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Biochimica et Biophysica Acta 1812 (2011) 909–918
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Biochimica et Biophysica Acta
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a d i s
Review
Transcriptional control of metabolic and inflammatory pathways by nuclear
receptor SUMOylation☆
Eckardt Treuter a,⁎, Nicolas Venteclef b
a
b
Karolinska Institutet, Center for Biosciences, Department of Biosciences and Nutrition, S-14183 Stockholm, Sweden
INSERM U872, Cordelier Research Center, Paris, France
a r t i c l e
i n f o
Article history:
Received 10 November 2010
Received in revised form 8 December 2010
Accepted 9 December 2010
Available online 21 December 2010
Keywords:
Nuclear receptor
Post-translational modification
SUMO
Metabolism
Inflammation
Acute phase response
Transrepression
LXR
PPAR
LRH-1
N-CoR
SMRT
GPS2
a b s t r a c t
Nuclear receptors (NRs) exert crucial functions in controlling metabolism and inflammation by both
positively and negatively regulating gene expression. Recent evidence suggests that the transcriptional
activities of many NRs can be modulated and even re-directed through post-translational modification by
small ubiquitin-related modifiers (SUMO). SUMOylation triggers a plethora of diverse molecular events that
can alter both the fate and function of modified NRs at the nongenomic, genomic, and epigenomic level.
However, it is the intriguing link of SUMOylation to transcriptional repression, and in particular to
transrepression, that has emerged as a common underlying mechanism that impacts on biological processes
controlled by NRs. It further appears that the cell-type-specific SUMOylation status of NRs can be regulated by
ligands and by signal-dependent crosstalk of post-translational modifications. Given the causal role of altered
NR signaling in the development and pathogenesis of human diseases, it is likely that aberrant SUMO
conjugation, deconjugation, or interpretation contributes to these alterations. Here, we review the current
progress made in both the study and understanding of the molecular mechanisms and consequences of NR
SUMOylation and also discuss the physiological and pharmacological implications with a particular focus on
transrepression pathways that link metabolism and inflammation. This article is part of a Special Issue
entitled: Translating nuclear receptors from health to disease.
© 2010 Elsevier B.V. All rights reserved.
1. Post-translational protein modification by reversible
SUMO conjugation
Post-translational modifications (PTMs) of proteins, through, for
example, phosphorylation, acetylation, methylation, and conjugation
to ubiquitin and ubiquitin-like proteins (UBLs), have critical roles in a
variety of cellular processes, including transcription, since they can
alter the fate and the functions of proteins responsible for these
processes. It is well known that conjugation of (poly-) ubiquitin has a
fundamental role in tagging proteins, including transcription factors
such as nuclear receptor (NRs), for degradation by the proteasome [1].
Ubiquitination-dependent proteasomal degradation and turnover
appear to be a requirement for transcriptional regulation by estrogen
receptors (ERs) [2] and other transcription factors. What has become
evident recently is that modifications by (mono-) ubiquitin and UBLs
appear to be not necessarily linked to proteasomal degradation but
☆ This article is part of a Special Issue entitled: Translating nuclear receptors from
health to disease.
⁎ Corresponding author. Tel.: +46 8 52481060; fax: +46 8 7745538.
E-mail address: [email protected] (E. Treuter).
0925-4439/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbadis.2010.12.008
instead play a direct role in modulating transcription factor function
[3,4].
Among the different UBLs, it is the small ubiquitin-related modifier
(SUMO) family that has attracted the most attention with respect to
its direct involvement in transcriptional processes [5–7]. SUMO was
first discovered in 1997 [8] and the family consists of three members
in mammals, SUMO-1 and the closely related SUMO-2 and SUMO-3.
SUMO-2/3 but not SUMO-1 can form polymeric chains, suggesting in
part distinct roles of, and functional consequences of conjugation to,
SUMO-1 versus SUMO-2/3. The reversible SUMO conjugation and
deconjugation pathway is quite similar to ubiquitination but uses a
different set of enzymes involved in processing, attachment, and
removal of SUMO (Fig. 1). SUMO is activated in an ATP-dependent
manner by the heterodimeric E1 SUMO-activating enzyme SAE1/2.
Activated SUMO is then transferred to the E2-conjugating enzyme
UBC9 and is conjugated to specific lysine residues in substrate
proteins. Efficient SUMO conjugation, especially in vivo, further
requires the action of specific SUMO E3 ligases. Several E3s have
been identified, notably proteins of the Protein Inhibitor of Activated
STAT (PIAS) family [9]. The histone deacetylases HDAC4/5 and HDAC2
have also been implicated in SUMO conjugation and may function
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E. Treuter, N. Venteclef / Biochimica et Biophysica Acta 1812 (2011) 909–918
either directly as E3 ligases or by recruiting an E3 ligase complex [10–14].
Whether other SUMO E3 ligases, such as the nuclear pore protein RanBP2,
the polycomb group protein PC2, or members of the TRIM family of
proteins, play roles in NR modification is currently unknown [15–18].
SUMOylation is a reversible and dynamic process through the
action of SUMO proteases (referred to as SENP or SuPr) that function
as isopeptidases to deconjugate SUMO from substrates [19]. The
action of SUMO proteases at specific substrates can be influenced by
intracellular signals and the cellular environment, which control and
fine-tune the SUMOylation status. Appreciating SUMO deconjugation
may resolve the apparent SUMO paradox, which refers to the small
detectable fraction of SUMOylated proteins in vivo. It has been
postulated that SUMOylation may act transient by marking proteins
with a history of modification, i.e., a “SUMO memory” [7]. This concept
is highly relevant for understanding the role of SUMOylation in
transcriptional processes linked to NR signaling.
