title: Iron regulatory protein 1 outcompetes iron regulatory protein 2 in regulating cellular iron homeostasis in response to nitric oxide.
abstract: In mammals, iron regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of genes involved in iron metabolism, including transferrin receptor 1, the ferritin (Ft) H and L subunits, and ferroportin by binding mRNA motifs called iron responsive elements (IREs). IRP1 is a bifunctional protein that mostly exists in a non-IRE-binding, [4Fe-4S] cluster aconitase form, whereas IRP2, which does not assemble an Fe-S cluster, spontaneously binds IREs. Although both IRPs fulfill a trans-regulatory function, only mice lacking IRP2 misregulate iron metabolism. NO stimulates the IRE-binding activity of IRP1 by targeting its Fe-S cluster. IRP2 has also been reported to sense NO, but the intrinsic function of IRP1 and IRP2 in NO-mediated regulation of cellular iron metabolism is controversial. In this study, we exposed bone marrow macrophages from Irp1(-/-) and Irp2(-/-) mice to NO and showed that the generated apo-IRP1 was entirely responsible for the posttranscriptional regulation of transferrin receptor 1, H-Ft, L-Ft, and ferroportin. The powerful action of NO on IRP1 also remedies the defects of iron storage found in IRP2-null bone marrow macrophages by efficiently reducing Ft overexpression. We also found that NO-dependent IRP1 activation, resulting in increased iron uptake and reduced iron sequestration and export, maintains enough intracellular iron to fuel the Fe-S cluster biosynthetic pathway for efficient restoration of the citric acid cycle aconitase in mitochondria. Thus, IRP1 is the dominant sensor and transducer of NO for posttranscriptional regulation of iron metabolism and participates in Fe-S cluster repair after exposure to NO.
authors.affiliation: Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzębiec, 05-552 Wólka Kosowska, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Styś
authors.forename: Bruno
authors.initials: B
authors.lastname: Galy
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Starzyński
authors.forename: Ewa
authors.initials: E
authors.lastname: Smuda
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Drapier
authors.forename: Pawel
authors.initials: P
authors.lastname: Lipiński
authors.forename: Cécile
authors.initials: C
authors.lastname: Bouton
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology*; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D045462:Endothelium-Dependent Relaxing Factors; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D009569:Nitric Oxide; D001052:Apoferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2