Post-transcriptional control via iron-responsive elements: the impact of aberrations in hereditary disease

Tight regulation of iron metabolism is crucial to avoid formation of delete rious radicals and is mainly executed at the post-transcriptional level. Th e regulatory loops are exerted by trans-acting iron regulatory proteins (IR Ps) 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 initiat ion. Simultaneous interaction of IRPs with multiple IREs in the 3'-UTR of t ransferrin receptor (TfR) mRNA selectively causes its stabilization. The pa ttern is reverted under iron overload: IRP-mRNA binding affinity is reduced , which results in efficient protein synthesis of target transcripts harbor ing 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 conditi ons, raising the possibility for additional regulatory events. Intensive an alysis of the palindromic IRE consensus sequence revealed the critical elem ents for the formation of a functional structure and demonstrated the conse quences of IRE mutations in IRP binding, Recent investigations indicated th e involvement of naturally occurring IRE mutations of the ferritin L subuni t in the hyperferritinemia;cataract syndrome, a hereditary disorder. This r eview summarizes the apparent links between iron-dependent post-transcripti onal control and its abnormalities, governed by the properties of a: single mRNA stem-loop structure. (C) 1999 Elsevier Science B.V. All rights reserv ed.