The SUMO acceptor lysine residues in substrates often fall within a
recognizable consensus sequence [20,21]. Most common is the classic
SUMO consensus motif ψKxE (where ψ is a large hydrophobic amino acid
residue and K the acceptor lysine), which is also found in many NRs
(Table 1). Variants of this motif have been recognized to function as
phospho-dependent SUMO motifs (PDSM), composed of a prolinedirected phosphorylation site adjacent to the acceptor lysine [22].
PDSMs have been identified in many transcription factors including the
N-terminal domains of NRs such as peroxisome proliferator-activated
receptor PPARγ and estrogen-related receptors ERRs [20,23]. Thus,
PDSMs can couple phosphorylation and SUMOylation, perhaps also
acetylation, to transcriptional repression. Negatively charged SUMO
motifs (NDSMs) represent another extension of the consensus motif
[21]. Interestingly, SUMO conjugation can also occur at acceptor lysines
that are not within a recognizable consensus sequence. The exact
mechanism of substrate recognition and conjugation at these nonconsensus sites remains to be clarified but may be linked to preferential
modification by SUMO-2/3 [24] and the action of specific E3 ligases or
modulating factors. A notable example for such a pathway is the ligand-
regulated conjugation of SUMO-2/3 to the ligand-binding domain (LBD)
of the oxysterol receptors (“liver X” receptors) LXRs [10,14] (discussed
further below).
Crosstalk between SUMOylation and other PTMs, which can target
the same acceptor site(s), is a fundamental mechanism that regulates
the function and stability of substrates and whose dysregulation is
linked to diverse disease states [6,25]. Crosstalk between SUMOylation
and ubiquitination or acetylation has been demonstrated, for example,
to be crucial for appropriate signaling by NFκB or p53, respectively, in
pathways linked to genotoxic stress and cancer [26,27], and needs to be
further explored in NR SUMOylation pathways (see Table 1). Also, little
is currently known about the signal- or cell-type-dependent regulation
of the SUMO machinery and of NR SUMOylation. Various cellular
stresses, including heat shock, osmotic stress, and reactive oxygen
species, can globally affect SUMO conjugation and deconjugation, as
revealed by proteomic analyses [5,24,28]. Whether such changes also
occur in response to metabolic and pathogenic stress associated with
diseases and infections remains an interesting issue to be explored.
Clearly, there are already indications that dysregulated SUMO conjugation contributes to the pathogenesis and development of cardiovascular
and autoimmune diseases [6,29,30].
2. Signal-dependent transcriptional regulation by NRs
NRs are signal-regulated transcription factors that exert diverse and
crucial biological functions in pathways governing developmental,
reproductive, metabolic, and inflammatory processes [31–35]. In most
of these processes, the primary function of NRs is to regulate gene
expression at the transcriptional level in response to cellular signals.
Coregulators have been recognized to be crucial components of NR
signaling since they are necessary to facilitate specific epigenomic
modifications such as histone (de-) acetylation and (de-) methylation,
as well as nucleosome remodeling. Coregulators usually act downstream
in the activation cascade by associating with DNA-bound NRs. However,
recent findings on ER and LXR signaling also point at crucial functions of
Fig. 1. The NR–SUMO cycle: conjugation, interpretation, de-conjugation. NR SUMOylation is facilitated by an enzymatic cascade that involves three classes of enzymes: a
heterodimeric E1 activating enzyme SAE1/2, a single E2-conjugating enzyme UBC9, and various E3 ligases (e.g., PIAS family members, HDAC4). NR SUMOylation is “interpreted” by
diverse cellular effectors, i.e., proteins that employ SUMO-interaction motifs (SIMs) to recognize the modification and then to trigger subsequent molecular events. Suspected
transcriptional effectors are SIM-containing subunits (e.g., CoREST, ARIP4, GPS2) of diverse corepressor (CoR) complexes linked to repressive histone modifications (e.g.,
deacetylation). NR SUMOylation is reversed through the action of SUMO proteases/isopeptidases (SuPr, SENP) that deconjugate SUMO from NRs. Both SUMO ligases and proteases
can function in a cell-type, NR-, and SUMO (Su-1/2/3)-specific manner. De-SUMOylation is necessary for turnover and degradation of NRs and SUMO components but may also occur
rapidly and transiently, thereby precluding SUMO interpretation and causing an apparent lack of functional effects. During the cycle, NRs adopt distinct conformational and
functional stages, i.e., apo (inactive, unliganded), holo (activated, liganded), and sumo (modified, unliganded, or liganded).
911
Table 1
Reported SUMOylation of NRs and of some selected coregulators.
