling Increased ABA response AtSCE1 co-suppression ABI5 [9,27
Flowering Early under long and short days esd4/ost1ost2 double mutant FLD [10,25,28
Abiotic stress Phosphate deficiency  PHR1 [11
 Heat and cold sensitivity  ICE1 [29,31
 Drought sensitivity   [32
Biotic stress Constitutive systemic acquired resistance   [33

SUMO targets in Arabidopsis

Identifying the proteins that must be SUMOylated in order to guarantee viability and preserve normal plant growth is a key issue in the study of SUMOylation. In plants, few SUMO targets have been identified when compared with mammals and yeast. In Arabidopsis, three approaches have been used for this purpose: prediction analyses, E3 ligase-interacting protein screening and biochemical purification. The first substrates were predicted based on the presence of a SUMOylation consensus site in proteins involved in biological processes altered in atsiz1 mutant plants, as is the case for AtPHR1 (phosphate starvation response 1), AtICE1 [inducer of CBF (CCAAT-binding factor) expression 1], AtFLD (flowering locus D) and AtABI5 (abscisic acid-insensitive 5) [11,2729]. Alternatively, the global transcription factor GTE (general transcription factor group) 3 was identified in a screening of AtSIZ1-interacting proteins by yeast-two hybrid assays, and the analysis of other family members concluded that AtGTE5, but not AtGTE7, is also SUMO-modified [30]. A recent proteomic analysis resulted in the identification of an additional set of SUMO targets, four of which were validated by in vitro conjugation assays, namely AML5 (Arabidopsis MEI2-like protein 5), TAF7 [TBP (TATA-box-binding protein)-associated factor 7], NAF (nucleosome assembly factor) and At3g56860 [14]. Despite the reduced number of reported targets, all of them are transcription factors or participate in DNA/RNA-related processes, which is consistent with the nuclear localization of most endogenous conjugates [22]. Less is known about the functional consequence of SUMOylation of these proteins and in planta conjugation has not been shown for any of them.

Overall, the results generated suggest that SUMOylation in Arabidopsis has developed a high degree of complexity according to the functional diversification of SUMO paralogues shown by genetic studies, and determining the relevance of this awaits further investigation. The study of other machinery members has also been addressed, but major effort has to be put in order to understand when, how and for what reason a set of proteins are SUMO-modified.

Ubiquitin–Proteasome System, Dynamics and Targeting: 4th Intracellular Proteolysis Meeting, a Biochemical Society Focused Meeting held at Institut d'Estudis Catalans, Casa de Convalescència, Barcelona, Spain, 27–29 May 2009. Organized and Edited by Bernat Crosas (Institute of Molecular Biology of Barcelona, Spain), Rosa Farràs (Centro de Investigación Príncipe Felipe, Valencia, Spain), Gemma Marfany (University of Barcelona, Spain), Manuel Rodríguez (CIC bioGUNE, Derio, Spain) and Timothy Thomson (Institute of Molecular Biology of Barcelona, Spain)

Abbreviations

     
  • At

    Arabidopsis thaliana

  •  
  • ESD4

    early in short days 4

  •  
  • EST

    expressed sequence tag

  •  
  • GTE

    general transcription factor group

  •  
  • HPY2

    high ploidy2

  •  
  • SUMO

    small ubiquitin-related modifier

  •  
  • SAE

    SUMO-activating enzyme

  •  
  • SCE

    SUMO-conjugating enzyme

  •  
  • ULP

    ubiquitin-like protease

Funding

The work in my laboratory is supported by the European Research Council [grant number ERC-2007-StG-205927] and the Spanish Ministry of Education and Science [grant number BIO2008-01495].

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