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Review

Protein SUMOylation and Its Functional Role in Nuclear Receptor Control

1
Department of Parasitology, Institute for Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes 1374, São Paulo 05508-000, SP, Brazil
2
Institute of Integrated Cell Biology and Physiology, University of Münster, Schlossplatz 8, D-48143 Münster, Germany
3
Institut Pasteur de São Paulo, Av. Prof. Lucio Martins Rodrigues 370, São Paulo 05508-020, SP, Brazil
*
Authors to whom correspondence should be addressed.
Receptors 2024, 3(3), 408-424; https://doi.org/10.3390/receptors3030020
Submission received: 10 May 2024 / Revised: 29 June 2024 / Accepted: 29 August 2024 / Published: 3 September 2024

Abstract

:
Post-translational protein modifications (PTMs) significantly enhance the functional diversity of proteins and are therefore important for the expansion and the dynamics of the cell’s proteome. In addition to structurally simpler PTMs, substrates also undergo modification through the reversible attachment of small proteins. The best understood PTM of this nature to date is the covalent conjugation of ubiquitin and ubiquitin-like proteins (UBLs) to their substrates. The protein family of small ubiquitin-like modifier (SUMO) is one of these UBLs that has received increasing scientific attention. The pathway of SUMOylation is highly conserved in all eukaryotic cells and is crucial for their survival. It plays an essential role in many biological processes, such as the maintenance of genomic integrity, transcriptional regulation, gene expression, and the regulation of intracellular signal transduction, and thereby influences DNA damage repair, immune responses, cell cycle progression, and apoptosis. Several studies have already shown that in this context protein SUMOylation is involved in the control mechanisms of various cellular receptors. This article unites data from different studies focusing on the investigation of the strictly conserved three-step enzyme cascade of protein SUMOylation and the functional analysis of the involved proteins E1, E2, and E3 and SUMOylation target proteins. Furthermore, this review highlights the role of nuclear receptor SUMOylation and its importance for the cellular functionality and disease development arising from defects in correct protein SUMOylation.

1. Introduction

Post-translational modifications (PTMs) of proteins constitute a fundamental mechanism for regulating protein function, localization, and interaction within the complex network of cellular processes [1,2,3]. Among these PTMs, protein SUMOylation has emerged as a key regulatory mechanism that orchestrates diverse cellular functions, including transcriptional regulation, protein stability, and signal transduction [2,4]. The intricate interplay between SUMOylation and receptor control represents a fascinating area of research with profound implications for understanding cellular homeostasis and disease pathogenesis [5,6,7].
SUMOylation describes the reversible covalent attachment of small ubiquitin-like modifier (SUMO) proteins to specific lysine residues of target proteins. SUMO proteins are members of the ubiquitin-like protein family (UBLs) and are highly conserved across evolution from yeast to humans. Unlike ubiquitin, which primarily targets proteins for degradation by the proteasome, SUMOylation predominantly modulates protein–protein interactions, subcellular localization, and activity, thereby regulating various cellular processes [8,9]. The enzymatic cascade responsible for SUMOylation consists of three key components: the SUMO-activating enzyme (E1), the SUMO-conjugating enzyme (E2), and the SUMO-E3 protein (Figure 1). The process begins with the activation of SUMO by the E1 enzyme in an ATP-dependent manner, followed by transferring the activated SUMO to the E2 conjugating enzyme. Finally, SUMO-E3 facilitates the transfer of SUMO from the E2 enzyme to the lysine residue of the target protein. This strictly controlled multistep process ensures the specificity and selectivity of SUMOylation towards its target substrates [7,10,11].
Receptor proteins represent a prominent class of substrates for SUMOylation, exerting profound effects on their associated downstream signaling cascades. The regulation of receptor activity by SUMOylation encompasses diverse aspects, including transcriptional regulation, crosstalk with other PTMs, and the control of receptor stability and their intracellular trafficking and translocation [6,12,13,14]. Aberrant SUMOylation of receptors can disrupt normal cellular signaling pathways, leading to uncontrolled cell proliferation, impaired neuronal function, metabolic dysfunction, or dysregulated immune responses. Therefore, dysregulation of SUMOylation has been implicated in various disease pathologies, including cancer, neurodegenerative conditions, metabolic disorders, and autoimmune diseases [10,15,16,17].
This paper aims to provide a comprehensive overview of the functional principles of the protein SUMOylation cascade and its role in the control of nuclear receptors, highlighting key regulatory mechanisms, physiological significance, and implications in disease pathogenesis. By integrating findings from diverse fields of research, this review seeks to analyze the complex interplay between SUMOylation and receptor signaling pathways, thereby paving the way for future studies aimed at unraveling the therapeutic potential of targeting nuclear receptor SUMOylation in human diseases.