NR
SUMO sites
SUMO pathway
Functional consequences of SUMOylation
References
LXRα
A, LBD, L
Su2/3, HDAC4
Ghisletti et al. [10,94]
Lee et al. [93]
LXRβ
A, LBD, L
Su2/3, HDAC4
Anti-inflammatory transrepression in macrophages
Anti-inflammatory transrepression of STAT1 in IFNγ -stimulated
brain astrocytes
Anti-inflammatory transrepression in macrophages
Target of N-phenyl tertiary amines as transrepression-selective
synthetic LXRβ ligands
Anti-inflammatory transrepression in liver (acute phase response),
GPS2 (SIM)-binding
Anti-inflammatory transrepression of STAT1 in IFN-gamma-stimulated
brain astrocytes
Anti-inflammatory transrepression in liver (acute phase response),
GPS2 (SIM)-binding
Sequestration of LRH-1 to nuclear PML bodies, ARIP4 (SIM)-binding
LRH-1
SF-1
C, NTD
Su1, PIAS
C, Hinge
Su1, PIAS
C, Hinge
Su1, PIAS
Su2/3
FXR
C, LBD
Su1
NURR1
P, LBD
Su2/3, PIAS
ERRα, γ
TR2
P, NTD
C, DBD
Su1/3, PIAS
Su1, PIAS
RXR
C, NTD
Su1
ROR
PPARα
C, Hinge
C, LBD, L
C, Hinge
C, NTD
C, LBD, L
Su1/2, PIAS
Su1/2
Su1, PIAS
Su1, PIAS
Su1, PIAS
C, NTD
Su1, PIAS
C, NTD
Su1, PIAS
PXR
C, Hinge
Su1/2/3
AR
C, NTD
Su1, PIAS
GR
C, NTD
Su1/2/3
PR
ERα
C, NTD
C, Hinge, L
Su1, PIAS
Su1, PIAS
PPARγ
Transcriptional reprogramming of mouse somatic to stem cells,
Oct4 replacement
Repression, synergy control motif, association with DP103 (E3 modulator
or putative E4)
Modulation of DNA-binding, decreased recognition of
SUMO-sensitive genes
Repression, ARIP4 (SIM)-association
Repression, reduction of CDK7-mediated phosphorylation of S203
(activation domain)
Anti-inflammatory transrepression in intestine, protective in a
mouse colitis model
Anti-inflammatory transrepression in microglia and astrocytes,
CoREST (SIM?) binding
Repression, in vivo binding site selection, metabolic regulation in liver
Repression, recruitment of corepressor RIP140, maintenance of stem
cell states
Repression, transrepression, cross-SUMOylation with PPARγ in
chondrosarcoma cells
Activation (i.e., SUMO site mutants were less active)
Gender-specific anti-inflammatory transrepression in liver
Repression, recruitment of N-CoR. ligand-decreased SUMOylation
Repression
Anti-inflammatory transrepression in macrophages, inhibition of
N-CoR degradation
Anti-inflammatory transrepression in macrophages, inhibition of
N-CoR degradation
Enhanced proliferation vascular smooth muscle cells (VSMCs),
pro-atherogenic
Transrepression, PXR ko mice: SUMO feedback in liver inflammation,
SUMO-3 chains
Repression, binding site selection, SUMO site within synergy control motif
SUMOylation attenuates polyQ-mediated aggregation
Repression, SUMO site within synergy control motif, Daxx
(SIM)-binding (?)
Repression, antagonism of SUMOylation by phosphorylation
Repression
Ghisletti et al. [10,94]
Chao et al. [95]
Venteclef et al. [14]
Lee et al. [93]
Venteclef et al. [14]
Chalkiadaki and Talianidis, Ogawa et al., and Yang
et al. [59,76,111]
Heng et al. [72]
Lee et al. and Komatsu et al. [60,112]
Campbell et al. [69]
Ogawa et al. [76]
Yang et al. [66]
Vavassori et al. [106]
Saijo et al. [79]
Tremblay et al. and Vu et al. [23,67]
Park et al. [62]
Burrage et al. and Choi et al. [113,114]
Hwang et al. [55]
Leuenberger et al. [68]
Pourcet et al. [115]
Ohshima et al. [116]
Pascual et al. [51]
Jennewein et al. [117]
Lim et al. [118]
Hu et al. [119]
Poukka et al., Kotaja et al., and Callewaert et al.
[54,120,121]
Mukherjee et al. [122]
Lin et al., Holmstrom et al., and Holmstrom et al.
[78,123,124]
Daniel et al. [125]
Sentis et al. [64]
Coregulator
SUMO sites
SUMO pathway
Functional consequences of SUMOylation
References
SRC2
C
Su1, PIAS
Kotaja et al. [126]
PGC-1α
RIP140
p300
N-CoR
HDAC1
ARIP4
KLF5
C
C
C
C
C
C
C
Su1, PIAS
Su1/2, PIAS
Su1/2/3
Su1, PIAS
Su, PIAS
Su1
Su1
Repression, abolishment of NR interactions, conserved in SRC
family members
Repression, recruitment of corepressor RIP140
De-repression, abolishment of NR interactions, subnuclear redistribution
Repression, recruitment of HDAC6 as putative SUMO ligase
Repression
De-repression, enhancement of AR activity, reversed by SENP1
De-repression, enhancement of AR activity, potential SIM mechanism
Repression, N-CoR association, PPARδ regulation of lipid metabolism
Rytinki and Palvimo [127]
Rytinki and Palvimo [128]
Girdwood et al. [129]
Tiefenbach et al. [130]
Cheng et al. [131]
Rosendorff et al. and Domanskyi et al. [132,133]
Oishi et al. [134]
Abbreviations: SUMO sites: A – atypical SUMO motif(s), C – SUMO consensus motif (ψKxE), P – phospho-dependent SUMO motif (ψKxExxS/T), L – ligand-enhanced; NR-domains:
NTD – N-terminal domain, DBD – DNA-binding domain, Hinge – hinge region, LBD – ligand-binding domain; SUMO machinery: Su – SUMO, PIAS – protein inhibitor or activated
STAT, HDAC – histone deacetylase, SIM – SUMO interaction motif.
coregulators (e.g., histone methylases, demethylases and GPS2) and
epigenomic modifications (e.g., histone 3 lysine 9 methylation) in
facilitating ligand-dependent NR recruitment to specific genomic loci
[36,37].
