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PMID: 18063693 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif.

Molecular endocrinology (Baltimore, Md.) ·Vol. 22 ·No. 3 ·2008-03-00 ·Pages 570-84

Tremblay AM, Wilson BJ, Yang XJ, Giguère V

Abstract

Interplay between different posttranslational modifications of transcription factors is an important mechanism to achieve an integrated regulation of gene expression. For the estrogen-related receptors (ERRs) alpha and gamma, regulation by posttranslational modifications is still poorly documented. Here we show that transcriptional repression associated with the ERR amino-terminal domains is mediated through sumoylation at a conserved phospho-sumoyl switch, psiKxEPxSP, that exists within a larger synergy control motif. Arginine substitution of the sumoylatable lysine residue or alanine substitution of a nearby phosphorylatable serine residue (serine 19 in ERRalpha) increased the transcriptional activity of both ERRalpha and -gamma. In addition, phospho-mimetic substitution of the serine residue with aspartate restored the sumoylation and transcriptional repression activity. The increased transcriptional activity of the sumoylation-deficient mutants was more pronounced in the presence of multiple adjacent ERR response elements. We also identified protein inhibitor of activated signal transducer and activator of transcription y as an interacting partner and a small ubiquitin-related modifier E3 ligase for ERRalpha. Importantly, analysis with a phospho-specific antibody revealed that sumoylation of ERRalpha in mouse liver requires phosphorylation of serine 19. Taken together, these results show that the interplay of phosphorylation and sumoylation in the amino-terminal domain provides an additional mechanism to regulate the transcriptional activity of ERRalpha and -gamma.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Animals Binding Sites COS Cells Chlorocebus aethiops DNA/chemistry,genetics Electrophoretic Mobility Shift Assay Gene Expression Regulation/physiology HeLa Cells Humans Male Mice Mice, Inbred C57BL Molecular Sequence Data Mutagenesis, Site-Directed Phosphorylation Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT/physiology Receptors, Cytoplasmic and Nuclear/genetics,metabolism Receptors, Estrogen/genetics,metabolism Small Ubiquitin-Related Modifier Proteins/genetics,physiology Transcription, Genetic
Chemicals
ERRalpha estrogen-related receptor ESRRG protein, human PIAS4 protein, human Poly-ADP-Ribose Binding Proteins Protein Inhibitors of Activated STAT Receptors, Cytoplasmic and Nuclear Receptors, Estrogen Small Ubiquitin-Related Modifier Proteins DNA
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tremblay Annie M
Molecular Oncology Group, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.
Wilson Brian J
Yang Xiang-Jiao
Giguère Vincent
References (83)
83 references, click to expand
  1. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand.
    Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8912-7 PMID: 15184675
  2. Pc2-mediated sumoylation of Smad-interacting protein 1 attenuates transcriptional repression of E-cadherin.
    J Biol Chem. 2005 Oct 21;280(42):35477-89 PMID: 16061479
  3. Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity.
    Mol Cell. 2003 Jul;12(1):63-74 PMID: 12887893
  4. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.
    Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83 PMID: 14530391
  5. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5 PMID: 15100410
  6. The nuclear receptor interaction domain of GRIP1 is modulated by covalent attachment of SUMO-1.
    J Biol Chem. 2002 Aug 16;277(33):30283-8 PMID: 12060666
  7. The DEAD-box protein DP103 (Ddx20 or Gemin-3) represses orphan nuclear receptor activity via SUMO modification.
    Mol Cell Biol. 2005 Mar;25(5):1879-90 PMID: 15713642
  8. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle.
    Mol Cell Biol. 2004 Oct;24(20):9079-91 PMID: 15456881
  9. Coordinated regulation of AIB1 transcriptional activity by sumoylation and phosphorylation.
    J Biol Chem. 2006 Aug 4;281(31):21848-21856 PMID: 16760465
  10. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma.
    Nature. 2005 Sep 29;437(7059):759-63 PMID: 16127449
  11. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma.
    Mol Cell. 2007 Jan 12;25(1):57-70 PMID: 17218271
  12. SUMOylation of the corepressor N-CoR modulates its capacity to repress transcription.
    Mol Biol Cell. 2006 Apr;17(4):1643-51 PMID: 16421255
  13. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number.
    Science. 2006 Feb 17;311(5763):1008-12 PMID: 16484497
  14. Isolation of a gene encoding a novel member of the nuclear receptor superfamily from the critical region of Usher syndrome type IIa at 1q41.
    Genomics. 1998 Jun 15;50(3):382-4 PMID: 9676434
  15. Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation.
    J Biol Chem. 2006 Feb 17;281(7):4423-33 PMID: 16356933
  16. SUMO modification of repression domains modulates function of nuclear receptor 5A1 (steroidogenic factor-1).
    J Biol Chem. 2004 Sep 10;279(37):38730-5 PMID: 15192092
  17. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.
    Cell Metab. 2007 Jul;6(1):25-37 PMID: 17618854
  18. Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity.