2. Post-Translational Protein Modifications

PTMs are cellular mechanisms that alter the properties of a protein through proteolytic cleavage or the addition of a modifying group. As a result, they significantly expand the functional diversity as well as the dynamics of the proteome [1]. Any protein in the proteome can be modified during or following the translation. PTMs are mostly reversible and have various functions in the organism’s different cellular organelles [18]. Because of their high variability, PTMs can influence almost all physiological processes. After the modification of specific amino acid residues of the protein, the modified residue can be recognized by specific reader proteins, which recognize specific PTMs; writer proteins, which can add other additional PTMs; and eraser proteins, which have the ability to remove specific PTMs. This recognition and the protein–protein interaction influence the complex regulation of the functional downstream outcome associated with the PTM [19,20,21].
Until today, more than 450 unique protein modifications have already been identified. There are different types of modifications with different structural and functional characters that can alter the charge state, hydrophobicity, conformation, and stability of the protein, which then ultimately affect its function regarding the activity of target proteins, intracellular distribution, protein interactions, and protein longevity in different ways [2,3,22]. In addition to simpler molecular modifications such as acetylation, methylation, phosphorylation, nitrosylation, neddylation, and lipidation, a family of small proteins has evolved that can be covalently attached to or detached from other proteins after their translation [3,23,24]. Today, the best understood PTM of this type is the conjugation of ubiquitin to proteins [25,26]. Numerous studies of protein ubiquitination propose its essential role in maintaining cellular homeostasis, coping with cellular stress and dealing with cell damage [27]. A PTM that is closely related to ubiquitination is the reversible covalent attachment of SUMO proteins to target proteins.
SUMOylation is an important PTM since the pathway exists in almost all eukaryotes and plays an essential role in many cellular processes. Even though SUMOylation of proteins has a variety of different physiological effects, its main molecular function is to regulate the interactions of the SUMOylated proteins with their interaction partners [4]. Through this, it influences the maintenance of genomic integrity, transcriptional regulation, and gene expression, as well as the regulation of intracellular signal transduction, and thereby affects DNA damage repair, immune responses, cell cycle progression, and apoptosis [2]. The covalent conjugation of SUMO to specific amino acid residues of the target protein is also involved in the regulation of mitochondrial division, the function of ion channels, and biological rhythms. The influence of protein SUMOylation on so many different facets of the cell’s complex protein regulatory network leads to the assumption that the dysregulation of protein SUMOylation is associated with human disease development [2,7].

3. The Protein SUMOylation Cascade

While five SUMO paralogs have already been identified in humans, there are other organisms that do not express all of them [9,11]. In mammals, SUMO1-3 are ubiquitously expressed and their conjugation cascade is functionally equal, while endogenous SUMO4 conjugates have not been identified yet and SUMO5 is still discussed to be a pseudogene [11,28,29,30,31,32].
Under physiological conditions, the conjugation of all SUMO paralogs to their target proteins occurs in a dynamic manner [11]. Since protein SUMOylation is critical for the maintenance of overall cellular function and influences general cellular stress, the SUMOylation pathway makes use of a highly conserved and strictly controlled three-step enzyme cascade (Figure 1) [8,11].
SUMO is encoded as an inactive precursor protein and first needs to be cleaved by SUMO-specific cysteine proteases of the sentrin-specific protease (SENP) family, revealing a C-terminal diglycine motif (Figure 1) [33]. This motif is then recognized by the heterodimeric E1-activating enzyme which adenylates the C-terminus of mature SUMO and is then transferred to the catalytic cysteine, forming a covalent thioester linkage. The SUMO-E2 conjugating enzyme interacts with the ubiquitin fold domain of SUMO-E1 to promote the transfer of SUMO to the catalytic cysteine of SUMO-E2 and the formation of a thioester bond [9,10]. The covalent attachment of SUMO to the substrate can either be mediated in a SUMO-E3-dependent or -independent manner. Many SUMO substrates directly interact with the SUMO-E2 conjugating enzyme through the SUMO consensus motif. Other SUMO substrates contain a SUMO-interacting motif (SIM) and become SUMOylated with the help of SUMO-E3 proteins [10,34,35]. Since SUMOylation is a reversible PTM, SUMO can also be cleaved off the target again. This process is catalyzed by SENPs and leads to a dynamic balance of SUMO conjugation and deconjugation (Figure 1) [9,10].