NRs have employed a variety of molecular strategies regarding their
ability to sense and transmit signaling inputs into coregulator-dependent
transcriptional responses. Many conventional NRs appear capable of
directly binding to small-molecule ligands (e.g., steroid hormones, lipids,
912
xenobiotics, synthetic drugs). Ligand-binding has direct consequences on
NR activity as it induces conformational changes that cause NRs to
associate with distinct sets of coregulators. Traditional models envisage
that agonists drive transcriptional activation by promoting the recruitment of NR coactivators, i.e., SRC1/2/3 and p300/CBP linked to histone
acetylation, ASC2/RAP250 linked to histone methylation, and the
mediator subunit MED1/TRAP220 linked to RNA polymerase II [31]. In
contrast, unliganded NRs, antagonists, or inverse agonists are usually
connected to transcriptional repression by promoting the recruitment of
corepressors such as N-CoR/SMRT and GPS2 linked to histone deacetylase
(HDAC) complexes [38]. NR activity can also be regulated by cellular
concentration-dependent interactions with coregulators whose expression is dynamically regulated by diverse signals. Well-established are the
metabolic roles of the ligand-inducible corepressor and orphan receptor
SHP (“small heterodimer partner”, NR0B2) [39] or of the cAMP-inducible
coactivator PGC-1α [40]. This strategy seems in particular crucial to
regulate the activity of some orphan NRs that cannot be directly regulated
by ligands.
The activity of potentially every NR can be regulated by PTMs, which is
traditionally viewed as a way to achieve “ligand-independent” regulation.
This may hold true for orphan receptors, but in case of ligand-regulated
NRs, it has become clear that ligand-binding also impacts on the PTM
status. (De-) phosphorylation of NRs appears to be linked both to
transcriptional activation [41], for example, in response to epidermal
growth factor signaling in ER-positive breast cancer cells [42], or to
repression, for example, in response to fibroblast growth factor 15/19
signaling in hepatocytes [43]. An increasing number of studies begin to
address the role of additional PTMs in NR signaling, such as acetylation,
methylation, glycosylation, ubiquitination, and SUMOylation [44–48].
Finally, NRs are capable of transcriptional crosstalk with a number
of other signaling pathways. For example, negative crosstalk between
the glucocorticoid receptor (GR) and NFκB signaling underlies the
clinical application of how synthetic glucocorticoids inhibit inflammatory processes [49,50]. Direct interactions of primary transcription
factors are presumed to trigger a genomic tethering mechanism by
which GR is recruited to DNA-bound NFκB. Intriguingly, more recent
work has identified negative crosstalk pathways linked to the antiinflammatory action of various lipid-activated NRs that appear to
depend on SUMOylation-dependent tethering to corepressor complexes
at inflammatory genes [10,14,33,35,51]. Current progress in analyzing the
molecular events that govern this SUMO-mediated crosstalk, commonly
referred to as transrepression, will be discussed in more detail below.
3. Discovery of NR SUMOylation
In a historical perspective, it is interesting to note that it was the
search for coregulators that led to the identification of components of the
SUMO machinery as NR-associated proteins. For example, the human
homologue of yeast UBC9 was identified in yeast two-hybrid screens as a
GR-associated protein [52] before its role as a SUMO E2-conjugating
enzyme was uncovered. Similarly, members of the PIAS family of SUMO
E3 ligases were originally identified and characterized as potential
coactivators of androgen receptor (AR) and additional steroid receptors
[53]. These studies implied that components of the SUMO machinery
modulate NR transcription, although the direct link to NR SUMOylation
was not established at that time. Indeed, there are some indications that
PIAS proteins can function as coregulators without triggering NR
SUMOylation [53]. UBC9, SUMO E3 ligases, and SUMO proteases were
found to associate with a variety of NRs, which often initiated
subsequent investigations of NR SUMOylation (Table 1). Evidence for
site-specific conjugation of SUMO to a NR was provided first for AR, along
with the demonstration that PIAS proteins function as SUMO E3 ligases
[54]. Interestingly, the AR SUMO consensus site appears to be conserved
in other steroid receptors and overlaps a transcriptional synergy control
motif in the N-termini of these NRs. AR plays major roles in regulating
the transcription of genes triggering prostate cancer cell proliferation,
both androgen-dependent and androgen-independent, and the role of
SUMOylation in these pathways is the subject of intense investigations,
as reviewed elsewhere [47,53].
4. Molecular consequences of NR SUMOylation
Because the major function of NRs is to act as gene-specific
transcriptional activators and repressors, many studies analyzing NR
SUMOylation have focused on its role in transcription. Only in very
few instances does SUMO modification correlate with increased
transcriptional activity, as reported for the orphan receptor RORα
[55]. In most described cases, SUMO modification clearly inhibits the
transcriptional activity of the modified NR and even triggers “active”
repression (Table 1), consistent with related observation made with
other transcription factors [56–58].
A variety of different inhibitory mechanisms are postulated to be a
consequence of NR SUMOylation (Fig. 2 and Table 1).
SUMOylation was early observed to trigger intranuclear localization
changes of the modified NRs. Translocation into a particular subnuclear
domain such as PML bodies or nuclear speckles has been reported for
liver receptor homologue LRH-1, steroidogenic factor SF-1, and
testicular receptor TR2 [59–62]. Whether PML-associated SUMOylated
NRs are bound to chromatin in vivo and thus capable of active
repression, or whether PML bodies serve as a “storage” compartment,
remains an interesting issue for further investigations.
