One of the more rapidly expanding fields in cell signalling nowadays is the characterization of proteins conjugated to Ub (ubiquitin) or Ub-like peptides, such as SUMO (small Ub-related modifier). The reversible covalent attachment of these small peptides remodels the target protein, providing new protein–protein interaction interfaces, which can be dynamically regulated given a set of enzymes for conjugation and deconjugation. First, ubiquitination was thought to be merely relegated to the control of protein turnover and degradation, whereas the attachment of SUMO was involved in the regulation of protein activity and function. However, the boundaries between the protein fates related to these tag molecules are becoming more and more fuzzy, as either the differences between mono-, multi- and poly-modifications or the lysine residue used for growth of the poly-chains is being dissected. The Ub and SUMO pathways are no longer separated, and many examples of this cross-talk are found in the literature, involving different cellular processes ranging from DNA repair and genome stability, to the regulation of protein subcellular localization or enzyme activity. Here, we review several cases in which SUMOylation and ubiquitination intersect, showing also that the same protein can be conjugated to SUMO and Ub for antagonistic, synergistic or multiple outcomes, illustrating the intricacy of the cellular signalling networks. Ub and SUMO have met and are now applying for new regulatory roles in the cell.

Introduction

Post-translational modifications are one of the most effective ways by which evolution has increased the versatility in protein function using a relative paucity of genes. These covalent modifications, such as phosphorylation, acetylation or ubiquitination, rely on a set of enzymes for reversible conjugation/deconjugation that respond promptly to the requirements of the cell state and hence are essential for the regulation of cellular processes in a dynamic manner [1].

The covalent conjugation of Ub (ubiquitin) and Ubls (Ub-like molecules), the best known of them being SUMO (small Ub-related modifier), has been intensely studied in the last few years. Ub and SUMO share a characteristic structural β-GRASP (β-Golgi reassembly stacking protein) fold (named the ubiquitin fold) and a similar conjugation mechanism, through their C-terminal carboxy group, to a particular lysine residue of their substrates. Despite these common structural and mechanistic traits, there are still some significant differences that allow them to be functionally classified into two separate groups.

Ub is the most well known molecular tag for proteolysis via proteasome [2]. This small peptide presents several lysine residues that can be used to assemble a poly-Ub (polyubiquitin) chain by sequential subsequent conjugation of new Ubs, the most prevalent being Lys48 and Lys63. The attachment of a Lys48 Ub chain addresses the tagged molecule to degradation, whereas Lys63 poly-Ub chains are involved in a wider range of functions including DNA repair, endocytosis or nuclear export [3]. Moreover, mono-Ub (mono-ubiquitination) and multimono-ubiquitination have been also shown to be relevant for regulating enzyme activity and protein subcellular localization, adding new nuances to the role of Ub. In contrast, SUMOylation usually relies on the conjugation of a single moiety. The covalent attachment of SUMO is involved in the regulation of protein function and activity, through changes in the conformation and new interfaces for protein interactions, and it is well known that mono-SUMOylated proteins are key players in multiple cellular processes, such as genome stability, progression of the cell cycle or subcellular transport [4]. Nonetheless, SUMO2/SUMO3 has been also reported to form chains through Lys11 located in a consensus modification site [5]. Notably, SUMO1, which lacks this conserved residue, is also able to form mixed SUMO2/SUMO3 chains [6], although the functional relevance of poly-SUMOylation is still poorly understood.

Signalling through covalent protein modifications requires the recognition by specific effectors of each type of modification. Usually, these effectors are modular domains embedded in larger host proteins, which, on binding to the tagged protein, shift their molecular conformation and trigger a molecular response. These motifs can be present as single or multiple arrayed domains. More than 15 UBDs (Ub-binding domains) [7] have been described to date, which are able to discriminate between the different Ub modification states of a particular tagged protein. In contrast, only one SIM (SUMO-interacting motif) has been described to date [8,9].

