Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species - PubMed (original) (raw)

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Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species

E S Hanson et al. Gene Expr. 1999.

Abstract

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are RNA binding proteins that posttranscriptionally regulate the expression of mRNAs coding for proteins involved in the maintenance of iron and energy homeostasis. The RNA binding activities of the IRPs are regulated by changes in cellular iron. Thus, the IRPs are considered iron sensors and the principle regulators of cellular iron homeostasis. The mechanisms governing iron regulation of the IRPs are well described. Recently, however, much attention has focused on the regulation of IRPs by reactive nitrogen and oxygen species (RNS, ROS). Here we focus on summarizing the iron-regulated RNA binding activities of the IRPs, as well as the recent findings of IRP regulation by RNS and ROS. The recent observations that changes in oxygen tension regulate both IRP1 and IRP2 RNA binding activities will be addressed in light of ROS regulation of the IRPs.

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Figures

FIG. 1

FIG. 1

Model for the regulation of IRP1 by iron, ROS, and RNS. IRP1 interconverts between a RNA binding form and a [4Fe-4S] c-aconitase form. Iron or hypoxia converts the apo-RNA binding form into the [4Fe-4S] aconitase form. NO•, H2O2, iron chelation, or reoxygenation (ReO2) results in the formation of the IRP1 RNA binding form. ONNO– results in the disassembly of the [4Fe-4S] cluster and oxidation of cysteines required for RNA binding. This results in the formation of an oxidized protein, lacking RNA binding and c-aconitase activities. Addition of reductants to oxidized IRP1 restores RNA binding activity.

FIG. 2

FIG. 2

Hypoxic regulation of IRP1 and IRP2 Hepa-1 cells. Mouse Hepa-1 clc4 were exposed to normoxia (N) or hypoxia (1% O2) for the indicated times. Bandshift analysis was performed by incubating cytosolic extracts (12 μg) with a 32P-labeled iron responsive element RNA probe. The RNA–protein complexes were resolved on a 5% nondenaturing polyacrylamide gel, and the gel was exposed to film. IRP1–RNA and IRP2–RNA complexes are indicated.

FIG. 3

FIG. 3

Model depicting oxygen regulation of IRP1. During normoxia IRP1 interconverts between its RNA binding form and its [4Fe-4S] c-aconitase form. This interconversion is dependent on the relative levels of iron and O2 •–. Hypoxia decreases RNA binding activity (see Fig. 2) and increases c-aconitase activity. The model suggests that hypoxic regulation of IRP1 could be due to increased iron and/or decreased cytosolic O2 •–, either of which would lead to stabilization of the [4Fe-4S] cluster at the expense of RNA binding activity. Reoxygenation (ReO2) activates IRP1 to a constitutively active RNA binding form. The dysregulated form of IRP1 (shaded) is refractory to iron downregulation. By adversely affecting iron levels, it is possible that this form of IRP1 may contribute to ReO2-induced oxidative damage.

FIG. 4

FIG. 4

Model for the oxygen regulation of IRP2. Normoxic degradation of IRP2 by the proteasome is dependent on the 73-amino acid degradation domain that contains three essential cysteines required to sense Fe2+ (hashed) (51). In this model, IRP2 stability is dependent on Fe2+ and H2O2, which are required for oxidative modification leading to ubiquitination (Ub) and proteasomal degradation (50). Hypoxia, iron chelation, and CoCl2 increase IRP2 protein levels by stabilization. Hypoxia may act through an unknown O2 sensor that lowers cytosolic H2O2 resulting in decreased IRP2 oxidation and degradation. CoCl2 mimics hypoxia by possibly altering the activity of an O2 sensor or by competing with iron at an iron binding site on the degradation domain.

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