At least 17 nuclear receptors have been discovered to be SUMOylated (reviewed in Treuter and Venteclef 2011, Wadosky et al. 2012, Knutson and Lange 2013). In all but a few cases (notably AR and RORA) SUMOylation causes transcriptional repression. Repression by SUMOylation is believed to occur through several mechanisms: interference with DNA binding, recruitment of corepressors, retention of corepressors at non-target promoters (transrepression), re-localization of nuclear receptors within the nucleus, interference with dimerization of receptors, and interference (crosstalk) with other post-translational modifications. SUMOylation of receptors affects inflammation and disease processes (Anbalagan et al. 2012).
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Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guérardel C, Dejean A, Leprince D.; ''An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity.''; PubMedEurope PMCScholia
Pourcet B, Pineda-Torra I, Derudas B, Staels B, Glineur C.; ''SUMOylation of human peroxisome proliferator-activated receptor alpha inhibits its trans-activity through the recruitment of the nuclear corepressor NCoR.''; PubMedEurope PMCScholia
Tallec LP, Kirsh O, Lecomte MC, Viengchareun S, Zennaro MC, Dejean A, Lombès M.; ''Protein inhibitor of activated signal transducer and activator of transcription 1 interacts with the N-terminal domain of mineralocorticoid receptor and represses its transcriptional activity: implication of small ubiquitin-related modifier 1 modification.''; PubMedEurope PMCScholia
Impens F, Radoshevich L, Cossart P, Ribet D.; ''Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli.''; PubMedEurope PMCScholia
Venteclef N, Jakobsson T, Ehrlund A, Damdimopoulos A, Mikkonen L, Ellis E, Nilsson LM, Parini P, Jänne OA, Gustafsson JA, Steffensen KR, Treuter E.; ''GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRbeta in the hepatic acute phase response.''; PubMedEurope PMCScholia
Chalkiadaki A, Talianidis I.; ''SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin.''; PubMedEurope PMCScholia
Anbalagan M, Huderson B, Murphy L, Rowan BG.; ''Post-translational modifications of nuclear receptors and human disease.''; PubMedEurope PMCScholia
Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMedEurope PMCScholia
Komatsu T, Mizusaki H, Mukai T, Ogawa H, Baba D, Shirakawa M, Hatakeyama S, Nakayama KI, Yamamoto H, Kikuchi A, Morohashi K.; ''Small ubiquitin-like modifier 1 (SUMO-1) modification of the synergy control motif of Ad4 binding protein/steroidogenic factor 1 (Ad4BP/SF-1) regulates synergistic transcription between Ad4BP/SF-1 and Sox9.''; PubMedEurope PMCScholia
Chen WY, Lee WC, Hsu NC, Huang F, Chung BC.; ''SUMO modification of repression domains modulates function of nuclear receptor 5A1 (steroidogenic factor-1).''; PubMedEurope PMCScholia
Knutson TP, Lange CA.; ''Dynamic regulation of steroid hormone receptor transcriptional activity by reversible SUMOylation.''; PubMedEurope PMCScholia
Hu G, Xu C, Staudinger JL.; ''Pregnane X receptor is SUMOylated to repress the inflammatory response.''; PubMedEurope PMCScholia
Tian S, Poukka H, Palvimo JJ, Jänne OA.; ''Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor.''; PubMedEurope PMCScholia
Kotaja N, Karvonen U, Jänne OA, Palvimo JJ.; ''PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases.''; PubMedEurope PMCScholia
Choi SJ, Chung SS, Rho EJ, Lee HW, Lee MH, Choi HS, Seol JH, Baek SH, Bang OS, Chung CH.; ''Negative modulation of RXRalpha transcriptional activity by small ubiquitin-related modifier (SUMO) modification and its reversal by SUMO-specific protease SUSP1.''; PubMedEurope PMCScholia
