Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2

Nat Cell Biol. 2003 Apr;5(4):336-40. doi: 10.1038/ncb952.


The ubiquitin system is involved in several basic cellular functions. Ubiquitination is carried out by a cascade of three reactions catalysed by the E1, E2 and E3 enzymes. Among these, the E3 ubiquitin-protein ligases have a pivotal role in determining the specificity of the system by recognizing the target substrates through defined targeting motifs. Although RING finger proteins constitute an important family of E3 ligases, only a few post-transcriptional modifications, including phosphorylation, proline hydroxylation and glycosylation, are known to function as recognition signals for E3. Iron regulatory protein 2 (IRP2), a modulator of iron metabolism, is regulated by iron-induced ubiquitination and degradation. Here we show that the RING finger protein HOIL-1 functions as an E3 ligase for oxidized IRP2, suggesting that oxidation is a specific recognition signal for ubiquitination. The oxidation of IRP2 is generated by haem, which binds to IRP2 in iron-rich cells, and by oxygen, indicating that the iron sensing of IRP2 depends on the synthesis and availability of haem.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Base Sequence / genetics
  • COS Cells
  • Cloning, Molecular
  • Eukaryotic Cells / enzymology*
  • Gene Expression Regulation, Enzymologic / genetics
  • Genetic Vectors
  • Heme / metabolism
  • Humans
  • Iron / metabolism*
  • Iron Regulatory Protein 2 / genetics
  • Iron Regulatory Protein 2 / metabolism*
  • Ligases / genetics
  • Ligases / isolation & purification*
  • Molecular Sequence Data
  • Mutation / genetics
  • Oxidation-Reduction
  • Transcription Factors
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases


  • Transcription Factors
  • Ubiquitin
  • Heme
  • Iron
  • RBCK1 protein, human
  • Ubiquitin-Protein Ligases
  • Iron Regulatory Protein 2
  • Ligases