To add further complexity, many proteins are multiply modified and this multiplicity of modifications may act in a combinatorial manner [10]. Therefore it is not so surprising to find situations were Ub and SUMO modifications communicate and even sometimes involve the same lysine residue with opposite functions, in what is classically defined as antagonistic modulation. However, the interplay may not be restricted to simple competition, as multisite modification is a means of co-ordinating dynamic regulatory processes. The present review considers some reports in which Ub and SUMO cross-talk draws a new landscape for protein regulation and aims to show examples where these two modifiers have starring roles in the same play.

The Ub connection to the SUMO pathway

The cross-talk between SUMO and Ub is by no means limited to the modification of common target proteins (see below). It is possible to find an intersection in which the Ub system is recruited as an important component of the SUMO pathway. In yeast and human cells, both SUMOylated and ubiquitinated proteins accumulated after the use of proteasome inhibitors [1113]. These studies reported that SUMO modification could also function as a targeting signal for the degradation of the Ub–proteasome system and identified the enzymes responsible for SUMO-modified protein recognition and subsequent degradation as a new class of E3 Ub ligases. To date, the STUbL (SUMO-targeted Ub ligase) family of proteins includes: Saccharomyces cerevisiae Hex3 (also known as Slx5) and Slx8; Schizosaccharomyces pombe Rfp1, Rfp2 and Slx8; Dictyostelium MIP1; Drosophila CG10981; and mammalian RNF4 [RING finger protein 4, also known as Snurf (small nuclear RING finger protein)]. Noticeably, all known STUbLs have an N-terminal SUMO-binding region, usually deploying a tandem of SIMs, as well as a C-terminal RING finger domain. In yeast, Slx5 and Rfp are able to bind SUMO-modified proteins, but lack Ub E3-ligase activity, although they contain a C-terminus RING finger domain. In fact, through the RING domain these two proteins recruit Slx8, an active Ub ligase, thus forming active Slx5–Slx8 and Rfp–Slx8 complexes capable of both binding SUMOylated proteins and ubiquitinating them [14]. SUMO-modified proteins accumulate in yeast Rfp1/Rfp2 double null or in Slx8 single mutants, but this effect could be reversed by overexpression of human RNF4, which resumes the two activities [11,12]. According to the characterized mutant phenotypes, this family of genes is clearly involved in transcriptional regulation and maintenance of genome integrity [15,16], as its members interact with DNA helicases, telomerases and DNA repair proteins [1719]. Degradation of SUMOylated forms of these proteins (via RING-finger-mediated ubiquitination) may be necessary to destabilize transcription factors as well as activated protein kinases in order to balance their activity. This could well be the case when DNA replication has to restart, once repair has been achieved. It is worth noting that STUbLs also contribute to replenishing the free pool of SUMO molecules. Schimmel et al. [20] identified a subset of SUMO conjugates that showed a significant decrease in SUMOylation state after MG-132 (the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-leucinal) treatment, probably because of a decrease in the availability of free SUMO, again indicating an interplay between the Ub and SUMO pathways.

In humans, acute PML (promyelocytic leukaemia) is effectively treated with arsenic trioxide. Recent reports showed that RFN4 was required for arsenic-induced proteasomal degradation of the PML protein. Treatment with arsenic promotes poly-SUMOylation at Lys160 of PML, which is then recognized by RFN4, polyubiquitinated and targeted to proteasome (Table 1). When RFN4 was depleted, the amount of SUMOylated targets increased, and conversely, when RFN4 was overexpressed, PML was efficiently SUMOylated and degraded, thus identifying RNF4 as the first poly-SUMO-specific effector protein [21,22]. As a corollary, in some cases poly-SUMO may precede poly-Ub chains in targeting proteins for proteasome degradation.

Table 1
Examples of proteins post-translationally modified by SUMO and Ub

References are given in the text.