3.1. SUMO-E1 Activating Enzyme

After the C-terminal cleavage which exposes the diglycine motif, the mature SUMO is ready to be conjugated to the heterodimeric SUMO-E1 activating enzyme [36,37]. More detailed structural analysis showed that SUMO-E1 contains three important domains: an adenylation domain, a catalytic domain, and a UBL domain with structural similarity to ubiquitin and other UBL modifiers [7,11]. The activation step uses adenosine triphosphate (ATP) hydrolysis at the adenylation domain to initiate the generation of a high-energy thioester-bond between the C-terminal glycine of SUMO and the active-site cysteine in the catalytic domain of SUMO-E1 [10,38]. Finally, SUMO-E1 recognizes the SUMO-E2 conjugating enzyme and enforces the SUMO transfer to SUMO-E2 (Figure 1) [11,38,39,40].

3.2. SUMO-E2 Conjugating Enzyme

The SUMO-E2 conjugating enzyme has a key function in the SUMOylation pathway. Its catalytic activity involves the transfer of SUMO from the E1 enzyme, the selection of many specific SUMO targets, and the formation of the peptide bond of SUMO to these target proteins [7,41]. SUMO-E2 binds to the ubiquitin fold domain of SUMO-E1 to promote the transfer of SUMO from the E1 to the E2 enzyme and the conjugation of SUMO to SUMO-E2 via a noncovalent thioester bond [10,40,42].
As shown by SUMO proteomic screens, approximately 50% of SUMOylation sites are found at the consensus motif ψKxE [13]. This specific sequence is composed of a hydrophobic amino acid (ψ), a lysine residue to which SUMO is attached (K), any amino acid (x), and an acidic residue (E) [34,43,44,45]. Other SUMO substrates require SUMO-E3 proteins for the interaction with the target protein. The SIM is of importance for the interaction of SUMO-E3 and the target and also plays an essential role in enhancing SUMO conjugation to the consensus sites or redirecting conjugation to the non-consensus sites of the target proteins (Figure 1) [35,43,44,46].

3.3. SUMO-E3 Proteins

The transfer and covalent attachment of SUMO from SUMO-E2 to the target protein’s acceptor lysine residue can be mediated in either a SUMO-E3-dependent or -independent manner [10,41,43]. While at least in vitro SUMO-E2 is sufficient to promote the direct transfer of SUMO to one or more lysine residues, the function of SUMO-E3 can facilitate and enhance this process by several fold [41,43,47,48,49]. SUMOylation has a vast number of target proteins and various proteins have already been suggested to act as “SUMO-E3 ligases”. The actual number of SUMO-E3 proteins is comparably small and it still remains to be investigated and clarified how this low number of SUMO-E3 proteins is able to differentiate a large number of SUMO substrates in a highly specific way (Figure 1) [10].

3.4. SUMO Proteases

SUMO proteases have two functions within the SUMOylation cascade. Since all SUMO paralogs are encoded as inactive precursor proteins, they first need to be C-terminally cleaved by the proteases to reveal the C-terminal diglycine motif of SUMO [33]. Furthermore, SUMOylation is a reversible PTM and SUMO can be enzymatically cleaved off the target protein again. This process is also catalyzed by the SUMO proteases. Therefore, they are responsible for the initiation of the SUMOylation process but also for maintaining the dynamic balance of SUMO conjugation and deconjugation (Figure 1) [4,9,10].
Today, the mechanistically best understood SUMO proteases belong to the SENP family. Humans and almost all other mammals express six different SENPs: SENP1, SENP2, SENP3, SENP5, SENP6, and SENP7 [4,50]. Moreover, there are three additional SUMO proteases identified in humans: deSUMOylating isopeptidase 1 and 2 (DeSI1, DeSI2) and ubiquitin-specific protease-like 1 (USPL1). All three of these proteases share only little sequence similarity with the other six SENPs [51,52].
The process of deconjugation of SUMO from its substrates is based on the cleavage of the amide bond between the C-terminus of SUMO and the ε-amine group of the target protein’s lysine residue. This deSUMOylation is enzymatically catalyzed by SUMO proteases. In a mechanistically similar way, these proteases also function during the initial SUMO processing. The difference here is that the peptide bond after SUMO’s C-terminal di-glycine motif is cleaved instead of the amide bond between SUMO and the substrate [53].

