RNA Structure and Function in Cellular Iron Homeostasis

Abstract

The expression of two proteins that participate in cellular iron homeostasis, ferritin and the transferrin receptor (TfR), are coordinately regulated at the posttranscriptional level by the intracellular iron (for background information on cellular iron metabolism, see Brock et al. 1994). When iron is abundant, synthesis of ferritin, the protein responsible for iron sequestration, increases, whereas expression of the TfR falls, resulting in less iron acquisition from the cell’s exterior. When the cell is deprived of iron, the opposite occurs—TfR synthesis increases and ferritin synthesis decreases.

The iron-dependent regulation of these two proteins is mediated by structurally related RNA elements found in their mRNAs (see Fig. 1) (Klausner et al. 1993; Harford et al. 1994; Theil 1994; Hentze and Kuhn 1996). These RNA elements, termed iron-responsive elements (IREs), are moderately stable stem-loop structures of approximately 30 nucleotides (see Fig. 2). In ferritin transcripts, a single IRE is found in the 5′-untranslated region (UTR), whereas in the TfR transcript, five IREs are found in the 3′ UTR.

The IREs of both transcripts interact with cytosolic IRE-binding proteins referred to as IRP1 and IRP2 (for iron regulatory proteins). The interaction(s) between IREs and IRPs is responsible for the posttranscriptional regulation of the expression of the genes encoding ferritin and the TfR (Fig. 1). In the case of ferritin regulation, the interaction of an IRP with the transcript inhibits protein synthesis through an inhibition of translation initiation. In the case of TfR regulation, interaction of one or more IRPs with IREs in the...