Transcriptional and translational control of ALAS2 expression

The expression of ALAS2 is regulated at both the transcrip-tional and the translational level. Transcriptional control is effected through the programmed differentiation of the ery-throid lineage, mainly through the erythropoietin-induced transcription factors, which include GATA-1, EKLF and NF-E2. In contrast, as one of the few examples of control of gene expression at the translational level, ALAS2 is involved in the regulation of heme synthesis in relation to iron availability. Central to this regulatory mechanism is a protein called IRE-binding protein (IRE-BP), which requires four atoms of iron to function and is also able to bind to an mRNA motif, called iron-responsive element (IRE). IRE has a characteristic hairpin secondary structure, present within the 5' untranslated region of the ALAS2 mRNA. IRE-BP does not bind to the IRE when it is iron-replete, thus allowing the translation of the ALAS2 mRNA to proceed unimpeded. When iron is in scarce supply, the iron-depleted IRE-BP binds to IRE and translation of the ALAS2 mRNA is repressed, thus decreasing the synthesis of heme and consequently of mature hemoglobin and leading to the production of hypochromic red cells. Interestingly, IRE-BP can also bind to IREs present in the mRNAs of ferritin and transferrin receptor. In conditions of iron depletion, real or functional, the translational regulation is such that translation of ferritin mRNA is repressed whereas translation of the transferrin receptor is favored. Reverse effects are seen in iron-replete conditions.

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