title: Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors.
abstract: The myocyte enhancer factor-2 (MEF2) family of transcription factors plays an important role in regulating cellular programs like muscle differentiation, neuronal survival, and T-cell apoptosis. Multisite phosphorylation is known to control the transcriptional activity of MEF2 proteins, but it is unclear whether other modifications are involved. Here, we report that human MEF2D, as well as MEF2C, is modified by SUMO2 and SUMO3 at a motif highly conserved among MEF2 proteins from diverse organisms. This motif is located within the C-terminal transcriptional activation domain, and its sumoylation inhibits transcription. As a transcriptional corepressor of MEF2, histone deacetylase 4 (HDAC4) potentiates sumoylation. This potentiation is dependent on the N-terminal region but not the C-terminal deacetylase domain of HDAC4 and is inhibited by the sumoylation of HDAC4 itself. Moreover, HDAC5, HDAC7, and an HDAC9 isoform also stimulate sumoylation of MEF2. Opposing the action of class IIa deacetylases, the SUMO protease SENP3 reverses the sumoylation to augment the transcriptional and myogenic activities of MEF2. Similarly, the calcium/calmodulin-dependent kinases [corrected] and extracellular signal-regulated kinase 5 signaling pathways negatively regulate the sumoylation. These results thus identify sumoylation as a novel regulatory mechanism for MEF2 and suggest that this modification interplays with phosphorylation to promote intramolecular signaling for coordinated regulation in vivo.
authors.affiliation: Molecular Oncology Group, Department of Medicine, McGill University Health Centre, 687 Pine Ave. West, Montréal, Quebec H3A 1A1, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Grégoire
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D017124:Conserved Sequence; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000502:physiology*; D006655:Histone Deacetylases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D025841:Small Ubiquitin-Related Modifier Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D007527:Isoenzymes; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C578043:MEF2D protein, human; D018006:Myogenic Regulatory Factors; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; C517596:CAMK1 protein, human; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048054:Mitogen-Activated Protein Kinase 7; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human; D006655:Histone Deacetylases
references.citation: J Biol Chem. 2001 Apr 20;276(16):12654-9
references.pmid: 11124955
references.citation: Eur J Biochem. 2001 May;268(10):2764-72
references.pmid: 11358490
references.citation: Mol Cell Biol. 2001 Sep;21(17):5992-6005
references.pmid: 11486037
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15758-63
references.pmid: 14663148
references.citation: Biochem J. 2004 Apr 1;379(Pt 1):23-9
references.pmid: 14750902
references.citation: J Mol Biol. 2004 Apr 16;338(1):17-31
references.pmid: 15050820
references.citation: Mol Biol Cell. 2004 Jun;15(6):2804-18
references.pmid: 15075374
references.citation: Novartis Found Symp. 2004;259:170-7; discussion 178-81, 223-5
references.pmid: 15171253
references.citation: Cancer Sci. 2004 Jun;95(6):503-7
references.pmid: 15182431
references.citation: J Biol Chem. 2004 Jun 25;279(26):27233-8
references.pmid: 15123604
references.citation: Semin Cell Dev Biol. 2004 Apr;15(2):201-10
references.pmid: 15209380
references.citation: Nat Genet. 2004 Aug;36(8):837-41
references.pmid: 15247916
references.citation: Structure. 2004 Aug;12(8):1519-31
references.pmid: 15296745
references.citation: J Biol Chem. 2004 Aug 13;279(33):34201-8
references.pmid: 15166223
references.citation: J Biol Chem. 2004 Aug 13;279(33):34537-46
references.pmid: 15205465
references.citation: Mol Cell Biol. 2004 Sep;24(18):8264-75
references.pmid: 15340086
references.citation: Genes Dev. 2004 Sep 1;18(17):2046-59
references.pmid: 15342487
references.citation: Mol Cell Biol. 2001 Dec;21(23):8035-44
references.pmid: 11689694
references.citation: Mol Cell Biol. 2004 Oct;24(19):8374-85
references.pmid: 15367659
references.citation: Bioessays. 2004 Oct;26(10):1076-87
references.pmid: 15382140
references.citation: Mol Cell Biol. 1995 Jun;15(6):2907-15
references.pmid: 7760790
references.citation: Nature. 1997 Mar 20;386(6622):296-9
references.pmid: 9069290
references.citation: EMBO J. 1997 Dec 1;16(23):7054-66
references.pmid: 9384584
references.citation: EMBO J. 1998 Jan 2;17(1):61-70
references.pmid: 9427741
references.citation: Mol Cell Biol. 1998 Feb;18(2):1065-73
references.pmid: 9448004
references.citation: Mol Cell. 1997 Dec;1(1):35-45
