Iron regulatory protein–iron responsive element system (IRP-IRE system)

The iron regulatory protein–iron responsive element (IRP-IRE) system is a fundamental post-transcriptional mechanism that maintains cellular iron homeostasis by controlling the expression of proteins involved in iron uptake, storage, and export. It consists of two cytoplasmic RNA-binding proteins, IRP1 and IRP2, which interact with conserved stem-loop structures called IREs located in the untranslated regions (UTRs) of target mRNAs (Muckenthaler et al., 2017, Cell). When cellular iron levels are low, IRPs bind to IREs; binding in the 5' UTR sterically hinders the assembly of the translation initiation complex (e.g., for ferritin and amyloid precursor protein), while binding in the 3' UTR protects the mRNA from endonucleolytic cleavage (e.g., for transferrin receptor 1). This dual mechanism allows the cell to rapidly adjust to iron fluctuations without the need for de novo transcription. In neurodegenerative diseases, the IRP-IRE system is exploited as a therapeutic target to reduce the translation of neurotoxic proteins like amyloid precursor protein (APP) and alpha-synuclein, which contain IRE-like sequences in their 5' UTRs. Drugs such as buntanetap (Posiphen) are designed to stabilize these IRP-IRE interactions, thereby lowering the production of pathogenic aggregates in the brain (Chen et al., 2022, Journal of Alzheimer's Disease).

Other names

IRP/IRE systemIron-responsive element/iron regulatory protein systemIRE-IRP regulatory pathwayCellular iron homeostatic machinery

The system is targeted by modulating the binding affinity of iron regulatory proteins (IRP1 and IRP2) to iron-responsive elements (IREs) in the untranslated regions (UTRs) of target mRNAs. Small molecules like buntanetap enhance the IRP-IRE interaction at the 5' UTR of specific transcripts (e.g., APP, SNCA) to suppress their translation, while iron chelators or supplements indirectly shift the equilibrium of IRP binding to regulate iron-related protein expression (Wilkinson & Pantopoulos, 2014, Frontiers in Pharmacology).