4. Receptor Protein SUMOylation

Receptors stand out among the multitude of proteins that are candidates for SUMOylation substrates since they are central components that orchestrate cellular responses to external signals. The signaling cascades controlled by receptors regulate all essential cellular mechanisms, including differentiation, proliferation, and apoptosis [54,55]. A general distinction can be made between nuclear receptors and plasma membrane receptors. Nuclear receptors are ligand-regulated proteins that are activated by steroid hormones and various other lipid-soluble signals that unlike most intercellular messengers can cross the plasma membrane autonomously to directly interact with nuclear receptors inside the cell [56]. They play pivotal roles in orchestrating gene expression programs in response to various extracellular signals, hormones, and ligands. The activity of nuclear receptors is tightly regulated by a huge number of post-translational modifications, among which SUMOylation has emerged as a critical regulatory mechanism which is well described [9,10]. Plasma membrane receptors are defined as integral membrane proteins that operate as molecular switches converting extracellular stimuli into intracellular responses [57,58]. In the following, this review will focus on SUMOylation of nuclear receptors.
Nuclear receptor proteins can be post-translationally modified by SUMOylation and thereby be functionally modulated, which offers an additional layer of regulatory control over numerous signaling pathways. In general, this post-translational modification can occur on multiple lysine residues within the receptor protein, leading to conformational changes or alterations in protein–protein interactions [59]. Importantly, the dynamic nature of SUMOylation enables rapid and reversible modulation of receptor activity in response to changing cellular conditions. Today, at least 22 of the 48 nuclear receptors are known to be SUMOylated (Table 1). The SUMOylation status of nuclear receptors exerts profound effects on their transcription activity, stability, and interaction with downstream effectors. Thereby it intricately regulates signal transduction pathways and cellular responses and has an important role in diverse physiological contexts, ranging from embryonic development to immune responses and neuronal plasticity (Figure 2) [60]. Therefore, it is interesting to have a closer look at the role of SUMOylation in the control and regulation of nuclear receptor proteins. The following sections highlight specific examples and elaborate on the diverse functional consequences of nuclear receptor SUMOylation.