Tirard M, Almeida OF, Hutzler P, Melchior F, Michaelidis TM.; ''Sumoylation and proteasomal activity determine the transactivation properties of the mineralocorticoid receptor.''; PubMedEurope PMCScholia
Balasubramaniyan N, Luo Y, Sun AQ, Suchy FJ.; ''SUMOylation of the farnesoid X receptor (FXR) regulates the expression of FXR target genes.''; PubMedEurope PMCScholia
Jena S, Lee WP, Doherty D, Thompson PD.; ''PIAS4 represses vitamin D receptor-mediated signaling and acts as an E3-SUMO ligase towards vitamin D receptor.''; PubMedEurope PMCScholia
Man JH, Li HY, Zhang PJ, Zhou T, He K, Pan X, Liang B, Li AL, Zhao J, Gong WL, Jin BF, Xia Q, Yu M, Shen BF, Zhang XM.; ''PIAS3 induction of PRB sumoylation represses PRB transactivation by destabilizing its retention in the nucleus.''; PubMedEurope PMCScholia
Abdel-Hafiz H, Dudevoir ML, Horwitz KB.; ''Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation.''; PubMedEurope PMCScholia
Hwang EJ, Lee JM, Jeong J, Park JH, Yang Y, Lim JS, Kim JH, Baek SH, Kim KI.; ''SUMOylation of RORalpha potentiates transcriptional activation function.''; PubMedEurope PMCScholia
Ogawa H, Komatsu T, Hiraoka Y, Morohashi K.; ''Transcriptional Suppression by Transient Recruitment of ARIP4 to Sumoylated nuclear receptor Ad4BP/SF-1.''; PubMedEurope PMCScholia
Sentis S, Le Romancer M, Bianchin C, Rostan MC, Corbo L.; ''Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity.''; PubMedEurope PMCScholia
Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S.; ''The bile acid receptor FXR is a modulator of intestinal innate immunity.''; PubMedEurope PMCScholia
Zhu L, Santos NC, Kim KH.; ''Small ubiquitin-like modifier-2 modification of retinoic acid receptor-alpha regulates its subcellular localization and transcriptional activity.''; PubMedEurope PMCScholia
Suda N, Shibata H, Kurihara I, Ikeda Y, Kobayashi S, Yokota K, Murai-Takeda A, Nakagawa K, Oya M, Murai M, Rainey WE, Saruta T, Itoh H.; ''Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1.''; PubMedEurope PMCScholia
Liu YY, Kogai T, Schultz JJ, Mody K, Brent GA.; ''Thyroid hormone receptor isoform-specific modification by small ubiquitin-like modifier (SUMO) modulates thyroid hormone-dependent gene regulation.''; PubMedEurope PMCScholia
Poukka H, Karvonen U, Janne OA, Palvimo JJ.; ''Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1).''; PubMedEurope PMCScholia
Wadosky KM, Willis MS.; ''The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation.''; PubMedEurope PMCScholia
Yokota K, Shibata H, Kurihara I, Kobayashi S, Suda N, Murai-Takeda A, Saito I, Kitagawa H, Kato S, Saruta T, Itoh H.; ''Coactivation of the N-terminal transactivation of mineralocorticoid receptor by Ubc9.''; PubMedEurope PMCScholia
Ghisletti S, Huang W, Ogawa S, Pascual G, Lin ME, Willson TM, Rosenfeld MG, Glass CK.; ''Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma.''; PubMedEurope PMCScholia
Treuter E, Venteclef N.; ''Transcriptional control of metabolic and inflammatory pathways by nuclear receptor SUMOylation.''; PubMedEurope PMCScholia
Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMedEurope PMCScholia
Nishida T, Yasuda H.; ''PIAS1 and PIASxalpha function as SUMO-E3 ligases toward androgen receptor and repress androgen receptor-dependent transcription.''; PubMedEurope PMCScholia
Daniel AR, Faivre EJ, Lange CA.; ''Phosphorylation-dependent antagonism of sumoylation derepresses progesterone receptor action in breast cancer cells.''; PubMedEurope PMCScholia
PIAS2-2 SUMOylates THRA (alpha-1 isoform, THRA-2 in UniProt) with SUMO1 at lysine-283 and lysine-389. (A lysine residue corresponding to lysine-389 does not exist in the alpha-2 isoform.)
