IRES

Iron-responsive elements (IREs) are short, conserved RNA stem-loop motifs found in the untranslated regions of several mRNAs involved in cellular iron metabolism. IREs are recognized by iron regulatory proteins (IRP1 and IRP2). In ferritin mRNA, an IRE is located in the 5' UTR; in transferrin receptor (TfR) mRNA, IREs are in the 3' UTR. The binding of IRPs to these elements couples iron availability to translation and mRNA stability, enabling rapid adjustments of iron storage and uptake without new transcription. The IRP/IRE regulatory system was characterized in the late 1980s by researchers including Marc Hentze.

Under low intracellular iron, IRPs bind to IREs. Binding to ferritin IREs in the 5' UTR blocks initiation of translation, reducing ferritin synthesis. Binding to TfR IREs stabilizes the mRNA, increasing TfR expression and iron uptake. When iron is abundant, IRP binding is reduced; ferritin translation proceeds to store iron, while TfR mRNA becomes less stable and is degraded.

Two IRPs, IRP1 and IRP2, mediate this regulation. IRP1 can switch between an RNA-binding form and a cytosolic aconitase depending on iron-sulfur cluster assembly. IRP2 is regulated mainly by iron-dependent degradation via the E3 ligase FBXL5; cellular iron sufficiency diminishes IRP2 levels. Together, IRPs provide a post-transcriptional iron-sensing circuit across tissues such as liver and brain.

IRE/IRP regulation maintains cellular iron homeostasis, and dysregulation is implicated in anemia, neurodegeneration, cancer, and iron-overload disorders. The system serves as a model of post-transcriptional control and a potential target for therapies that modulate iron metabolism.