Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors.
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.
Grégoire
Serge
S
Molecular Oncology Group, Department of Medicine, McGill University Health Centre, 687 Pine Ave. West, Montréal, Quebec H3A 1A1, Canada.
Yang
Xiang-Jiao
XJ
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
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
J Biol Chem. 2001 Apr 20;276(16):12654-9
11124955
Eur J Biochem. 2001 May;268(10):2764-72
11358490
Mol Cell Biol. 2001 Sep;21(17):5992-6005
11486037
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15758-63
14663148
Biochem J. 2004 Apr 1;379(Pt 1):23-9
14750902
J Mol Biol. 2004 Apr 16;338(1):17-31
15050820
Mol Biol Cell. 2004 Jun;15(6):2804-18
15075374
Novartis Found Symp. 2004;259:170-7; discussion 178-81, 223-5
15171253
Cancer Sci. 2004 Jun;95(6):503-7
15182431
J Biol Chem. 2004 Jun 25;279(26):27233-8
15123604
Semin Cell Dev Biol. 2004 Apr;15(2):201-10
15209380
Nat Genet. 2004 Aug;36(8):837-41
15247916
Structure. 2004 Aug;12(8):1519-31
15296745
J Biol Chem. 2004 Aug 13;279(33):34201-8
15166223
J Biol Chem. 2004 Aug 13;279(33):34537-46
15205465
Mol Cell Biol. 2004 Sep;24(18):8264-75
15340086
Genes Dev. 2004 Sep 1;18(17):2046-59
15342487
Mol Cell Biol. 2001 Dec;21(23):8035-44
11689694
Mol Cell Biol. 2004 Oct;24(19):8374-85
15367659
Bioessays. 2004 Oct;26(10):1076-87
15382140
Mol Cell Biol. 1995 Jun;15(6):2907-15
7760790
Nature. 1997 Mar 20;386(6622):296-9
9069290
EMBO J. 1997 Dec 1;16(23):7054-66
9384584
EMBO J. 1998 Jan 2;17(1):61-70
9427741
Mol Cell Biol. 1998 Feb;18(2):1065-73
9448004
Mol Cell. 1997 Dec;1(1):35-45
9659901
Mol Cell. 1998 Aug;2(2):233-9
9734360
Nucleic Acids Res. 1998 Oct 15;26(20):4771-7
9753748
Mol Cell Biol. 1999 Jan;19(1):21-30
9858528
EMBO J. 1999 Sep 15;18(18):5099-107
10487761
Mol Cell Biol. 1999 Nov;19(11):7816-27
10523670
J Cell Biol. 1999 Oct 18;147(2):221-34
10525530
Mol Biol Cell. 2004 Dec;15(12):5208-18
15456902
J Biol Chem. 2004 Dec 3;279(49):51218-25
15364908
Oncogene. 2005 Mar 3;24(10):1653-62
15744326
Science. 2003 Nov 28;302(5650):1578-81
14645853
J Biol Chem. 2001 Sep 21;276(38):35368-74
11451954
Genes Dev. 2001 Dec 1;15(23):3088-103
11731474
Cell. 2002 Jan 11;108(1):109-20
11792325
Trends Biochem Sci. 2002 Jan;27(1):40-7
11796223
Chem Biol. 2002 Jan;9(1):3-16
11841934
Cell. 2002 Feb 8;108(3):345-56
11853669
EMBO J. 2002 Jun 3;21(11):2682-91
12032081
Mol Biol Cell. 2002 Jun;13(6):1940-52
12058061
Dev Cell. 2002 Jun;2(6):745-56
12062087
Mol Cell Biol. 2002 Jul;22(14):5222-34
12077349
EMBO J. 2002 Jul 1;21(13):3358-69
12093737
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13425-30
12354939
Mol Cell. 2002 Oct;10(4):831-42
12419227
Mol Cell. 2002 Oct;10(4):843-55
12419228
Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64
12506199
EMBO Rep. 2003 Feb;4(2):137-42
12612601
J Biol Chem. 2003 Mar 14;278(11):9134-41
12511558
Mol Cell Biol. 2003 Apr;23(8):2953-68
12665592
Curr Opin Genet Dev. 2003 Apr;13(2):143-53
12672491
Cell. 2003 Apr 4;113(1):127-37
12679040
Neuron. 2003 Apr 10;38(1):33-46
12691662
J Biol Chem. 2003 Apr 25;278(17):15297-303
12586839
Trends Genet. 2003 May;19(5):286-93
12711221
J Biol Chem. 2003 May 2;278(18):16059-72
12590135
Mol Cell. 2003 Apr;11(4):1043-54
12718889
Immunity. 2003 May;18(5):687-98
12753745
Nat Rev Mol Cell Biol. 2003 Sep;4(9):690-9
14506472
Nature. 2003 Oct 2;425(6957):475-9
14523437
Trends Biochem Sci. 2003 Nov;28(11):612-8
14607092
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13118-20
14597707
Genes Dev. 2003 Nov 15;17(22):2733-40
14630937
Science. 1999 Oct 22;286(5440):785-90
10531066
Science. 1999 Oct 22;286(5440):790-3
10531067
EMBO J. 2000 Mar 15;19(6):1176-9
10716917
J Cell Physiol. 2000 Jul;184(1):1-16
10825229
Microbiol Mol Biol Rev. 2000 Jun;64(2):435-59
10839822
J Biol Chem. 2000 Jun 16;275(24):18534-40
10849446
Curr Opin Neurobiol. 2000 Jun;10(3):375-80
10851169
Mol Cell Biol. 2000 Aug;20(16):6040-50
10913186
Mol Cell Biol. 2000 Sep;20(18):6904-12
10958686
Eur J Biochem. 2000 Nov;267(21):6423-7
11029585
Mol Cell Biol. 2000 Nov;20(22):8382-9
11046135
Trends Cardiovasc Med. 2000 Jan;10(1):19-22
11150724
Curr Opin Genet Dev. 2001 Apr;11(2):162-6
11250139
Nat Rev Mol Cell Biol. 2001 Mar;2(3):202-10
11265250