Different types of synergistic or antagonistic PTM crosstalk can
cause – or contribute to – several inhibitory mechanisms. Observations made with many non-NR substrates revealed that SUMOylation
can antagonize ubiquitination and thereby inhibit proteasomal
degradation [63]. Since degradation-dependent turnover has been
recognized to be necessary for transcriptional activation of ERα,
which is a target for SUMO modification [64], SUMOylation would
result in transcriptional inhibition. A related mechanism may apply to
the LXRs, crucial regulators of lipid, and glucose metabolism in a
number of tissues. Inferred from data of different studies, SUMOylation,
ubiquitination, and acetylation appear to target a conserved acceptor
lysine residue adjacent to the LBD helix 12, the modification of which
could be dynamically regulated by ligands and other signals [10,14,65].
With regard to metabolic consequences, it is an interesting possibility that
inhibition of LXRα transcription by elevated SUMOylation would decrease
its lipogenic activity in liver [65]. Another type of PTM antagonism was
reported for steroidogenic factor SF-1, where SUMOylation inhibited
phosphorylation of an acceptor lysine-adjacent serine residue within a
phosphorylation-dependent activation domain [66]. In contrast, transcriptional repression of ERR α and γ is mediated by phosphorylationdependent SUMOylation of a synergy control motif within the N-terminal
activation domain [23,67].
Intriguing are indications that SUMOylation may prevent some
NRs from efficiently dimerizing with retinoic acid receptors (RXRs), a
pre-requisite for direct DNA-binding and thus transcriptional activation
of all RXR heterodimers. This potentially fundamental inhibitory
mechanism of remarkable simplicity emerged from our recent study
on the role of LXR SUMOylation in controlling liver inflammatory (acute
phase response) gene expression [14]. When analyzing the promoter
recruitment of SUMOylated LXRs by chromatin immunoprecipiation
(ChIP) assays combined with RNA interference-mediated depletion of
SUMOs or UBC9, we observed that RXR was not recruited to these SUMOdependent loci, although it was recruited together with LXR to classic
LXR/RXR target genes. In support of this possibility, molecular modeling
suggests that one of the putative SUMO acceptor lysines in human LXRβ
(K410) is located in close proximity to the RXR heterodimerization
surface within the LBD (E.T., unpublished observation). While a future
validation of the generality of this mechanism is necessary, it is notable
that additional heterodimeric NRs can be SUMOylated within this LBD
region, for example, PPARs [51,68].
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Fig. 2. Molecular consequences of NR SUMOylation. SUMOylation triggers a plethora of molecular events that depend on the modified NR, including its ligand and coregulator status,
the location of the SUMO acceptor lysine(s) within an NR, the affinity of a given NR to UBC9 and specific E3 ligases, and diverse cell-type-specific modulators. Abbreviations are as in
Fig. 1, except NRE: NR-response elements, direct genomic binding sites. PML: component of a multiprotein complex termed nuclear PML bodies/oncogenic domains, originally
discovered in patients suffering from acute promyelocytic leukaemia (APL), effector that recognizes SUMOylated proteins via SIMs. PTM: post-translational modifications such as
ubiquitination, acetylation, methylation, all with the potential to target the same SUMO acceptor lysine(s), and phosphorylation.
SUMOylation may also directly modulate or inhibit DNA-binding
of both NR monomers and dimers. This has been characterized in case
of SF-1, where DNA-binding and SUMOylation at sites adjacent to the
DNA-binding domain occurred mutually exclusively [69]. The study
suggested that SUMOylation of SF-1, and perhaps of other NRs,
impairs recognition of a subset of SUMO-sensitive target genes. Since
LRH-1 (NR5A2) is the closest homolog to SF-1 (NR5A1) and can be
SUMOylated at conserved sites, it will be interesting to analyze the
effect of SUMOylation on LRH-1 binding to target genes. Indeed, our
preliminary data suggested that the expression of the hepatic LRH-1
target genes shp and cyp7A1 was enhanced in SUMO-1 knockout mice,
which was related to elevated LRH-1 recruitment to the promoters
of these genes [14]. Concerning the physiological implications,
SUMOylation of SF-1 is expected to impact on steroidogenic gene
expression in the gonads and in the adrenal. Additionally, SF-1
controls crucial metabolic pathways via its action in the ventromedial
hypothalamus (VMH), possibly by communicating with leptin
signaling [70,71]. In contrast, LRH-1 SUMOylation may have an
impact on inflammation, lipid and glucose metabolism in liver and
intestine, and on steroidogenesis in the gonads. Intriguingly, both
LRH-1 and SF-1 can transcriptionally re-program somatic cells into
pluripotent stem cells, which in the case of LRH-1 requires SUMOylation
[72].
