The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase

EMBO J. 2002 Jun 3;21(11):2682-91. doi: 10.1093/emboj/21.11.2682.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • COS Cells
  • Cell Nucleus / metabolism
  • Chromatin / metabolism
  • Cytoplasm / metabolism
  • Dimerization
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • HeLa Cells
  • Histone Deacetylases / metabolism*
  • Humans
  • Lysine / chemistry
  • Microscopy, Fluorescence
  • Molecular Chaperones
  • Mutation
  • Nuclear Pore Complex Proteins / genetics*
  • Nuclear Pore Complex Proteins / physiology*
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Repressor Proteins / metabolism*
  • Signal Transduction
  • Transcription, Genetic
  • Transfection

Substances

  • Chromatin
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • Repressor Proteins
  • ran-binding protein 2
  • Glutathione Transferase
  • HDAC4 protein, human
  • Histone Deacetylases
  • Lysine