4.1. SUMOylation of Nuclear Receptors Influences the Regulation of Transcriptional Activity

In general, SUMOylation of nuclear receptors can profoundly influence their transcriptional activity, either positively or negatively, depending on the specific receptor and cellular context [61,62,63,64,65]. Nevertheless, most SUMOylation modifications of nuclear receptors correlate with decreased transcriptional activity [6,66]. The reversible character of SUMOylation represents a dynamic regulatory mechanism that fine-tunes their transcriptional activity in response to various physiological and pathological stimuli. The context-dependent effects of SUMOylation events on nuclear receptor activity highlight the complexity of receptor signaling networks and can also help to provide insights into the molecular mechanisms of different gene expression programs [6,14]. Several nuclear receptors undergo dynamic SUMOylation, which modulates their transcriptional activity and therefore target gene expression. SUMOylation can either enhance or suppress the transcriptional activity of these receptors by influencing their recruitment to target gene promoters, interaction with transcriptional co-regulators, or stability within the nucleus (Table 1) [6,14].
Table 1. SUMOylated nuclear receptors and the influence on their transcriptional activity.
Table 1. SUMOylated nuclear receptors and the influence on their transcriptional activity.
ReceptorUniProtSUMO
Isoform
SUMOylation SiteTranscriptional EffectReferences
estrogen receptor 1
(ESR1, NR3A1)
P03372SUMO1K266
K268
K299
K302
K303
transcription activity repression[64]
androgen receptor
(AR, NR3C4)
P10275SUMO1K386
K520
transcription activity repression[67,68,69]
liver X receptor beta
(LXR-β, NR1H2)
F1D8P7SUMO2
SUMO3
K409
K447
promoter trans-repression[70,71]
farnesoid X receptor
(FXR, NR1H4)
B6ZGS9SUMO1K132
K289
transcription activity trans-
repression of inflammation genes;
ligand-activated transcription
inhibition
[72,73]
testicular receptor 2
(TR2, NR2C1)
P13056SUMO1K250transcription activity repression[74,75]
mineralcorticoid receptor
(MR, NR3C2)
P08235SUMO1K89
K399
K428
K494
transcription activity repression[76,77,78]
thyroid hormone receptor beta
(THR-β, NR1A2)
P10828SUMO1
SUMO3
K50
K146
K443
ligand activated transcription
induction
[79]
peroxisome proliferator-activated receptor gamma
(PPAR-γ, NR1C3)
P37231SUMO1K107
K395
transcription activity activation[80,81]
steroidogenic factor 1
(SF1, NR5A1)
Q13285SUMO1
SUMO2
K119
K194
synergistic SOX9 transcription
activity repression
[82,83,84]
liver receptor homolog 1
(LRH-1, NR5A2)
Q8WY08SUMO1K270transcription activity trans-
repression of inflammatory genes
[70,85,86]
glucocorticoid receptor
(GR, NR3C1)
P04150SUMO1K293transcription activity repression[87,88]
progesterone receptor
(PR, NR3C3)
P06401SUMO1K7
K388
K531
inhibits hormone-dependent transcription activation[89,90,91]
pregnane X receptor
(PXR, NR1I2)
H0Y8E2SUMO3K108
K128
K129
transcription activity trans-
repression of inflammatory genes
[92,93,94,95]
retinoic acid receptor alpha
(RAR-α, NR1B1)
P10276SUMO2K166
K171
K399
receptor localization inhibition;
transcription activity repression
[96]
nuclear receptor ROR alpha
(ROR-α, NR1F1)
P35398SUMO1
SUMO2
K240transcription activity activation[97]
retinoid X receptor alpha
(RXR-α, NR2B1)
P19793SUMO1K108transcription activity repression[98]
thyroid hormone receptor alpha
(THR-α, NR1A1)
P10827SUMO1
SUMO3
K283
K389
ligand-activated transcription
induction
[79]
peroxisome proliferator-
activated receptor alpha
(PPAR-α, NR1C1)
Q07869SUMO1K185transcription activity trans-
repression
[99]
nuclear receptor subfamily 4
group A member 2
(NUR1, NR4A2)
P43354SUMO2 SUMO3K558
K577
transcription activity trans-
repression of inflammatory genes
[100,101]
vitamin D3 receptor
(VDR, NR1I1)
P11473SUMO2K91transcription activity repression[102,103]
small heterodimer partner
(SHP, NR0B2)
Q15466SUMO2K68transcription activity repression[104]
nuclear receptor subfamily 4 group A member 1
(NUR77, NR4A1)
H3BSB9SUMO1K102
K558
K577
transcription activity repression[100]
The strategies of enhancing or repressing the transcriptional activity of these nuclear receptors are functionally often similar to each other. The post-translational modification by SUMO can increase their transcriptional activity by promoting the recruitment of co-activators and facilitating the assembly of transcriptional complexes on ligand-responsive gene promoters. However, in most cases, the SUMOylation of the nuclear receptors or associated co-factors results in the repression of the transcriptional activity, often by recruiting co-repressors and inhibiting the association with co-activators [6,65,97,105,106]. Nevertheless, the precise molecular mechanisms underlying nuclear receptor SUMOylation-mediated repression of the transcriptional activity remain incompletely understood and may also involve alterations in chromatin structure, DNA binding affinity, or interactions with other transcriptional regulators [107,108,109].
ERs are one example of nuclear receptors that act as ligand-dependent transcription factors regulating gene transcription and mediating the biological effects of estrogen [110]. For ERα, the predominant of the three different ER isoforms, it has been shown that repression of ERα activity by dynamic SUMOylation events is involved in fine-tuning ERα-mediated transcriptional responses to hormonal stimuli [111,112,113]. Consequently, it influences estrogen biosynthesis, metabolism, and cell cycle progression and thus affects cell proliferation, differentiation, and apoptosis (Table 1) [114,115,116].
AR is another example for SUMOylation influencing the transcriptional activity of a nuclear receptor. It belongs to the family of steroid hormone receptors and is responsible for mediating the physiologic effects of androgens. This is realized by binding to specific DNA sequences which then influence the transcription of androgen-responsive genes [117,118]. AR is also known to be a key regulator of male sexual development and prostate cancer progression [119]. SUMOylation of AR has been shown to modulate its transcriptional activity and stability, with implications for androgen-dependent gene expression and tumorigenesis. This SUMOylation-dependent enhancement or repression of AR activity has been implicated in the regulation of genes involved in many other different cellular processes, such as prostate cell proliferation, differentiation, and survival and androgen resistance (Table 1) [6,120].
This SUMOylation-dependent enhancement or repression of the nuclear receptor activity has been implicated in the regulation of genes involved in many different cellular processes, depending on the specific class of receptors and the lysine residue that becomes SUMOylated. Therefore, abnormal signaling of nuclear receptors also raises the risk of various diseases, including different types of cancers and inflammatory defects [14,110,121,122].

