5.2 Regulation of glucocorticoid signaling by receptor SUMOylation
5.2.2 The role of GR SUMOylation in cell stress
The secretion of glucocorticoids is regulated by the HPA axis that responds to various stress stimuli (Rhen & Cidlowski 2005, Silverman & Sternberg 2012, Vitale et al. 2013). Stress can impair the function of the immune system (Glaser & Kiecolt-Glaser 2005), and while glucocorticoids function as anti-inflammatory mediators during short-term stress, prolonged stress can transform the effect of glucocorticoids so that they become pro-inflammatory (Sorrells & Sapolsky 2007, Sorrells et al. 2009). Interestingly, various cell stress conditions, including electrophilic and oxidative stress, lead to the accumulation of SUMOylated proteins; hyper-SUMOylation of proteins (Manza et al. 2004, Tempé et al. 2008, Golebiowski et al. 2009). For example, the AR is hyper-SUMOylated in prostate cancer cells exposed to cell stress (Rytinki et al. 2012).
The electrophilic lipid mediator 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) that is derived from the cyclo-oxygenase pathway and which is capable of inducing oxidative stress (Kondo et al. 2001, Oeste & Pérez-Sala 2014) activates cytoprotective Keap1-nuclear factor erythroid 2-related factor 2 (NRF2) system (Kansanen et al. 2009, Kansanen et al.
2012). On the other hand, 15d-PGJ2 is known to inhibit the activities of various TFs such as AP1 (Pérez-Sala et al. 2003), NF-κB (Cernuda-Morollón et al. 2001), and p53 (Kim et al. 2010).
In addition, the activities of SRs, such as GR (Cheron et al. 2004, Fig. 1A-B in III), ER (Kim et al. 2007), and AR (Kaikkonen et al. 2013b) can be inhibited by 15d-PGJ2. Both the activation of NRF2 and the inhibition of TFs by 15d-PGJ2 are thought to be largely attributed to the reactive electrophilic α,β-unsaturated carbonyl moiety present in the cyclopentenone ring, through which it can form covalent adducts with thiol groups in target proteins via a Michael addition reaction (Oeste & Pérez-Sala 2014). Interestingly, besides forming covalent
adducts (Fig. 2A in III), 15d-PGJ2 induced hyper-SUMOylation of both AR and GR (Fig. 2B in III, Kaikkonen et al. 2013b). While the inhibitory potential of 15d-PGJ2 on AR signaling has been postulated to be modulated by receptor SUMOylation (Kaikkonen et al. 2013b), the inhibition of GR signaling was significantly SUMOylation-sensitive, on a genome-wide scale (Fig. 3 and Fig. 4 in III). Since GR3KR evoked a similar degree of formation of covalent adducts with 15d-PGJ2 as wtGR (Fig. 2A in III), the weaker inhibition of the GR3KR by the compound could not be due to altered adduct formation.
Oxidative stress has also been associated with inflammation induced by the activation of AP1 and NF-κB (Zhou et al. 2001, Benz & Yau 2008, de Nadal et al. 2011). While the GR is capable of inhibiting the action of AP1 and NF-κB (Oakley & Cidlowski 2013, Fig. 6C in III), it can also inhibit the action of TFs involved in the regulation of oxidative stress conditions, such as hypoxia-inducible factor 1α (HIF1A) (Lim et al. 2014), activating TF4 (ATF4) (Adams 2007) (Fig. 6C in III), and NRF2 (Kratschmar et al. 2012, Fig. 1C in III). Furthermore, the heat shock factor 1 (HSF1) that is an essential mediator of acute stress (Åkerfelt et al.
2010), has been reported to be inhibited by the GR (Wadekar et al. 2004). Thus, in addition to mediating anti-inflammatory action, GR can attenuate the properties of cell stress-associated TFs under normal cellular conditions.
In the oxidative stress conditions induced by 15d-PGJ2, the SUMOylation-sensitive inhibition of GR signaling could modulate activation of cell stress-associated TFs, such as HIF1A, ATF4, HSF1, and pro-inflammatory factors AP1 and NF-κB (Fig. 5C and 6C in III).