Evidence has accumulated that SUMOylation triggers direct
transcriptional repression mechanisms, referred to as “active
repression”. Central to current models is the idea that SUMOylation
changes the interactions of transcription factors such as NRs with
numerous coregulators. Dissociation of coactivators may be one
possible inhibitory mechanism, for example, in cases where
SUMOylation occurs within – or adjacent to – the transcription
activation domains of NRs. Much more common, however, appears
that SUMOylation generates new interaction surfaces at NRs
(including at ligand-activated NRs that typically are not associated
with repression) that recruit corepressor complexes involved in
active repression. Indeed, proteomic and targeted approaches have
already revealed a number of SUMO-binding corepressors linked to
histone deacetylation, (de-) methylation, and other chromatinmodifying complexes [14,73–76]. SUMO recognition and binding,
i.e., non-covalent interaction with SUMO, appear the common key
feature of these factors and led to the identification of SUMO
interaction motifs (SIMs) [77]. The classic SIM consensus consists of
a hydrophobic core (I/V–x–I/V–I/V or I/V–I/V–x–I/V)) flanked by
acidic residues and is implicated in the binding of all three SUMO
isoforms. Variations in the consensus sequence, including SUMO
subtype-specific motifs, have been identified [74] with different
types of SIMs awaiting future identification. Examples of SIMcontaining NR corepressors include (i) Daxx, demonstrated to
repress SUMOylated GR in conjunction with HDAC2 [78]; (ii)
CoREST, demonstrated to recruit the histone demethylase LSD1/
KDM1 to SUMO-2/3 substrates and known for its link to HDACs and
to NRs [74,79]; (iii) ARIP4, purified as partner of SUMOylated SF-1
and demonstrated to interact with modified LRH-1, GR, and AR [76];
and (iv) GPS2, a stoichiometric subunit of the N-CoR/HDAC3
corepressor complex, which attracts SUMOylated LRH-1 and LXRβ
914
during anti-inflammatory transrepression in the liver [14], as
discussed further below.
pression pathway in response to reversible and dynamic SUMOylation
cycles.
5. SUMO-dependent NR transrepression pathways that link
metabolism and inflammation
6. Open issues to be addressed
Work over the last decade has identified negative crosstalk
mechanisms, referred to as transrepression, that are linked to the
anti-inflammatory actions of various NRs in macrophages and other
cell-types of the immune system [33–35,50,80]. The academic and
pharmaceutical interest in these pathways is not limited to classic
inflammatory diseases, such as those targeted by anti-inflammatory
glucocorticoids [81], as inflammatory processes have emerged as key
players in the development of metabolic diseases such as diabetes,
atherosclerosis, and obesity [80,82]. A number of significant studies
suggest crucial roles for numerous lipid-activated NRs in linking lipid
metabolism to inflammatory processes and disease [83–88]. These
NRs include PPARs – receptors for fatty acids, LXRs – receptors for
oxysterols and other cholesterol metabolites, and LRH-1, a putative
receptor for phospholipids.
Efforts to understand the underlying molecular mechanisms
indicated that lipid-activated NRs, apparently similar to GR, inhibit
inflammatory gene transcription by interfering with the activities of
pro-inflammatory transcription factors such as AP-1, NFκB, or C/EBPs.
Although the resulting repression is promoter-specific, it does not
appear to involve direct NR DNA-binding to NR response elements,
suggesting a tethering mechanism known as transrepression
[10,14,51]. Interestingly, the transrepression mechanism of PPARγ
and LXRs appears to be distinct from the GR mechanism [50,87,89].
Although it was thought to be the involvement of corepressors in the
PPAR/LXR mechanism that caused these differences, it was the link to
NR SUMOylation that began to resolve this issue. Glass and coworkers
clearly demonstrated that ligand-induced SUMOylation of the LBD
was critical for tethering liganded PPARγ or LXRs to inflammatory
promoters in macrophages, which then prevented signal-induced
removal of the corepressor complex from these promoters [10,51].
What remained unresolved was the specific mechanism of how
agonist-bound and SUMOylated NRs would recognize the corepressor
complex [13]. A study from our laboratory has addressed this issue
and led to the identification of the corepressor complex subunit GPS2
as one likely molecular target of SUMOylated NRs in the SUMOdependent transrepression pathway [14]. GPS2 was initially identified
biochemically by Roeder and coworkers [90] and independently by
means of two-hybrid interaction screens in our laboratory [91]. We
then demonstrated that GPS2 functions in both cholesterol metabolism,
via coregulating LRH-1 and the bile acid receptor FXR in the liver, and in
cholesterol transport, via coregulating LXRs in macrophages [37,92]. In our
recent study, we investigated the potential role of these receptors, their
synthetic ligands, and their coregulators, in inhibiting inflammatory gene
expression in the liver during the acute phase response (APR). A key result
was that liver transrepression by LXR and LRH-1 occurred via the same
SUMO/corepressor pathway that was previously identified in macrophages. We could further demonstrate that (a) GPS2 is associated with the
corepressor complex at APR promoters, (b) GPS2 depletion results in the
lack of NR-SUMO docking and transrepression (both in hepatocytes and in
macrophages), (c) GPS2 directly interacts with agonist-bound NRs, and
(d) GPS2 interacts with free and NR-conjugated SUMOs (via a putative
SIM region in its N-terminus). Our proposal that GPS2 acts as a
transrepression mediator clarifies the apparent paradox of how ligandactivated NRs can bind to the N-CoR corepressor complex at inflammatory
genes. The peculiar NR–SUMO binding feature of GPS2 appears to
distinguish it from other subunits of the corepressor complex, some of
which are likely to further specify the SUMO targeting mechanism.
However, it is perhaps this unique capability of GPS2 to recognize also
“free”, i.e., non-SUMOylated liganded NRs, that pre-disposes GPS2-NR
complexes to rapidly enter the corepressor complex-depending transre-
Of interest is to define the molecular features that enable
SUMOylated NRs to selectively enter the transrepression pathway
but possibly prevent them from conventional activation. The
application of transrepression-selective ligands could be one way to
achieve this (discussed further below), the interference with RXR
heterodimerization, another way. Indeed, ChIP assays have suggested
that LXR acts without RXR in the liver transrepression pathway in
comparison to activation pathways where LXR heterodimerizes with
RXR [14,37]. Inhibition of RXR heterodimerization by SUMOylation
not only would exclude SUMOylated NRs from classic activation
pathways but could also be a way of generating pools of modified NRs
available for the transrepression pathway. Since SUMOylation is a
reversible and dynamic process susceptible to deconjugation by
isopeptidases, only a small fraction of SUMOylated NRs might be
detectable in vivo. Future studies of the ratio of free versus
SUMOylated NRs and of their promoter recruitment upon knockdown
of SUMO proteases may further address this issue.