PIAS2-2 SUMOylates THRA (alpha-1 isoform, THRA-2 in UniProt) with SUMO3 at lysine-283 and lysine-389. (A lysine residue corresponding to lysine-389 does not exist in the alpha-2 isoform.)
PIAS1,2-1 SUMOylate AR at lysine-386 and lysine-520 with SUMO1 (Poukka et al. 2000, Kotaja et al. 2002, Nishida and Yasuda 2002). SUMOylation reduces transcription activation by AR.
PIAS1,3 SUMOylate ESR1 (Estrogen Receptor alpha, ER-alpha, ER, NR3A1) at lysines-266,268,299,302,303 with SUMO1 (Sentis et al. 2005). SUMOylation reduces transcription activation by ESR1.
PIAS1 SUMOylates NR3C2 (Mineralcorticoid receptor, MR) at lysine-89, lysine-399, lysine-428, and lysine 494 with SUMO1 (Tallec et al. 2003, Tirard et al. 2007, Yokota et al. 2007). SUMOylation represses the transcription activation activity of NR3C2.
NR3C1 (Glucocorticoid receptor, GR) is SUMOylated at lysine-277 and lysine-293 with SUMO1 (Tian et al. 2002, Impens et al. 2014). SUMOylation is enhanced when NR3C1 binds ligand (dexamethasone). SUMOylation reduces transcription activation by NR3C1.
PIAS4 SUMOylates PPARA at lysine-185 with SUMO1 (Pourcet et al. 2010). SUMOylation decreases the transactivation activity of PPARA. SUMOylation is decreased in the presence of ligand of PPARA.
RARA (Retinoic acid receptor alpha) is SUMOylated at lysine-166, lysine-171, and lysine-399 with SUMO2 (Zhu et al. 2009). SUMOylation at lysine-166 and lysine-171 is induced by all-trans retinoic acid and inhibits nuclear localization of RARA. SUMOylation at lysine-399 is observed in the absence of all-trans retinoic acid and enhances nuclear localization of RARA. SUMOylation of all 3 sites inhibits transcriptional activation by RARA.
PIAS3 SUMOylates PGR (Progesterone receptor, PR) at lysine-7, lysine-388, and lysine-531 with SUMO1 (Man et al. 2006, Daniel et al. 2007, Abdel-Hafiz et al. 2009). SUMOylation inhibits hormone-dependent transcription activation by PGR.
PIAS1,3 SUMOylate NR5A1 (Steroidogenic factor 1, SF1, SF-1) at lysine-119 and lysine-194 with SUMO2 (Chen et al. 2004, Komatsu et al. 2004, Suda et al. 2011). SUMOylation reduces synergistic activation of SOX9 by NR5A1.
PIAS1,3 SUMOylate NR5A1 (Steroidogenic factor 1, SF1, SF-1) at lysine-119 and lysine-194 with SUMO1 (Chen et al. 2004, Komatsu et al. 2004, Suda et al. 2011). SUMOylation reduces the synergistic activation of SOX9 by NR5A1.
E3 SUMO-protein ligase (PIAS4) SUMOylates Vitamin D3 receptor (VDR) with SUMO2 (Jena et al. 2012). SUMOylation inhibits transcriptional activation by VDR in response to vitamin D.
As inferred from mouse homologs, PIAS1,2-2 SUMOylate PPARG with SUMO1 at lysine-107 and lysine-395 (lysine-77 and lysine-365 of the shorter variant 1). SUMOylation decreases the transcriptional activation activity of PPARG. SUMOylation at lysine-395 is ligand-dependent and causes PPARG to recruit corepressors such as NCOR and HDAC3.
As inferred from mouse homologs, PIAS1 SUMOylates NR2C1 (TR2) with SUMO1 at lysine-250. UnSUMOylated NR2C1 is localized to PML bodies and activates expression of OCT4. SUMOylated NR2C1 delocalizes from PML bodies and acts as a repressor of transcription.