4.2. SUMOylation Influences Nuclear Receptor Stability

The dynamic SUMOylation of nuclear receptors also plays a critical role in regulating their stability, thereby modulating the duration and intensity of the signaling and the cellular responses [12,123,124]. Since the dysregulated SUMOylation of nuclear receptors has implications in various disease states, it is important to highlight the importance of deciphering the molecular mechanisms underlying receptor SUMOylation in disease pathogenesis.
Studies have unveiled a link between SUMOylation and the stability of peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear hormone receptor superfamily. It is essential for the development and differentiation of adipocytes, and has emerged as a key factor for both glucose and lipid homeostasis [125,126]. By covalently attaching SUMO to specific lysine residues within PPARγ, SUMOylation influences not only the receptor’s transcriptional activity but also its stability and turnover rate. As a result, PPARγ SUMOylation impacts downstream signaling pathways involved in metabolic homeostasis and inflammatory processes [127,128]. Elucidating the molecular mechanisms underlying SUMOylation-mediated regulation of PPARγ stability holds promise for uncovering novel therapeutic targets for metabolic disorders and inflammatory diseases [129].

4.3. Crosstalk with Other Post-Translational Modifications Modifies Nuclear Receptor Activity

Receptor SUMOylation often intersects with other post-translational modifications, such as ubiquitination or phosphorylation. This crosstalk between SUMOylation and other PTMs adds a layer of complexity to the regulation of receptor function and provides a mechanism for integrating diverse signaling inputs [13,130,131]. It plays a crucial role in precisely adjusting and regulating cellular responses and the dynamic interplay between these modifications increases the diversity of signaling networks [132,133,134].
SUMOylation and ubiquitination are dynamic and reversible modifications that often compete for the same lysine residues on target proteins. Crosstalk between these two PTMs can influence the stability, localization, and activity of receptor proteins since these modifications may have different and sometimes even completely opposing consequences [14,135,136]. For instance, SUMOylation has been reported to inhibit the ubiquitination and proteasomal degradation of certain receptors, thereby stabilizing them and prolonging their signaling activity [127,135,137]. Conversely, ubiquitination can specifically target SUMOylated receptors for proteasomal degradation, thereby influencing the associated signaling cascades [138,139]. In this context SUMO-targeted ubiquitin ligases (STUbLs) are of great importance. They can recognize SUMOylated proteins, modulate their ubiquitin status, and therefore link the SUMO modification to the ubiquitin system [140,141].
The nuclear receptor NR4A1 is one example where SUMO-induced ubiquitination occurs. NR4A1 is involved in cell cycle mediation and apoptosis in several cell types and plays a key role in mediating inflammatory responses in macrophages [142,143]. Because NR4A1 has multiple functions, its stability and activity are carefully regulated. This is implemented by modifying the receptor with different combinations of PTMs, including SUMOylation-dependent ubiquitination [100,143]. Only after SUMOylation, the ring finger protein 4 (RNF4), a STUbL, recognizes the receptor and modifies it by subsequent ubiquitination [14,143]. Studies show that NR4A1 can have different ubiquitination sites in different cellular contexts. For example, during inflammation, ubiquitinated NR4A1 is not sent to proteasomal degradation but functions as a label for proteasome engulfment and elimination by mitophagy, while after induced cellular stress polyubiquitination functions as a proteasome degradation signal [100,143,144].
Besides ubiquitination, SUMOylation can also influence protein phosphorylation dynamics, affecting receptor activity, localization, and interactions with downstream effectors. Crosstalk between SUMOylation and phosphorylation has been reported for various nuclear receptors. Some of them, including estrogen-related receptor (ERR) α, β, and γ, as well as PPARγ, contain a phosphorylation-dependent SUMO consensus motif (PDSM) within their sequence [44,145,146]. The PDSM ψKxExxSP is bipartite and consists of the SUMO consensus site (ψKxE) and a proline (P)-directed serine (S) phosphorylation site, separated by two amino acids (xx) [145]. The phosphorylation of this motif can then either promote or inhibit the receptor SUMOylation and therefore differently modulate the signaling activity of the nuclear receptor.
PPARγ2 has been shown to contain a PDSM that enables receptor phosphorylation, which then triggers the SUMOylation of the nuclear receptor, finally resulting in the repression of its activity [145,146,147]. Reporter gene assays indicated that the ligand-independent and ligand-dependent transcriptional activity of PPARγ2 were negatively regulated by SUMOylation [146,148]. The molecular mechanisms behind this are not completely understood yet, but it seems likely that an activation domain of the receptor may be negatively regulated by this PTM combination of phosphorylation and SUMOylation. Another theory states that the recruitment of transcriptional repressor molecules or other additional cellular factors causes the PPARγ2 downregulation [146].