references.pmid: 9659901
references.citation: Mol Cell. 1998 Aug;2(2):233-9
references.pmid: 9734360
references.citation: Nucleic Acids Res. 1998 Oct 15;26(20):4771-7
references.pmid: 9753748
references.citation: Mol Cell Biol. 1999 Jan;19(1):21-30
references.pmid: 9858528
references.citation: EMBO J. 1999 Sep 15;18(18):5099-107
references.pmid: 10487761
references.citation: Mol Cell Biol. 1999 Nov;19(11):7816-27
references.pmid: 10523670
references.citation: J Cell Biol. 1999 Oct 18;147(2):221-34
references.pmid: 10525530
references.citation: Mol Biol Cell. 2004 Dec;15(12):5208-18
references.pmid: 15456902
references.citation: J Biol Chem. 2004 Dec 3;279(49):51218-25
references.pmid: 15364908
references.citation: Oncogene. 2005 Mar 3;24(10):1653-62
references.pmid: 15744326
references.citation: Science. 2003 Nov 28;302(5650):1578-81
references.pmid: 14645853
references.citation: J Biol Chem. 2001 Sep 21;276(38):35368-74
references.pmid: 11451954
references.citation: Genes Dev. 2001 Dec 1;15(23):3088-103
references.pmid: 11731474
references.citation: Cell. 2002 Jan 11;108(1):109-20
references.pmid: 11792325
references.citation: Trends Biochem Sci. 2002 Jan;27(1):40-7
references.pmid: 11796223
references.citation: Chem Biol. 2002 Jan;9(1):3-16
references.pmid: 11841934
references.citation: Cell. 2002 Feb 8;108(3):345-56
references.pmid: 11853669
references.citation: EMBO J. 2002 Jun 3;21(11):2682-91
references.pmid: 12032081
references.citation: Mol Biol Cell. 2002 Jun;13(6):1940-52
references.pmid: 12058061
references.citation: Dev Cell. 2002 Jun;2(6):745-56
references.pmid: 12062087
references.citation: Mol Cell Biol. 2002 Jul;22(14):5222-34
references.pmid: 12077349
references.citation: EMBO J. 2002 Jul 1;21(13):3358-69
references.pmid: 12093737
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13425-30
references.pmid: 12354939
references.citation: Mol Cell. 2002 Oct;10(4):831-42
references.pmid: 12419227
references.citation: Mol Cell. 2002 Oct;10(4):843-55
references.pmid: 12419228
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64
references.pmid: 12506199
references.citation: EMBO Rep. 2003 Feb;4(2):137-42
references.pmid: 12612601
references.citation: J Biol Chem. 2003 Mar 14;278(11):9134-41
references.pmid: 12511558
references.citation: Mol Cell Biol. 2003 Apr;23(8):2953-68
references.pmid: 12665592
references.citation: Curr Opin Genet Dev. 2003 Apr;13(2):143-53
references.pmid: 12672491
references.citation: Cell. 2003 Apr 4;113(1):127-37
references.pmid: 12679040
references.citation: Neuron. 2003 Apr 10;38(1):33-46
references.pmid: 12691662
references.citation: J Biol Chem. 2003 Apr 25;278(17):15297-303
references.pmid: 12586839
references.citation: Trends Genet. 2003 May;19(5):286-93
references.pmid: 12711221
references.citation: J Biol Chem. 2003 May 2;278(18):16059-72
references.pmid: 12590135
references.citation: Mol Cell. 2003 Apr;11(4):1043-54
references.pmid: 12718889
references.citation: Immunity. 2003 May;18(5):687-98
references.pmid: 12753745
references.citation: Nat Rev Mol Cell Biol. 2003 Sep;4(9):690-9
references.pmid: 14506472
references.citation: Nature. 2003 Oct 2;425(6957):475-9
references.pmid: 14523437
references.citation: Trends Biochem Sci. 2003 Nov;28(11):612-8
references.pmid: 14607092
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13118-20
references.pmid: 14597707
references.citation: Genes Dev. 2003 Nov 15;17(22):2733-40
references.pmid: 14630937
references.citation: Science. 1999 Oct 22;286(5440):785-90
references.pmid: 10531066
references.citation: Science. 1999 Oct 22;286(5440):790-3
references.pmid: 10531067
references.citation: EMBO J. 2000 Mar 15;19(6):1176-9
references.pmid: 10716917
references.citation: J Cell Physiol. 2000 Jul;184(1):1-16
references.pmid: 10825229
references.citation: Microbiol Mol Biol Rev. 2000 Jun;64(2):435-59
references.pmid: 10839822
references.citation: J Biol Chem. 2000 Jun 16;275(24):18534-40
references.pmid: 10849446
references.citation: Curr Opin Neurobiol. 2000 Jun;10(3):375-80
references.pmid: 10851169
references.citation: Mol Cell Biol. 2000 Aug;20(16):6040-50
references.pmid: 10913186
references.citation: Mol Cell Biol. 2000 Sep;20(18):6904-12
references.pmid: 10958686
references.citation: Eur J Biochem. 2000 Nov;267(21):6423-7
references.pmid: 11029585
references.citation: Mol Cell Biol. 2000 Nov;20(22):8382-9
references.pmid: 11046135
references.citation: Trends Cardiovasc Med. 2000 Jan;10(1):19-22
references.pmid: 11150724
references.citation: Curr Opin Genet Dev. 2001 Apr;11(2):162-6
references.pmid: 11250139
references.citation: Nat Rev Mol Cell Biol. 2001 Mar;2(3):202-10
references.pmid: 11265250