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Molecular and Cellular Biology, March 2005, p. 2273-2287, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2273-2287.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Association with Class IIa Histone Deacetylases Upregulates the Sumoylation of MEF2 Transcription Factors

Serge Grégoire1 and Xiang-Jiao Yang1*

Molecular Oncology Group, Department of Medicine, McGill University Health Centre, Montréal, Quebec, Canada1

Received 17 September 2004/ Returned for modification 28 October 2004/ Accepted 14 December 2004

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 M kinase 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.

* Corresponding author. Mailing address: Molecular Oncology Group, Royal Victoria Hospital, Room H5.41, McGill University Health Centre, 687 Pine Ave. West, Montréal, Quebec H3A 1A1, Canada. Phone: (514) 934-1934, ext. 34490. Fax: (514) 843-1478. E-mail: xiang-jiao.yang{at}mcgill.ca.

Molecular and Cellular Biology, March 2005, p. 2273-2287, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2273-2287.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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