It remains also enigmatic why some NRs are preferentially modified
by a specific SUMO subtype and what the consequences of this subtypespecific modification may be. As inferred from published studies, it
seems that PPARγ, LRH-1, and other NRs (Table 1) are modified by
SUMO-1 at acceptor lysine(s) within the classic consensus sequence
ψKxE, while LXRβ and the orphan NR (“nuclear receptor-related”)
NURR1 are modified by SUMO-2/3 at non-consensus sites. Whether this
is due to the specific involvement of HDAC4, other SUMO-2/3-selective
E3 ligases or additional modulators of SUMOylation, is currently
unknown. Notably, HDAC4 is known to respond to intracellular signals
such as phosphorylation, which may influence its E3 activity, intracellular localization, or turnover.
The LXR studies suggest that the extent of SUMOylation for each
subtype and the choice of preferred acceptor lysine residues seem to
be influenced by the cellular environment and/or the experimental
conditions of analysis. In macrophages, both LXR subtypes appear to
be modified by SUMO-2, consistent with both SUMOylated LXRα and
LXRβ to trigger the transrepression pathway [10]. In liver, however,
only LXRβ appeared significantly modified by SUMO-2, consistent
with the specific requirement of LXRβ for transrepression in human
primary hepatocytes and in mouse liver in vivo [14]. The reason LXRα
is not SUMOylated in liver remains unclear but could be related to the
fact that some acceptor lysines are not conserved between the LXRs.
Alternatively, a liver-specific SUMO protease activity or PTM antagonism may cause the difference. Indeed, one of the two SUMO acceptor
lysines within the LXRα LBD appears subject to reversible acetylation/
ubiquitination cycles during metabolic gene transcription in liver [65].
To complicate matters further, different SUMOylation events have been
described for LXRs during the inhibition of interferon-stimulated
STAT1-signaling in brain astrocytes [93]. Here, LXRβ was modified by
SUMO-1 and PIAS at a unique consensus site in the N-terminus, while
LXRα was, as in macrophages, modified by SUMO-2 and HDAC4.
Possibly, direct interactions of LXRs with STAT1 modulated the
specificity of SUMOylation, in addition to other cell-type-specific factors.
What can be concluded from these examples is, first, that NRs utilize
alternative and highly cell-type-specific strategies to ensure signal- or
ligand-dependent SUMO modification, and second, that we are still far
from understanding the underlying molecular mechanisms.
Regarding the transcriptional consequences of selective SUMOylation,
it is conceivable that subtype-specific SUMO binders such as CoREST [74]
or specific SUMO proteases play distinctive roles in differentiating the
responses. However, most of the currently known SUMO-binding proteins
including PIAS E3 ligases, SUMO proteases, and the corepressors GPS2 and
ARIP4 appear to recognize modified NRs irrespective of the SUMO
subtype. Additional open questions concern the mechanisms by which the
two related corepressors N-CoR and SMRT, both are implicated in
assembling the core complex containing GPS2 and TBL/TBLR1 [90], specify
the transrepression pathway in a cell-type-dependent manner. In
macrophages, both N-CoR and SMRT appear to be required for LXR
transrepression at most inflammatory genes, although some genes were
selectively dependent on only one of the two corepressors [94]. In
contrast, key inflammatory APR genes in liver that were transrepressed by
LXR seemed to require N-CoR but not SMRT, together with GPS2 and
additional shared subunits of the corepressor complex [14].
7. Implications for human diseases and potential
therapeutic applications
The dual control of metabolic and associated inflammatory pathways
via the same NR(s), and often the same ligand(s), has direct implications
for our understanding and the future pharmacological management of
metabolic and inflammatory diseases. A major therapeutic concept would
be to identify ligands that differentially modulate the activation, active
repression, and transrepression functions of NRs, in order to achieve a
safer and more specific targeting of pathogenic processes. This concept
proposes ligand-specific distinct NR conformations, inducing regulatory
surfaces that specifically trigger SUMOylation and GPS2 docking, to
facilitate the identification of pathway-selective ligands. We suggest that
the term “selective NR SUMO modulators” (SSMs) would be appropriate
for such future compounds (Fig. 3).
In the case of LXRs and probably other metabolic NRs, a variety of
pharmacologic strategies for how to develop compounds with improved
subtype and pathway selectivity have been proposed [95–97]. New types
of selective LXR modulators such as LXR antagonists or LXRβ agonists may
915
allow pharmacological intervention to improve reverse cholesterol
transport and anti-inflammatory activities in macrophages and liver
without affecting undesired hepatic lipogenesis [95,98]. These examples,
together with the documented LXRβ-selectivity of SUMOylation and
transrepression [14], suggest that it might be possible to develop such
compounds. The case of LRH-1 exemplifies that certain orphan receptors
can be adopted for pharmacological development. Synthetic ligands such
has cis-bicyclo[3.3.0]-oct-2-enes [99] may not only affect metabolic
pathways linked to cholesterol metabolism but also potently inhibit
inflammatory gene expression in the liver [14] and potentially in the
intestine [100]. Since LRH-1, unlike LXRs, is not expressed in macrophages
and more limited to the enterohepatic axis, targeting LRH-1 would
perhaps improve the tissue-selectivity of pharmaceutical strategies.