The adaptation to cell stress occurred primarily via the change in the gene expression pattern through the activation of TFs inducing stress-responsive genes and the repression of non-essential TFs (Finkel & Holbrook 2000, Pearce & Humphrey 2001, de Nadal et al.
2011). The repression of GR and activation of HIF1A, NRF2, AP1 and NF-κB during oxidative and redox stress have been previously observed (Brigelius-Flohé & Flohé 2011).
Exposure of cells to a more general oxidative stress inducer, H2O2, also attenuated GR signaling (Okamoto et al. 1999, Asaba et al. 2004), inhibiting GR target gene expression in a SUMOylation-sensitive manner (data not shown).
Stress in ischemia has been reported to worsen the endothelial function, which is reduced by the inhibition of GR signaling (Balkaya et al. 2011). Interestingly, a proteomic screen of SUMOylated proteins from pre- and post-ischemic brains of mice revealed hyper-SUMOylation of GR after ischemia, suggesting that hyper-SUMOylation had attenuated the transcriptional activity of GR which is a protective stress response (Yang et al. 2014). These results along with the present data strongly suggest that cell stress-induced SUMOylation of the GR inhibited the activation of the receptor, ensuring the release of essential TFs that alleviated cell stress (Fig. 7 in III).
NR SUMOylation has been associated with transrepression of inflammatory TFs (Pascual & Glass 2006, Treuter & Venteclef 2011, Venteclef et al. 2011). This type of transrepression mediated by peroxisome proliferator-activated receptor (PPAR) γ, liver X receptor (LXR), and liver receptor homolog-1 (LRH1) appears to mainly be a result of inhibition of corepressor clearance from promoters of NF-κB target genes (Pascual et al.
2005, Ghisletti et al. 2007, Venteclef et al. 2010). In the case of LXR, SUMOylation can also mediate transrepression of STAT1 (Lee et al. 2009b). Due to the fact that GR is one of the most potent inhibitors of pro-inflammatory signaling, and because PTMs of GR can influence the transrepression of inflammatory TFs (Ito et al. 2006, Galliher-Beckley et al.
2008, Oakley & Cidlowski 2013), it is highly possible that SUMOylation of GR plays a role also in the repression of the activities of the inflammatory TFs. This concept is in line with some preliminary analyses indicating that the SUMOylation-defective GR is more prone to TNFα-mediated inflammatory repression than the wtGR (data not shown). Furthermore, transcriptome and ChIP-seq analyses revealed differences between the wtGR and the GR3KR in the regulation of target genes involved in inflammatory processes, such as NFKBIA (Fig. 1D and 6B in II) and interleukin 8 (IL8) (Supplementary Fig. S8B and Fig. 8B
in II), even in the absence of inflammatory stimuli. However, more detailed analyses will be needed to confirm these interesting preliminary observations.
6 Summary and Conclusions
Glucocorticoid signaling is essential for life as it regulates many vital biological processes, such as glucose metabolism and the cardiovascular system (Oakley & Cidlowski 2013, Kadmiel & Cidlowski 2013). Clinically, the most interesting function of glucocorticoids is their anti-inflammatory and -proliferative effects that are thought to mainly rely on the transrepression mechanisms of GR with AP1 and NF-κB (De Bosscher et al. 2003). However, newly published genome-wide studies are beginning to alter that concept (Uhlenhaut et al.
2013). In recent years, SUMOylation has emerged as an important PTM, potentially associated with human health and disease since it is involved in a multitude of central cellular processes (Flotho & Melchior 2013). SUMOylation of GR was previously thought to simply restrict the transcriptional activity of the receptor (Tian et al. 2002). However, genome-wide techniques have indicated that SUMOylations do not exert a general repression of the TF activity. At the beginning of this thesis work, nothing was known about the genome-wide affects of GR SUMOylation.
