Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.

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Abstract
Iron‐responsive elements (IREs) are regulatory RNA elements which are characterized by a phylogenetically defined sequence‐structure motif. Their biological function is to provide a specific binding site for the IRE‐binding protein (IRE‐BP). Iron starvation of cells induces high affinity binding of the cytoplasmic IRE‐BP to an IRE which has at least two different known biological consequences, repression of ferritin mRNA translation and stabilization of the transferrin receptor transcript. We report the identification of a novel, evolutionarily conserved IRE motif in the 5′ UTR of murine and human erythroid‐specific delta‐aminolevulinic acid synthase (eALAS) mRNA which encodes the first, and possibly rate limiting, enzyme of the heme biosynthetic pathway. We demonstrate the function of the eALAS IRE as a specific binding site for the IRE‐BP by gel retardation analyses and by in vitro translation experiments. In addition, we show that the 5′ UTR of eALAS mRNA is sufficient to mediate iron‐dependent translational regulation in vivo. These findings strongly suggest involvement of the IRE‐IRE‐BP system in the control of heme biosynthesis during erythroid differentiation.