    BMC Biochem. 2006 Feb 14;7:5 PMID: 16478538
  19. Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha.
    Cancer Res. 2005 Jul 15;65(14):6120-9 PMID: 16024613
  20. Small ubiquitin-related modifier-1 (SUMO-1) modification of the glucocorticoid receptor.
    Biochem J. 2002 Nov 1;367(Pt 3):907-11 PMID: 12144530
  21. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6472-7 PMID: 15087503
  22. Estrogen-related receptor alpha (ERRalpha) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine.
    J Biol Chem. 2004 Dec 10;279(50):52052-8 PMID: 15466464
  23. Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1).
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14145-50 PMID: 11121022
  24. The transactivating function of peroxisome proliferator-activated receptor gamma is negatively regulated by SUMO conjugation in the amino-terminal domain.
    Genes Cells. 2004 Nov;9(11):1017-29 PMID: 15507114
  25. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.
    Mol Cell Biol. 1997 Sep;17(9):5400-9 PMID: 9271417
  26. Large-scale phosphorylation analysis of mouse liver.
    Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1488-93 PMID: 17242355
  27. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha).
    J Biol Chem. 2003 Mar 14;278(11):9013-8 PMID: 12522104
  28. Hormone-independent transcriptional activation and coactivator binding by novel orphan nuclear receptor ERR3.
    J Biol Chem. 1999 Aug 6;274(32):22618-26 PMID: 10428842
  29. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3.
    Mol Cell. 2002 Feb;9(2):303-13 PMID: 11864604
  30. P300 transcriptional repression is mediated by SUMO modification.
    Mol Cell. 2003 Apr;11(4):1043-54 PMID: 12718889
  31. Modulating nuclear receptor function: may the phos be with you.
    J Clin Invest. 1999 Jun;103(12):1617-8 PMID: 10377165
  32. Post-translational modification by the small ubiquitin-related modifier SUMO has big effects on transcription factor activity.
    Curr Opin Genet Dev. 2003 Apr;13(2):108-13 PMID: 12672486
  33. PIAS3 induction of PRB sumoylation represses PRB transactivation by destabilizing its retention in the nucleus.
    Nucleic Acids Res. 2006;34(19):5552-66 PMID: 17020914
  34. Versatile protein tag, SUMO: its enzymology and biological function.
    J Cell Physiol. 2002 Jun;191(3):257-68 PMID: 12012321
  35. Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1.
    Cell. 2002 Feb 8;108(3):345-56 PMID: 11853669
  36. SUMO: a history of modification.
    Mol Cell. 2005 Apr 1;18(1):1-12 PMID: 15808504
  37. Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT.
    Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9791-6 PMID: 12904571
  38. A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters.
    Mol Endocrinol. 2006 Feb;20(2):302-10 PMID: 16150865
  39. Sumoylation of the progesterone receptor and of the steroid receptor coactivator SRC-1.
    J Biol Chem. 2003 Apr 4;278(14):12335-43 PMID: 12529333
  40. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells.
    Nucleic Acids Res. 1991 May 11;19(9):2499 PMID: 2041787
  41. An extended consensus motif enhances the specificity of substrate modification by SUMO.
    EMBO J. 2006 Nov 1;25(21):5083-93 PMID: 17036045
  42. A calcium-regulated MEF2 sumoylation switch controls postsynaptic differentiation.
    Science. 2006 Feb 17;311(5763):1012-7 PMID: 16484498
  43. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.
    Cell Metab. 2007 May;5(5):345-56 PMID: 17488637
  44. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.
    Mol Cell Biol. 2003 Nov;23(22):7947-56 PMID: 14585956
  45. X-ray crystal structures of the estrogen-related receptor-gamma ligand binding domain in three functional states reveal the molecular basis of small molecule regulation.
    J Biol Chem. 2006 Dec 8;281(49):37773-81 PMID: 16990259
  46. Estrogen-related receptor alpha1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway.
    Mol Cancer Res. 2007 Jan;5(1):71-85 PMID: 17259347
  47. Identification of a new class of steroid hormone receptors.
    Nature. 1988 Jan 7;331(6151):91-4 PMID: 3267207
  48. Large-scale characterization of HeLa cell nuclear phosphoproteins.
    Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12130-5 PMID: 15302935
  49. A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy.
    Mol Cell Biol. 2000 Aug;20(16):6040-50 PMID: 10913186
  50. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.
    J Biol Chem. 2004 Apr 30;279(18):18504-10 PMID: 14978033
  51. Transcriptional activity of peroxisome proliferator-activated receptor gamma is modulated by SUMO-1 modification.
    J Biol Chem. 2004 Jul 9;279(28):29551-7 PMID: 15123625
  52. A role for estrogen-related receptor alpha in the control of mitochondrial fatty acid beta-oxidation during brown adipocyte differentiation.