Genome-wide techniques have also revealed that NRs mainly bind to sites that are distal to their target gene promoters (Biddie et al. 2010), suggesting CTCF and cohesin ensure proper long-range interactions (Jin et al. 2013, Zuin et al. 2014). The present characterization of FKBP51, a sensitive biomarker of corticosteroid responsiveness, provided evidence that CTCF and cohesin participate in the long-range chromatin interactions with the GR. Furthermore, an intergenic GR super-enhancer was identified in chromosome 6 that may participate in the long-range chromatin regulation exerted by glucocorticoids.
Moreover, this thesis work has clarified how GR SUMOylation could have an impact on genome-wide gene regulation. The major findings were:
x Genome-wide binding of SUMO-2/3 was associated with active chromatin and transcription of GR target genes.
x Basal GR SUMOylation influenced in the chromatin occupancy of the receptor in a locus-selective fashion, playing an important role in the regulation of gene and gene programs involved in cellular growth and survival.
x Cell stress-induced hyper-SUMOylation of GR attenuated the receptor activity in order to ensure the activation of cell stress-associated TF, such as HIF1A, ATF4 HSF1, AP1 and NF-κB.
These results provide novel information on how GR SUMOylation influences the function of the GR. Two types of GR SUMOylations with different consequences on gene regulation were identified. Firstly, basal SUMOylation (under normal cell growth conditions) could modulate receptor chromatin occupancy and subsequently the regulation of cellular growth pathways (Fig. 14). GR SUMOylation influences both glucocorticoid up- and down-regulated genes, but not all GR target genes were sensitive to receptor SUMOylation. Secondly, cell stress-induced hyper-SUMOylation of GR attenuated the receptor chromatin binding and target gene expression. This attenuation ensures the activation of cell stress-associated TFs that are otherwise inhibited by GR (Fig. 15). In addition, these results were among the first to demonstrate that SUMOylated proteins could bind to chromatin and that they were associated with active transcription.
Two recent proteomic screens have identified GR as a target for both SUMO-2 and SUMO-3 at under normal as well as pathophysiological conditions (Schimmel et al. 2014, Yang et al. 2014). The discovery of hyper-SUMOylated GR from post-ischemic mouse brains strongly supports the concept that attenuation of GR activity is a protective response, ensuring the activation of essential TFs to alleviate cell stress.
Figure 14. Model of the genome-wide effect of basal GR SUMOylation. While SUMOylation-competent GR (blue) preferentially regulates the genes associated with anti-proliferation, SUMOylation-defective GR (red) preferentially regulated genes promoting cell growth. In addition to altered chromatin occupancy, the SUMOyaltion of GR is believed to influence the protein-protein interactions of GR with other TFs (V and P) and coregulators (v and p). These changes influence to the differential regulation of gene expression observed between receptor forms.
In addition to altered chromatin occupancy between wtGR and GR3KR, SUMOylation of GR could alter the protein-protein interaction of the receptor. Proteomic screens for GR-protein interactions altered by SUMOylation would be valuable for clarifying the underlying coregulatory-networks altered by the modification.
Figure 15. Model of the genome-wide action of cell stress triggered hyper-SUMOylation of GR.
Activated GR is able to repress (blunt arrow) the properties of cell stress-associated TFs (left side). 15d-PGJ2 triggers hyper-SUMOylation of GR, which results in an inhibition of GR signaling.
This in turn leads to the activation of cell stress-associated TFs (arrow) (right side).
The genome-wide techniques, such as ChIP-seq are highly powerful tools that could be also utilized in animal model systems. Interestingly, a mouse model containing SUMOylation-defective SF-1 knockin has proven to represent a valuable in vivo approach to study NR SUMOylation (Lee et al. 2011). Since the GR SUMOylation seemed to influence the inflammatory responses, a knockin animal model expressing SUMOylation-defective GR would give information on how GR SUMOylation could modify inflammatory responses in a genuine mammalian organism.
The most important functions of glucocorticoids in disease treatment are attributable to their anti-proliferative and -inflammatory capabilities and these are both influenced by GR SUMOylation. The results presented in this thesis represent novel information on GR signaling that will be valuable for the development of more efficient GR modulators for medical purposes.
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