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  • The EMBO Journal (2002) 21, 2682 - 2691
  • doi:10.1093/emboj/21.11.2682

The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase

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

  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

Correspondence to:

Anne Dejean, E-mail: adejean@pasteur.fr

Received 4 January 2002; Accepted 11 April 2002; Revised 9 April 2002

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.

  • Keywords:

    • E3 ligase,
    • HDACs,
    • nuclear pore complex,
    • SUMO,
    • ubiquitin-like modification