REVIEW PAPER
The role of iron regulatory proteins in the control of iron metabolism in mammals

The iron regulatory proteins (IRP1 and IRP2) are two cytoplasmic RNA-binding proteins involved in the mechanisms

that control iron metabolism in mammalian cells. They modulate the expression of iron-related proteins

at a post-transcriptional level by binding to specific iron regulatory elements (IREs) on their mRNAs. IRP-IRE

interaction can block protein synthesis or stabilize the mRNA. At low intracellular iron concentration, IRPs bind

to the IRE of ferritin or ferroportin mRNAs and block their translation. Direct interactions between IRPs and

several IRE motifs stabilize transferrin receptor mRNA. The converse regulation of ferritin and TfR synthesis,

being a consequence of the lack of binding of IRPs to IRE, occurs in cells with high iron level. Thus, IRP-mediated

regulation rapidly restores the physiological level of iron during its deficiency as well as excess. The role of IRPs

in maintaining the intracelluar iron balance has been relatively well characterized in numerous types of mammalian

cells. However, the importance of IRPs in the regulation of systemic iron metabolism in mammals, particularly,

in signaling between the cells which play major roles in body iron metabolism, such as duodenal enterocytes,

reticuloendothelial macrophages, hepatocytes, and bone marrow precursors of red blood cells, is only beginning

to be investigated. Several studies have shown that IRP2 is a predominant regulator of iron homeostasis in

mice housed under standard conditions, thus limiting the impact of IRP1 on this metabolic pathway. Although

IRP1-deficient mice do not display a strong pathological phenotype, a deletion of both IRPs is embryonic lethal.

In addition, in vitro and in vivo studies have reported that nitric oxide (NO) and hydrogen peroxide (H2O2), which

are produced during inflammation, are potent IRP1 regulators that mediate the disassembly of Fe-S cluster of

IRP1. There is also an increasing evidence that NO and superoxide anion (O2) may induce a strong down-regulation

of IRP1 at the protein level and thus have an impact on the binding of IRP1 to IREs. All these data suggest

a predominant role of IRP1 in the regulation of iron homeostasis under specific physiopathological conditions.