title: Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis.
abstract: The two iron regulatory proteins IRP1 and IRP2 bind to transcripts of ferritin, transferrin receptor and other target genes to control the expression of iron metabolism proteins at the post-transcriptional level. Here we compare the effects of genetic ablation of IRP1 to IRP2 in mice. IRP1-/- mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2-/- mice misregulate the expression of target proteins in all tissues. Surprisingly, the RNA-binding activity of IRP1 does not increase in animals on a low-iron diet that is sufficient to activate IRP2. In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein. Our findings indicate that the small RNA-binding fraction of IRP1, which is insensitive to cellular iron status, contributes to basal mammalian iron homeostasis, whereas IRP2 is sensitive to iron status and can compensate for the loss of IRP1 by increasing its binding activity. Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals.
authors.affiliation: Cell Biology and Metabolism Branch, NIHCD, Bethesda, MD, USA.
authors.forename: Esther G
authors.initials: EG
authors.lastname: Meyron-Holtz
authors.forename: Manik C
authors.initials: MC
authors.lastname: Ghosh
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.forename: Timothy
authors.initials: T
authors.lastname: LaVaute
authors.forename: Xavier
authors.initials: X
authors.lastname: Brazzolotto
authors.forename: Urs V
authors.initials: UV
authors.lastname: Berger
authors.forename: William
authors.initials: W
authors.lastname: Land
authors.forename: Hayden
authors.initials: H
authors.lastname: Ollivierre-Wilson
authors.forename: Alex
authors.initials: A
authors.lastname: Grinberg
authors.forename: Paul
authors.initials: P
authors.lastname: Love
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
mesh_terms: D000818:Animals; D002458:Cell Fractionation; D002531:Cerebellum / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism; D018390:Gene Targeting; D006706:Homeostasis; D017403:In Situ Hybridization; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000502:physiology*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements; D013154:Spleen / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2