title: The pathway for IRP2 degradation involving 2-oxoglutarate-dependent oxygenase(s) does not require the E3 ubiquitin ligase activity of pVHL.
abstract: Iron regulatory protein 2 (IRP2), a posttranscriptional regulator of iron metabolism, is subjected to iron-dependent degradation by the proteasome. Recent experiments proposed a mechanism involving 2-oxoglutarate-dependent oxygenases. Enzymes of this class, such as prolyl-4-hydroxylases, mediate the oxygen and iron-dependent degradation of the hypoxia inducible factor HIF-1alpha, which requires the E3 ubiquitin ligase activity of pVHL. Considering that the pathways for IRP2 and HIF-1alpha degradation share remarkable similarities, we investigated whether pVHL may also be involved in the degradation of IRP2. We show here that IRP2 can interact with pVHL in co-transfection/co-immunoprecipitation assays. Furthermore, pVHL is able to promote the ubiquitination and the decay of transfected IRP2. However, the iron-dependent degradation of endogenous IRP2 is not impaired in VHL-deficient cell lines, suggesting that pVHL is not a necessary component of this pathway.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Kostas
authors.initials: K
authors.lastname: Pantopoulos
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007501:Iron / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
chemical_list: D007656:Ketoglutaric Acids; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D007501:Iron; D010105:Oxygenases; D011393:Procollagen-Proline Dioxygenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D035942:Iron Regulatory Protein 2; C497446:VHL protein, human; D010100:Oxygen