A particular area of future drug applications may be the
pharmacological inhibition of the inflammation by selectively
activating SUMO-dependent NR transrepression pathways in liver
and potentially additional tissues and cell types. Elevated levels of
acute phase proteins, such as those associated with infections and
metabolic diseases, may alter the composition of high-density
lipoprotein (HDL) particles, e.g., depletion of ApoA1 and enrichment
of haptoglobin and serum amyloid A (SAA) to generate acute-phase
HDL. Acute-phase HDL is believed to be pro-atherogenic as it cannot
protect against low-density lipoprotein (LDL) oxidation and thus does
not reduce macrophage foam cell formation [101]. In addition,
epidemiologic studies suggest a greater risk of coronary artery disease
in subjects with high levels of acute phase proteins [102].
Notably, the liver is not the only source of acute phase proteins and
thus not the only site for pharmacological intervention with NR drugs. For
example, plasminogen activator inhibitor-1 (PAI-1), haptoglobin, and SAA
are also synthesized in white adipocyte tissue of obese subjects,
Fig. 3. Putative NR-SUMO-regulated disease pathways that imply future therapeutic applications. Highlighted are some intriguing examples of NRs, tissues, and diseases, where
SUMOylation-dependent NR pathways, in particular transrepression, might occur. Included are only the NRs that already have been experimentally demonstrated to be SUMOylated
(Table 1). Future therapeutic approaches may employ drugs that function as “Selective NR SUMO Modulators”, which would represent a conceptually new category of synthetic NR
compounds.
916
presumably in response to adipokines and cytokines from adiposeassociated macrophages [103]. Intriguingly, it has been reported that
adipocyte-derived acute phase proteins may influence cholesterol efflux
[104], emphasizing the interplay of lipid metabolism and inflammatory
processes in various metabolic disease pathways. In light of these
observations, it will be important to determine to what extent SUMOmediated transrepression pathways play roles in adipocytes and obesity.
Indeed, corepressor complexes (containing GPS2 and N-CoR/SMRT) can
be detected at inflammatory genes in human adipose tissue of normal and
obese subjects (N.V., unpublished data). Considering that clinical
treatment of type-2 diabetic obese patients with PPARγ agonists (TZDs,
thiazolidinediones, glitazones) appears to reduce adipose tissue inflammation [80,96,105], it is tempting to speculate that PPARγ controls
inflammation in adipocytes, as in macrophages, by the transrepression
pathway.
8. Future perspectives: NR–SUMO pathways within physiology and
disease are expanding
Considering current progress in characterizing SUMO–NR pathways, it
is likely that substantially more SUMO-dependent NR pathways will be
uncovered. A large number of NRs can be SUMOylated (Table 1), many of
which are already implicated in regulating metabolic and inflammatory
pathways in a variety of tissues (Fig. 3). For example, recent evidence
points at protective functions of LRH-1 and FXR in mouse models of
intestinal inflammation, suggesting an involvement of these NRs, and
their respective ligands, in the pathogenesis of human inflammatory
bowel diseases [100,106]. Whether or not these anti-inflammatory
actions depend on NR SUMOylation in the intestine remains a challenging
task to address. Also, gender-dependent steroid hormone signaling is
assumed to differentially modulate inflammatory processes linked to
cardiovascular disease, osteoporosis, liver cancer, neurodegenerative, and
autoimmune diseases [48,107–110]. Steroid receptors are established
SUMO substrates and may (trans-) repress via direct crosstalk but also via
SUMO-dependent mechanisms, another interesting aspect to address.
Surprisingly, largely unexplored are the molecular and physiological
consequences of NR coregulator SUMOylation (some examples are given
in Table 1) that could play equally important roles in modulating and redirecting NR pathways.
Evidently, studies in the past have already indicated that
SUMOylation potentially affects every possible aspect of NR function,
including many NR-regulated metabolic and inflammatory processes.
Therefore, the focused molecular and physiological characterization of
these processes is of immense relevance for the understanding and
pharmacological management of human metabolic and inflammatory
diseases. One priority of future research should be to expand the
experimental repertoire for analyzing NR SUMOylation by disease
mechanism-oriented in vivo approaches. Such approaches may
include diverse mouse models that are defective for a specific
component of SUMO modification (e.g., SUMOs, SUMO ligases and
proteases, NR acceptor lysine mutants) or SUMO interpretation (e.g.,
GPS2, CoREST, SIM mutants). These models will not only reveal new
insights into mechanisms and consequences of SUMO function, they
will also be invaluable tools to test future synthetic ligands that as
SSMs specifically modulate NR SUMOylation. Equally importantly,
genomic, epigenomic and proteomic approaches should aim to
identify those components of the SUMO modification and interpretation machinery that are altered in human disease states. Certainly,
these and many other possible future investigations will be necessary
to fully establish and appreciate the role of SUMOylation in NR
pathways governing physiology and disease.
Acknowledgments
We apologize to all researchers whose work could not be
appropriately discussed or cited due to space limitations, and we
acknowledge the expert input from our colleagues Drs. Knut R.
Steffensen, Tomas Jakobsson, Kirsten Remen, and Jorma J. Palvimo. E.
T. was supported by grants from the Center for Biosciences, the Novo
Nordisk Foundation, the Swedish Research Council, and the Swedish
Cancer Society. N.V. received a postdoctoral fellowship of the Swedish
Research Council.
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