PIAS2-2 (PIASx-alpha, PIAS3, and PIAS4 SUMOylate RORA with SUMO2 at lysine-240 (Hwang et al. 2009). SUMOylation increases the transcriptional activity of RORA.
PIAS2-2 (PIasx-alpha) SUMOylates THRA (isoform alpha-1) with SUMO3 at lysine-283 and lysine-389 (Liu et al. 2012). (A lysine residue corresponding to lysine-389 does not exist in the alpha-2 isoform of THRA.) SUMOylation by SUMO3 enhances transcription in response to ligand binding.
PIAS1 SUMOylates THRB with SUMO1 at lysine-50, lysine-146, and lysine-443 (Liu et al. 2012). SUMOylation is required for induction of gene expression in response to ligand (triiodothyroxine). In the absence of SUMOylation the repressor NCOR is not dismissed in response to ligand binding.
PIAS2-2 (PIASx-alpha), PIAS3, and PIAS4 SUMOylate RORA with SUMO1 at lysine-240 (Hwang et al. 2009). SUMOylation increases transcriptional activation by RORA.
PIAS2-2 (PIASx-alpha) SUMOylates THRA (alpha-1 isoform) with SUMO1 at lysine-283 and lysine-389 (Liu et al. 2012). (A lysine residue corresponding to lysine-389 does not exist in the alpha-2 isoform.) SUMOylation by SUMO3 but not SUMO1 enhances induction of gene expression in response to the ligand triiodothyroxine.
PIAS1 SUMOylates THRB with SUMO3 at lysine-50, lysine-146, and lysine-443 (Liu et al. 2012). SUMOylation is required for induction of transcription in response to ligand binding.
HDAC4 SUMOylates NR1H2 (LXR-beta) with SUMO2,3 at lysine-409 and lysine-447 (lysine-410 and lysine-448 of the isoform used by Ghisletti et al. 2007) (Venteclef et al. 2010). SUMOylation is enhanced when NR1H2 binds specific oxysterols and causes NR1H2 to recruit the NCOR repressor and transrepress promoters such as iNOS.
HDAC4 SUMOylates NR1H3 with SUMO2,3 (Ghisletti et al. 2007). SUMOylation is enhanced when NR1H3 binds specific oxysterols. SUMOylation causes NR1H3 to recruit the NCOR repressor and act as a transrepressor at promoters such as iNOS.
NR1H4 (FXR, Bile Acid Receptor) is SUMOylated with SUMO1 at lysine-132 and lysine-289 (lysine-122 and lysine-275 of isoform 4, UniProt Q96RI1-2) (Vavassori et al. 2009, Balasubramaniyan et al. 2013). SUMOylation appears to be enhanced when NR1H4 binds ligands (Vavassori et al. 2009). SUMOylated NR1H4 transrepresses genes involved in inflammation (Vavassori et al. 2009) and inhibits ligand-induced activation of FXR targets: bile salt export pump (BSEP) and small heterodimer partner (SHP) (Balasubramaniya et al. 2013).
PIAS1,2-1 SUMOylate NR5A2 (LRH-1) with SUMO1 at lysine-270 (lysine-224 in the shorter isoform) (Chalkiadaki and Talianidis 2005, Ogawa et al. 2009, Venteclef et al. 2010). SUMOylation is enhanced when NR5A2 is bound to ligand. SUMOylated NR5A2 acts as a transrepressor of genes involved in inflammation such as haptoglobin, SAA, and CRP.
NR1I2 (Pregnane X Receptor, PXR) is SUMOylated with SUMO3 (Hu et al. 2010). SUMOylation is stimulated when NR1I2 binds ligand (rifampicin) and causes NR1I2 to transrepress genes encoding inflammatory cytokines.
As inferred from mouse homologs, PIAS4 SUMOylates NR4A2 (NUR1) with SUMO2,3 at lysine-558 and lysine-577. SUMOylation causes NR4A2 to interact as a monomer with the Co-REST complex and transrepress promoters of genes involved in inflammation.
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