Protein Function SUMOylation Lysine residue Ubiquitination Lysine residue 
Cross-talk between SUMO and Ub pathways 
 USP25 DUB Inactivation Lys99, Lys141 Activation Lys99 
 E2-25K SUMO E2 Inactivation Lys41   
 Mdm2 Ub E3 Stabilization Lys446 Degradation Lys446 
SUMO and Ub interplay 
 PML Oncoprotein Favours ubiquitylation Lys160 Degradation Lys337, Lys380, Lys394, Lys400, Lys401, Lys476, Lys515 
 IκBα Inhibits NF-κB Stabilization Lys21 Degradation Lys21, Lys22 
 NEMO IKK regulator Accumulation in the nucleus Lys277, Lys309 Translocation to the cytoplasm Lys277, Lys309 
 BMAL1 Transcription factor Favours ubiquitylation Lys259 Degradation Lys259 
 PCNA Translational factor Prevention of homologous recombination Lys164 Mono-Ub: error-prone DNA repair. Poly-Ub: error-free DNA repair Lys164 
Protein Function SUMOylation Lysine residue Ubiquitination Lysine residue 
Cross-talk between SUMO and Ub pathways 
 USP25 DUB Inactivation Lys99, Lys141 Activation Lys99 
 E2-25K SUMO E2 Inactivation Lys41   
 Mdm2 Ub E3 Stabilization Lys446 Degradation Lys446 
SUMO and Ub interplay 
 PML Oncoprotein Favours ubiquitylation Lys160 Degradation Lys337, Lys380, Lys394, Lys400, Lys401, Lys476, Lys515 
 IκBα Inhibits NF-κB Stabilization Lys21 Degradation Lys21, Lys22 
 NEMO IKK regulator Accumulation in the nucleus Lys277, Lys309 Translocation to the cytoplasm Lys277, Lys309 
 BMAL1 Transcription factor Favours ubiquitylation Lys259 Degradation Lys259 
 PCNA Translational factor Prevention of homologous recombination Lys164 Mono-Ub: error-prone DNA repair. Poly-Ub: error-free DNA repair Lys164 

SUMO messing around with the Ub pathway

Not only Ub connects to the SUMO pathway, but conversely, SUMO can regulate enzymes of the Ub pathway, as exemplified by the DUB (deubiquitinating enzyme) USP25 (ubiquitin-specific peptidase 25) (Table 1). DUBs are important key components of the Ub pathway, as they hydrolyse the Ub moieties conjugated to substrates and thus are responsible for the processing of newly synthesized Ub, recycling Ub, or editing poly-Ub chains [23,24]. USP25 presents a muscle-specific isoform, USP25m, which among other substrates specifically interacts with myosin binding protein C1 (MyBPC1) rescuing it from proteasomal degradation [25]. USP25 has recently been shown to be regulated by SUMOylation and ubiquitination at the same lysine residue, Lys99 [26,27]. SUMO conjugation at Lys99 (and also at the secondary site Lys141) depends on the interaction with the proximal SIM domain, and results in inhibition of the USP25 protease activity on poly-Ub chains in vitro [26]. Therefore, in physiological conditions, SUMOylation would impair the rescue of substrates from proteasome degradation by USP25. On the other hand, the same residue was reported to be ubiquitinated and this modification led to enzyme activation, by either preventing SUMOylation and/or by allowing new protein–protein interactions, thus representing a new model of the regulation of enzyme activity [27].

Many Ub- and Ubl-E3 ligases form part of multisubunit heteromeric complexes that include E2 ligases, adaptor proteins as well as regulatory proteins, thus modulating the activation and the tempo of the distinct enzymatic activities [28,29]. This is a favourable scenario in which to find more examples of mutual regulation, e.g. the inactivation of the Ub conjugating enzyme E2-25K is achieved by SUMOylation at Lys41, which hampers the interaction with the upstream E1 activating enzyme. The functional implications are not easy to discern, as there is no E2-25K-dependent E3 ligase in vivo, but it is plausible that SUMOylation acts as an inhibitor of E2-25K-dependent ubiquitination, given that the intracellular levels of SUMO-modified E2-25K are low. In more generic terms, E2 SUMOylation might also spatially or temporarily regulate the assembly/disassembly of Ub E1–E2–E3 ligase complexes [30].

