Messenger RNAs with 5′-untranslated region iron response elements (5′-UTR IRE-mRNAs)

Messenger RNAs (mRNAs) containing iron response elements (IREs) in their 5′-untranslated region (UTR) are essential regulators of cellular iron homeostasis (Hentze et al., 2004, Cell). These IREs are phylogenetically conserved stem-loop structures that interact with Iron Regulatory Proteins (IRP1 and IRP2) to control the translation of proteins such as ferritin, ferroportin, and erythroid 5-aminolevulinate synthase (Muckenthaler et al., 2008, Cell). Under low-iron conditions, IRPs bind to the 5′-UTR IRE, sterically blocking the assembly of the 43S pre-initiation complex and inhibiting translation (Gray & Hentze, 1994, EMBO J). Conversely, high iron levels lead to the dissociation of IRPs, allowing protein synthesis to proceed. Mutations in the 5′-UTR IRE of the L-ferritin gene cause hereditary hyperferritinemia-cataract syndrome (HHCS), characterized by excessive ferritin production (Cazzola et al., 1997, Blood). Furthermore, dysregulation of this pathway is implicated in neurodegenerative diseases like Alzheimer's and Parkinson's due to iron-induced oxidative stress (Belaidi & Bush, 2016, J Neurochem). Therapeutic targeting of these elements, such as with the small molecule Posiphen, aims to modulate the translation of specific mRNAs to restore iron balance or reduce toxic protein levels (Campion et al., 2023, Mol Neurobiol).

Other names

5′-IRE mRNAsIron-responsive element-containing mRNAsIRE-mRNAs5′-UTR IREsIron-responsive elements in the 5′-untranslated region

Modulation of protein translation through the steric hindrance of the 43S pre-initiation complex assembly by Iron Regulatory Proteins (IRPs) binding to the IRE hairpin structure (Gray & Hentze, 1994, EMBO J).