title: The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase.
abstract: 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.
authors.affiliation: Unité de Recombinaison et Expression Génétique, INSERM U 163, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris Cedex 15, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kirsh
authors.forename: Jacob-S
authors.initials: JS
authors.lastname: Seeler
authors.forename: Andrea
authors.initials: A
authors.lastname: Pichler
authors.forename: Andreas
authors.initials: A
authors.lastname: Gast
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Eric
authors.initials: E
authors.lastname: Miska
authors.forename: Marion
authors.initials: M
authors.lastname: Mathieu
authors.forename: Annick
authors.initials: A
authors.lastname: Harel-Bellan
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.forename: Frauke
authors.initials: F
authors.lastname: Melchior
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D002843:Chromatin; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; D012097:Repressor Proteins; C094493:ran-binding protein 2; D005982:Glutathione Transferase; C400300:HDAC4 protein, human; D006655:Histone Deacetylases; D008239:Lysine