The E3 ligase Mdm2 (murine double minute 2) is another example of the regulation of a Ub pathway enzyme via SUMO. Mdm2 is responsible for the ubiquitination and subsequent degradation of the tumour suppressor protein p53. A variety of genotoxic stresses activate p53 as a transcription factor through a complex net of post-translational modifications carried out by a variety of enzymes [31], among them Mdm2. Mdm2 activity is regulated by ubiquitination, SUMOylation and phosphorylation [32]. Concerning SUMO and Ub modifications, Mdm2 self-ubiquitinates and is also SUMOylated at the same residue, Lys446. Although the cellular signals responsible for Mdm2 SUMOylation are still unknown, in vitro and in vivo assays suggest that the SUMO conjugation prevents self-ubiquitination and hence, stabilizes Mdm2 and increases its E3 Ub ligase activity on p53 [33].

TOPORS (topoisomerase I-binding, arginine/serine-rich): the first example of a dual SUMO and Ub E3 ligase

TOPORS is a nuclear protein also involved in the regulation of p53. Although Mdm2 is the main Ub E3-ligase of p53, TOPORS can also ubiquitinate this protein. Originally identified as a topoisomerase-1 partner, TOPORS is now considered the first Ub and SUMO E3 ligase. TOPORS contains a C3HC4-type RING finger domain in its N-terminus that acts as a conventional Ub E3 ligase in conjunction with specific E2 enzymes (UbcH5a, UbcH5c and UbcH6) [34]. Besides, recent studies showed that the TOPORS-mediated ubiquitination of p53 required the phosphorylation on TOPORS Ser718 by Plk1 (Polo-like kinase 1), as an unphosphorylatable mutant S718A led to a dramatic accumulation of p53 [35]. Yet, TOPORS is not only a Ub E3 ligase but can also SUMOylate p53. TOPORS-mediated SUMOylation increased endogenous p53 levels. Notably, the effects on p53 were TOPORS dose-dependent: whereas SUMOylated p53 levels reached a maximum at low concentrations of transfected TOPORS, the activity of p53 increased steadily with increasing TOPORS concentrations. These results suggested that besides stabilizing protein, SUMO modification of p53 might not be directly related to an increase in its transcriptional function [36].

Phosphorylation of TOPORS at serine 98, very close to the RING domain, acts as an enhancer for the E3 Ub ligase activity both in vitro and in vivo, probably by increasing the binding to the E2 enzyme. Intriguingly, the SUMO conjugation activity was not affected by the phosphorylation of this residue, thus indicating a possible switch of control from ubiquitination to SUMOylation activities [37].

SUMO and Ub playing together

Same residue, antagonistic effects

One of the best-reviewed paradigms for the antagonistic relationship between these two modifiers is the inhibitory effect of SUMO on Ub-mediated proteolysis observed in the NF-κB (nuclear factor κB) system [38,39]. NF-κB is the major transcriptional activator involved in immune response and cell survival. In response to internal (DNA damage) or external (bacterial endotoxin) stimuli, NF-κB is translocated into the nucleus and activates transcription. In non-stimulating conditions, NF-κB remains in the cytoplasm where the inhibitory particle IκB (inhibitor of NF-κB) α conceals the nuclear import signal. The dual modification of IκBα defines the regulatory mechanism (Table 1): ubiquitination of Lys21 and Lys22, with prior phosphorylation of Ser32 and Ser36, induces the proteasomal degradation of IκBα and subsequent activation of NF-κB. Interestingly, Lys21 is also the target residue for SUMO, which blocks ubiquitination and hence, stabilizes IκBα and represses NF-κB [38].

