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| Subject Categories: Chromatin & Transcription | Proteins |
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| The EMBO Journal
(2002) 21, 2682–2691, doi: 10.1093/emboj/21.11.2682 |
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| The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase |
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| Olivier Kirsh1, 7, Jacob-S. Seeler1, 7, Andrea Pichler2, Andreas Gast2, Stefan Müller1, 3, Eric Miska4, 5, Marion Mathieu6, Annick Harel-Bellan6, Tony Kouzarides4, Frauke Melchior2 and Anne Dejean1 |
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1 Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris Cedex 15, France 2 Max Planck Institute for Biochemistry, Am Klopferspitz 18a, D-82152 Martinsried, Germany 3 Present address: Max Planck Institute of Biochemistry, Department of Molecular Cell Biology, Am Klopferspitz 18a, D-82152 Martinsried, Germany 4 Wellcome/CRC Institute, Department of Pathology, Cambridge University, Tennis Court Road, Cambridge CB2 1QR, UK 5 Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139-4307, USA 6 Laboratoire Oncogénèse, Différenciation et Transduction du Signal, CNRS UPR 9079, IFC-O1, F-94801 Villejuif, France 7 O.Kirsh and J.-S.Seeler contributed equally to this work To whom correspondence should be addressed Anne Dejean, adejean@pasteur.fr Received 4 January 2002; Revised 9 April 2002; Accepted 11 April 2002. |
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| Abstract |
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| Transcriptional repression mediated through histone deacetylation is a critical component of eukaryotic gene regulation. Here we demonstrate that the class II histone deacetylase HDAC4 is covalently modified by the ubiquitin-related SUMO-1 modifier. A sumoylation-deficient point mutant (HDAC4-K559R) shows a slightly impaired ability to repress transcription as well as reduced histone deacetylase activity. The ability of HDAC4 to self-aggregate is a prerequisite for proper sumoylation in vivo. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which induces nuclear export, abrogates SUMO-1 modification of HDAC4. Moreover, the modification depends on the presence of an intact nuclear localization signal and is catalysed by the nuclear pore complex (NPC) RanBP2 protein, a factor newly identified as a SUMO E3 ligase. These findings suggest that sumoylation of HDAC4 takes place at the NPC and is coupled to its nuclear import. Finally, modification experiments indicate that the MEF2-interacting transcription repressor (MITR) as well as HDAC1 and -6 are similarly SUMO modified, indicating that sumoylation may be an important regulatory mechanism for the control of transcriptional repression mediated by both class I and II HDACs. |
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| Keywords: E3 ligase, HDACs, nuclear pore complex, SUMO, ubiquitin-like modification |
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