Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP

J Biol Chem. 2011 Jan 7;286(1):607-19. doi: 10.1074/jbc.M110.153122. Epub 2010 Oct 14.


Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP (C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1·CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal-treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 (residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or "docking" of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Cell Line, Tumor
  • HSP70 Heat-Shock Proteins / metabolism
  • Heat-Shock Response
  • Humans
  • Interferon Regulatory Factor-1 / chemistry
  • Interferon Regulatory Factor-1 / metabolism*
  • Metals, Heavy / toxicity
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination* / drug effects


  • HSP70 Heat-Shock Proteins
  • Interferon Regulatory Factor-1
  • Metals, Heavy
  • Peptide Fragments
  • Tumor Suppressor Proteins
  • UBE2D1 protein, human
  • UBE2E1 protein, human
  • Ubiquitin-Conjugating Enzymes
  • STUB1 protein, human
  • Ubiquitin-Protein Ligases