5. Implications of Receptor SUMOylation in Disease Pathogenesis

Aberrant SUMOylation of nuclear receptors has been implicated in various disease states. In this context, it plays an important role as the normal signaling pathways are becoming disrupted, leading to altered transcription dynamics and cellular responses. Understanding the molecular mechanisms underlying aberrant receptor SUMOylation in disease pathogenesis therefore holds the promise of developing targeted therapeutic interventions aimed at restoring normal activity of the receptor and all involved downstream processes [149,150].
The dysregulation of nuclear hormone receptor SUMOylation, such as PPARγ and liver X receptor (LXR), has been implicated in the pathogenesis of metabolic disorders, insulin resistance, and non-alcoholic fatty liver disease [125,151,152]. Altered SUMOylation of PPARγ disrupts the transcriptional regulation of genes involved in adipogenesis, lipid metabolism, and glucose homeostasis, leading to dysregulated lipid and glucose metabolism and the development of metabolic disorders, such as obesity and type 2 diabetes [14,71,125,153]. SUMO overexpression experiments revealed insulin resistance and vascular endothelial dysfunction associated with an endogenous cascade that enhances this effect [154,155]. In this context, synthetic PPARγ ligands can be used for the treatment of the occurring insulin resistance. However, serious side effects have occurred using this form of treatment. In order to minimize these, one promising approach that should be considered in drug development is modulating the PTMs on PPARγ, since blocking the SUMOylation of PPARγ in mice has shown achievements in enhanced insulin sensitivity without causing excessive obesity [81,125,151,154,156].
Moreover, dysregulated SUMOylation of nuclear hormone receptors, such as ER and AR, has been implicated in hormone-dependent cancers, including breast and prostate cancer, where it contributes to hormone resistance and disease development [6,120,157]. Experimental data indicate that dynamic ER modifications by PTMs, including SUMOylation, coordinate its ligand sensitivity, whereas its deregulation may play a critical role in the early stages of breast cancer progression [157]. Furthermore, a correlation between ER positive breast cancer cells and SUMOylated insulin-like growth factor 1 receptor (IGF-1R) in cell nuclei was demonstrated [158]. IGF-1R is not a nuclear receptor, but is one of the few well understood cell membrane receptors that become SUMOylated. After SUMOylation, IGF-1R is known to be translocated from the cell membrane into the nucleus where it modulates gene expression by binding to enhancer molecules. As a result, it affects the downstream mechanisms that control and coordinate the expression of cell cycle regulators, leading to enhanced G1-S progression and uncontrolled cell proliferation [159,160,161]. This example shows that SUMO modification of nuclear receptors may also play a role in crosstalk with other receptors and their effects on disease progression. It is therefore important to consider these correlations in future studies on receptor SUMOylation.

6. Summary and Conclusions

SUMOylation of nuclear receptor proteins is a dynamic and diverse mechanism for the precise control of receptor signaling as well as cellular responses and homeostasis. By modulating the receptor’s transcriptional activity, its stability, and its interaction networks, SUMOylation contributes to the fidelity and specificity of signal transduction pathways and governs diverse cellular processes. Elucidating and better understanding the molecular mechanisms and functional consequences of receptor SUMOylation holds great promise for uncovering novel therapeutic targets and strategies for the treatment of various human diseases that are associated with impaired receptor signaling.
As several studies show, the SUMOylation status of nuclear receptors can influence their stability as well as the interaction cascades with downstream effectors and thus have an impact on the receptor-associated signaling effect. This becomes apparent when looking at the SUMOylation of nuclear hormone receptors that has been shown to regulate their transcriptional activity and target gene expression. In addition, aberrant SUMOylation of receptors has been found in various diseases. However, as the exact underlying molecular mechanisms are still not completely understood, this review also emphasizes the need for further in-depth studies to investigate and understand the potential benefits of using the targeting of post-translational nuclear receptor modifications in the future development and application of treatments for nuclear receptor SUMOylation-associated diseases.

Author Contributions

N.W. wrote the draft; C.S.K. verified and reviewed the text; and E.L., G.W. and C.W. conceptualized, reviewed, and edited the manuscript, and acquired funding. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by FAPESP (Fundação de Apoio a Pesquisa do Estado de São Paulo), grant numbers 2021/13727-2 (G.W.) and 2015/26722-8 (C.W.). G.W. and C.W. are CNPq Productivity Research fellows. Furthermore, the authors acknowledge the support of the German Federal Ministry of Education and Research via the DAAD (Deutscher Akademischer Austauschdienst) within the “Integrated International Degree Programs with Double Degrees” entitled SãMBio between the Universities of Münster, Germany, and São Paulo, Brazil. N.W. is fellow of the SãMBio Master double degree program.

