Combinatorial mRNA regulation: iron regulatory proteins and iso-iron-responsive elements (Iso-IREs).

Combinations of RNA elements (mRNA specific) with binding proteins give a wide range of responses to biological signals from iron, oxygen, NO, or growth factors. Combinatorial regulation of transcription to coordinate synthesis of groups of proteins is well known and is exemplified by steroid hormone-responsive genes (1). Combinatorial regulation of mRNA utilization to coordinate synthesis of groups of proteins is unique currently to iron and oxygen metabolism in animals (2–15) (see Fig. 1). The RNA elements are called iso-iron-responsive elements (iso-IREs), and the binding proteins, called iso-iron regulatory proteins (iso-IRPs), are aconitase homologues. Examples of iso-IRE mRNAs are ferritin to concentrate iron, TfR and DMT-1 for iron uptake, and ferroportin (Fpn1/IREG1/MTP1) for iron efflux. Several proteins for oxygen metabolism are also encoded in iso-IRE mRNAs, exemplified by aminolevulinate synthase (eALAS) in heme synthesis and mt-aconitase in the trichloroacetic acid cycle. Signals that control isoIRE/iso-IRP binding include iron, oxygen, hydrogen peroxide, NO, and activators of protein kinase C. When IRE regulation of mRNA function was last described in a Minireview (1990) only two IRE-mRNAs (ferritin and TfR) were known (2), in contrast to the many IRE mRNAs currently known. Iron was the only known signal, and knowledge of structure was limited to RNA sequence and secondary structure determined by prediction and enzymatic/chemical probes (2). Annotation of the literature in the intervening period is in Refs. 4–7. Now much is known about IRE tertiary structure (7). Multiple signaling pathways are known to converge on the IRE/IRP interaction (4, 6, 8–11). The combinatorial RNA/protein family and the effects of the RNA protein complex on protein synthesis are illustrated in Fig. 1. The result of the RNA-binding protein specificity, for the different iso-IRE-containing mRNAs, is quantitative differences in the expression of proteins that are finely tuned over a wide range. Such precise control over the synthesis of each of the proteins relates to the central role of the proteins in normal cell biology: iron trafficking, heme synthesis, and cellular ATP production. The flexibility of regulation using the IRE/IRP mRNA/protein interactions is illustrated by the liver where the same amount of iron induces ferritin synthesis up to 100-fold (2), but mitochondrial aconitase is only induced 2–3-fold (3); the difference likely relates to a narrow tolerance of cells to concentration changes in trichloroacetic acid cycle enzymes. Differences in the iso-IRE binding in each mRNA suggest a higher percentage of ferritin mRNA will be bound to IRPs than mt-aconitase mRNA (see Fig. 3), allowing quantitative variations in the response of protein synthesis to signals. An alternate mechanism for IRE/IRP control of protein synthesis is regulated mRNA turnover, illustrated by the TfR IRE.