Although not with antagonistic results, it is worth mentioning that the phosphate kinase activity responsible for the phosphorylation of IκBα, IKK (IκB kinase), is also under sequential control by SUMO and Ub through its C-terminal regulatory particle NEMO (NF-κB essential modulator) (Table 1). Under genotoxic stress, NEMO is SUMOylated on Lys277 and Lys309 and translocates into the nucleus, where it accumulates. The ATM (ataxia telangiectasia mutated) checkpoint kinase phosphorylates nuclear NEMO and, as a consequence, it is ubiquitinated at Lys277 and Lys309, triggering the translocation back to the cytosol, where it assembles with the IKK catalytic subunits to form an active kinase [40].

Indeed the regulation of USP25, E2-K25 and Mdm2 could also be considered examples of this type of interplay.

Same residue, same effect

Recent works have shown an example in which circadian timekeeping is also determined by SUMO and Ub intersection. Circadian rhythms rule the physiology and behaviour of most organisms, and, in mammals, the heterodimeric transcription factor CLOCK (circadian locomotor output cycles kaput)/BMAL1 [brain and muscle ARNT (aryl hydrocarbon receptor nuclear translocator)-like 1] manage the expression of clock-controlled genes. The ubiquitination and subsequent degradation by the proteasome of BMAL1 led to the circadian activation of the complex, also activating its own negative regulators in an autoregulatory transcription–translation feedback system. However, the weak oscillations of the negative regulators appeared to be insufficient to explain the robust oscillation of the circadian clock, indicating the involvement of post-translational events [41]. It has been reported recently that BMAL1 undergoes SUMO2/SUMO3 modification at Lys259in vivo (Table 1) and, by using a K259R mutant, SUMOylation appeared to stimulate the E-box binding activity, thus enhancing the transcriptional activity [42]. Futhermore, SUMO-BMAL1 is targeted to PML NBs (nuclear bodies), which are discrete nuclear domains extensively associated with chromatin fibres that are transcriptionally active. Interestingly, mutation of the SUMOylation site dramatically decreased the ubiquitination and proteasome degradation of BMAL1. Moreover, overexpression of SUMO proteases decreased the levels of SUMOylated as well as ubiquitinated BMAL1, whereas when using Ub proteases only ubiquitinated BMAL1 was affected. In summary, in mammalian cells, BMAL1 is sequentially modified by SUMO2/SUMO3 and Ub in the NBs, leading to the transactivation of the CLOCK/BMAL1 complex and eventually, degradation of BMAL1 [42].

Same residue, multiple effects

DNA damage tolerance mechanisms allow cells to get over stalled replication forks upon DNA lesions and contribute to genotoxic resistance. PCNA (proliferating-cell nuclear antigen), the sliding clamp conferring processivity on the replicative DNA polymerases, also acts as a key switchboard for DNA repair polymerases and other proteins involved in chromatin assembly and cell-cycle regulation. In the budding yeast S. cerevisiae, one of the best characterised models, PCNA is SUMOylated and ubiquitinated at the same lysine residue, but with different physiological consequences (Table 1) [43,44]. SUMOylation at Lys164 during the S-phase by the SUMO E2-Ubc9 and E3-Siz1 ligases appeared to be DNA damage-independent [45]. When SUMOylated, PCNA recruits an anti-recombinogenic helicase Srs2 to the replication fork. This Srs2–PCNA interaction, mediated by a conserved Srs2 C-terminal SIM motif, prevents homologous recombination in favour of Ub-dependent lesion bypass, as Srs2 prevents the formation of Rad51 recombinogenic filaments on single-stranded DNA [46,47]. In DNA-damage conditions, the Ub conjugation enzymes of the Rad6 family catalyse PCNA ubiquitination. PCNA is mono-ubiquitinated at the highly conserved Lys164, by the Rad6–Rad18 complex. Then, Ubc13–Mms2, in co-operation with Rad5, extends this modification to a poly-Ub Lys63 chain. Mono-ubiquitinated PCNA triggers an error-prone DNA repair in a process called TLS (translesion synthesis), which uses damage-tolerant DNA polymerases (Polη and Rev1) [48]. In contrast, Lys63 polyubiquitinated PCNA activates an error-free repair pathway [45], which probably relies on the genetic information encoded by the newly synthesized sister chromatid.