Data Availability Statement

All data used were from public databases; see references.

Conflicts of Interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Figure 1. Schematic illustration of the protein SUMOylation cascade. In a preliminary step, the inactive SUMO precursor protein is cleaved by a SUMO-specific SENP cysteine protease, revealing a C-terminal diglycine motif. Subsequently, SUMO is then activated in an ATP-dependent reaction by the SUMO-E1 activating enzyme, forming a thioester bond between the C-terminal diglycine motif of SUMO and the catalytically active cysteine residue of SUMO-E1. In a trans-thioester reaction, SUMO is transferred from SUMO-E1 to the catalytically active cysteine residue of the SUMO-E2 conjugating enzyme in the next step. Finally, with the help of the SUMO-E3 protein a covalent peptide bond is established between SUMO and the target protein. Since the SENP can also catalyze the deconjugation of SUMO, the overall process of post-translational protein SUMOylation is reversible [10,11]. This figure was generated with the help of BioRender.com (License #2364–1511, Toronto, ON, Canada).
Figure 1. Schematic illustration of the protein SUMOylation cascade. In a preliminary step, the inactive SUMO precursor protein is cleaved by a SUMO-specific SENP cysteine protease, revealing a C-terminal diglycine motif. Subsequently, SUMO is then activated in an ATP-dependent reaction by the SUMO-E1 activating enzyme, forming a thioester bond between the C-terminal diglycine motif of SUMO and the catalytically active cysteine residue of SUMO-E1. In a trans-thioester reaction, SUMO is transferred from SUMO-E1 to the catalytically active cysteine residue of the SUMO-E2 conjugating enzyme in the next step. Finally, with the help of the SUMO-E3 protein a covalent peptide bond is established between SUMO and the target protein. Since the SENP can also catalyze the deconjugation of SUMO, the overall process of post-translational protein SUMOylation is reversible [10,11]. This figure was generated with the help of BioRender.com (License #2364–1511, Toronto, ON, Canada).
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Figure 2. Schematic overview of the diverse molecular consequences of nuclear receptor SUMOylation. The SUMOylation status of nuclear receptors affects the crosstalk of the receptor with other PTMs and influences the receptor’s stability. In addition, modification by SUMO can positively or negatively influence the transcriptional regulation of specific genes. This regulates complex signal transduction pathways as well as various cellular responses and plays an essential role in different physiological contexts. Therefore, receptor SUMOylation is also involved in the pathogenesis of different diseases [10,59]. This figure was generated with the help of BioRender.com (License #2364–1511, Toronto, ON, Canada).
Figure 2. Schematic overview of the diverse molecular consequences of nuclear receptor SUMOylation. The SUMOylation status of nuclear receptors affects the crosstalk of the receptor with other PTMs and influences the receptor’s stability. In addition, modification by SUMO can positively or negatively influence the transcriptional regulation of specific genes. This regulates complex signal transduction pathways as well as various cellular responses and plays an essential role in different physiological contexts. Therefore, receptor SUMOylation is also involved in the pathogenesis of different diseases [10,59]. This figure was generated with the help of BioRender.com (License #2364–1511, Toronto, ON, Canada).
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Wild, N.; Kaiser, C.S.; Wunderlich, G.; Liebau, E.; Wrenger, C. Protein SUMOylation and Its Functional Role in Nuclear Receptor Control. Receptors 2024, 3, 408-424. https://doi.org/10.3390/receptors3030020

AMA Style

Wild N, Kaiser CS, Wunderlich G, Liebau E, Wrenger C. Protein SUMOylation and Its Functional Role in Nuclear Receptor Control. Receptors. 2024; 3(3):408-424. https://doi.org/10.3390/receptors3030020

Chicago/Turabian Style

Wild, Nele, Charlotte Sophia Kaiser, Gerhard Wunderlich, Eva Liebau, and Carsten Wrenger. 2024. "Protein SUMOylation and Its Functional Role in Nuclear Receptor Control" Receptors 3, no. 3: 408-424. https://doi.org/10.3390/receptors3030020

APA Style

Wild, N., Kaiser, C. S., Wunderlich, G., Liebau, E., & Wrenger, C. (2024). Protein SUMOylation and Its Functional Role in Nuclear Receptor Control. Receptors, 3(3), 408-424. https://doi.org/10.3390/receptors3030020

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