Tight regulation of
iron metabolism is crucial to avoid formation of deleterious radicals and is mainly executed at the post-transcriptional level. The regulatory loops are exerted by trans-acting
iron regulatory proteins (IRPs) and cis-acting stem-loop motifs, termed
iron-responsive elements (IREs), located in the
untranslated regions (
UTRs) of target mRNAs.
Iron scarcity induces binding of IRPs to a single IRE in the 5'-UTR of
ferritin, eALAS,
aconitase and SDHb mRNAs, which specifically suppresses translation initiation. Simultaneous interaction of IRPs with multiple IREs in the 3'-UTR of
transferrin receptor (TfR)
mRNA selectively causes its stabilization. The pattern is reverted under
iron overload: IRP-
mRNA binding affinity is reduced, which results in efficient
protein synthesis of target transcripts harboring IREs in the 5'-UTR and rapid degradation of TfR
mRNA. Although multiple evidences support this model, several studies reported massive alterations in the regulation of
iron homeostasis under specific physiological conditions, raising the possibility for additional regulatory events. Intensive analysis of the palindromic IRE consensus sequence revealed the critical elements for the formation of a functional structure and demonstrated the consequences of IRE mutations in IRP binding. Recent investigations indicated the involvement of naturally occurring IRE mutations of the
ferritin L subunit in the
hyperferritinemia-cataract syndrome, a hereditary disorder. This review summarizes the apparent links between
iron-dependent post-transcriptional control and its abnormalities, governed by the properties of a single
mRNA stem-loop structure.