Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2.
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.
Yamanaka
Koji
K
Department of Molecular & System Biology, Graduate School of Biostudies, Kyoto University, Sakyo-Ku, Kyoto 606-8501, Japan.
Ishikawa
Haruto
H
Megumi
Yuzuru
Y
Tokunaga
Fuminori
F
Kanie
Masato
M
Rouault
Tracey A
TA
Morishima
Isao
I
Minato
Nagahiro
N
Ishimori
Koichiro
K
Iwai
Kazuhiro
K
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D003001:Cloning, Molecular; D005057:Eukaryotic Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005822:Genetic Vectors; D006418:Heme / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D008025:Ligases / Q000235:genetics / Q000302:isolation & purification*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D014157:Transcription Factors; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D014157:Transcription Factors; D025801:Ubiquitin; D006418:Heme; D007501:Iron; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases; D035942:Iron Regulatory Protein 2; D008025:Ligases