Last but not least, it is crucial to co-ordinate all these three different PCNA modifications, and for this, the relevant cellular signals should be integrated, the most pertinent being the nature of the DNA damage, the cell cycle phase and other additional factors, such as the checkpoint res ponse and subcellular localization [44].

Concluding remarks

Although, at first, the roles of Ub and SUMO tag molecules seemed well established, the boundaries between the protein fates of their targeted proteins are now no longer clear-cut (Figure 1). As more examples of interplay between SUMO and Ub are described, some patterns for their cross-talk are emerging, which surely will become more refined with future results. In a very brief and simplified view, the interplay between these two post-translational modifications can be considered to be: (i) co-operative and sequential, usually by SUMO preceding and facilitating Ub conjugation, and eventually, aiming at the same effect; (ii) competitive on the same lysine residue, so that one precludes the other and acts antagonistically, e.g. on protein stability/degradation or on enzyme activation/inactivation; and (iii) differential, because, by being conjugated on the same or different lysine residues and depending on the cellular stimuli, these alternative modifications trigger distinct physiological outcomes. Whether mutually controlling their pathways or acting on a common protein target, dissecting SUMO and Ub signalling is apparently a rather complicated issue.

Protein fates after Ub and SUMO modifications

Figure 1
Protein fates after Ub and SUMO modifications

(A) Classical effects of ubiquitination and SUMOylation. (B) Expanded effects of new forms of ubiquitination. (C) Combinatorial effects of the cross-talk of Ub and SUMO modifications.

Figure 1
Protein fates after Ub and SUMO modifications

(A) Classical effects of ubiquitination and SUMOylation. (B) Expanded effects of new forms of ubiquitination. (C) Combinatorial effects of the cross-talk of Ub and SUMO modifications.

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

     
  • BMAL1

    brain and muscle ARNT (aryl hydrocarbon receptor nuclear translocator)-like 1

  •  
  • CLOCK

    circadian locomotor output cycles kaput

  •  
  • DUB

    deubiquitinating enzyme

  •  
  • IκB

    inhibitor of nuclear factor κB

  •  
  • IKK

    IκB kinase

  •  
  • Mdm2

    murine double minute 2

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NEMO

    NF-κB essential modulator

  •  
  • PCNA

    proliferating-cell nuclear antigen

  •  
  • PML

    promyelocytic leukaemia

  •  
  • poly-Ub

    polyubiquitin

  •  
  • RNF4

    RING finger protein 4

  •  
  • SUMO

    small ubiquitin-related modifier

  •  
  • SIM

    SUMO-interacting motif

  •  
  • STUbL

    SUMO-targeted ubiquitin ligase

  •  
  • TOPORS

    topoisomerase I-binding, arginine/serine-rich

  •  
  • Ub

    ubiquitin

  •  
  • Ubl

    ubiquitin-like molecule

  •  
  • USP25

    ubiquitin-specific peptidase 25

We thank Manuel Rodríguez for a critical reading of this paper and Anna Bosch-Comas, Roser Gonzàlez-Duarte and other past and present members of our group for useful discussions.

Funding

The research work in our group is funded by the Ministerio de Ciencia y Tecnologi­a, Spain [grant number BFU2007-60823 to G.M.], and A.D is supported by a BRD Ph.D. fellowship from the University of Barcelona.

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