IRP2

IRP2, or iron regulatory protein 2, is an RNA-binding protein that plays a central role in cellular iron homeostasis. It is part of the iron regulatory protein family and is encoded by the IREB2 gene. IRP2 binds to iron-responsive elements (IREs) located in the untranslated regions of specific mRNAs involved in iron metabolism, thereby modulating their stability and translation. The primary targets include transferrin receptor 1 (TFRC) and ferritin heavy (FTH1) and light (FTL) chains.

Mechanism and function: In conditions of low cellular iron, IRP2 binds to IREs. Binding to the 3' UTR of TFRC mRNA stabilizes the transcript, increasing transferrin receptor expression and promoting iron uptake. Binding to the 5' UTR of ferritin mRNAs inhibits their translation, reducing iron storage. When iron is abundant, IRP2 is ubiquitinated and degraded by the proteasome, a process mediated by the iron-sensing E3 ligase FBXL5, leading to decreased IRE binding. This regulatory cycle helps balance iron acquisition, storage, and utilization.

Relation to IRP1: IRP2 is closely related to IRP1, another regulator of IRE-containing mRNAs. IRP1 can function as a cytosolic aconitase when bound to an iron-sulfur cluster, whereas IRP2 does not have this enzymatic activity and is controlled mainly through iron-dependent degradation.

Physiology and clinical relevance: IRP2 is broadly expressed and essential for maintaining cellular iron homeostasis. In animal models, loss of IRP2 can cause iron misregulation and neurodegenerative phenotypes, underscoring its importance in neuronal iron balance. Dysregulation of IRP2 activity has been explored in research on iron-related disorders and neurodegeneration.