    J Biol Chem. 1997 Dec 12;272(50):31693-9 PMID: 9395511
  53. Modification with SUMO. A role in transcriptional regulation.
    EMBO Rep. 2003 Feb;4(2):137-42 PMID: 12612601
  54. SUMOylation of Tr2 orphan receptor involves Pml and fine-tunes Oct4 expression in stem cells.
    Nat Struct Mol Biol. 2007 Jan;14(1):68-75 PMID: 17187077
  55. Sumoylation of the estrogen receptor alpha hinge region regulates its transcriptional activity.
    Mol Endocrinol. 2005 Nov;19(11):2671-84 PMID: 15961505
  56. SUMO-dependent compartmentalization in promyelocytic leukemia protein nuclear bodies prevents the access of LRH-1 to chromatin.
    Mol Cell Biol. 2005 Jun;25(12):5095-105 PMID: 15923626
  57. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha.
    J Biol Chem. 2002 Apr 19;277(16):13918-25 PMID: 11854298
  58. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta.
    Mol Endocrinol. 1997 Mar;11(3):353-65 PMID: 9058381
  59. Nuclear and unclear functions of SUMO.
    Nat Rev Mol Cell Biol. 2003 Sep;4(9):690-9 PMID: 14506472
  60. Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells.
    Mol Endocrinol. 2005 Jun;19(6):1584-92 PMID: 15831516
  61. Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis.
    Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1418-23 PMID: 17229846
  62. Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2.
    Mol Endocrinol. 1999 Dec;13(12):2151-62 PMID: 10598588
  63. A recurrent phospho-sumoyl switch in transcriptional repression and beyond.
    Mol Cell. 2006 Sep 15;23(6):779-86 PMID: 16973431
  64. A superfamily of protein tags: ubiquitin, SUMO and related modifiers.
    Trends Biochem Sci. 2003 Jun;28(6):321-8 PMID: 12826404
  65. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9.
    J Biol Chem. 2001 Sep 21;276(38):35368-74 PMID: 11451954
  66. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription.
    J Biol Chem. 2006 Jan 6;281(1):99-106 PMID: 16267049
  67. Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.
    Mol Endocrinol. 2007 Jan;21(1):62-76 PMID: 17053040
  68. ERRgamma directs and maintains the transition to oxidative metabolism in the postnatal heart.
    Cell Metab. 2007 Jul;6(1):13-24 PMID: 17618853
  69. PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism.
    Mol Cell Biol. 2005 Dec;25(24):10684-94 PMID: 16314495
  70. 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.
    Mol Endocrinol. 2003 Dec;17(12):2529-42 PMID: 14500761
  71. Something about SUMO inhibits transcription.
    Curr Opin Genet Dev. 2005 Oct;15(5):536-41 PMID: 16095902
  72. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.
    J Biol Chem. 2002 Oct 25;277(43):40265-74 PMID: 12181319
  73. Sumoylation and proteasomal activity determine the transactivation properties of the mineralocorticoid receptor.
    Mol Cell Endocrinol. 2007 Mar 30;268(1-2):20-9 PMID: 17314004
  74. A synergy control motif within the attenuator domain of CCAAT/enhancer-binding protein alpha inhibits transcriptional synergy through its PIASy-enhanced modification by SUMO-1 or SUMO-3.
    J Biol Chem. 2003 Mar 14;278(11):9134-41 PMID: 12511558
  75. SUMO: ligases, isopeptidases and nuclear pores.
    Trends Biochem Sci. 2003 Nov;28(11):612-8 PMID: 14607092
  76. Nuclear receptors: integration of multiple signalling pathways through phosphorylation.
    Cell Signal. 2003 Apr;15(4):355-66 PMID: 12618210
  77. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha.
    J Biol Chem. 2004 Nov 19;279(47):49330-7 PMID: 15337744
  78. Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element.
    J Mol Endocrinol. 2005 Apr;34(2):473-87 PMID: 15821111
  79. Steroid receptor phosphorylation: a key modulator of multiple receptor functions.
    Mol Endocrinol. 2007 Oct;21(10):2311-9 PMID: 17536004
  80. Orphan nuclear receptors: from gene to function.
    Endocr Rev. 1999 Oct;20(5):689-725 PMID: 10529899
  81. PDSM, a motif for phosphorylation-dependent SUMO modification.
    Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):45-50 PMID: 16371476
  82. Direct and distinguishable inhibitory roles for SUMO isoforms in the control of transcriptional synergy.
    Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15758-63 PMID: 14663148
  83. Phosphorylation of serine 303 is a prerequisite for the stress-inducible SUMO modification of heat shock factor 1.
    Mol Cell Biol. 2003 Apr;23(8):2953-68 PMID: 12665592
Article Info
Journal
Molecular endocrinology (Baltimore, Md.)
Abbr.
Mol Endocrinol
ISSN
0888-8809
DOI
10.1210/me.2007-0357
Published
2008-03-00
Epub
2007-00-06
Pages
570-84
Language
English
Region
United States
NLM ID
8801431
PMCID
PMC5419619
Subset
IM
External Links
PubMed source DOI: 10.1210/me.2007-0357 PMC Full Text View journal details
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