Iron-responsive element-binding protein 2 (IRP2) (IRP2)

Iron-responsive element-binding protein 2 (IRP2), encoded by the IREB2 gene, is a critical cytosolic RNA-binding protein that functions as the primary sensor and regulator of intracellular iron homeostasis in mammals (UniProt P48200; GeneCards). Unlike its paralog IRP1, IRP2 does not possess aconitase activity and is regulated primarily through iron-dependent proteasomal degradation mediated by the E3 ubiquitin ligase FBXL5 (Wikipedia; NIH). In iron-deficient conditions, IRP2 binds to iron-responsive elements (IREs) in the untranslated regions of target mRNAs, such as ferritin and transferrin receptor 1, to coordinate iron uptake, storage, and export (Frontiers in Pharmacology). This regulatory mechanism is essential for maintaining the labile iron pool required for mitochondrial function, DNA synthesis, and cell survival (NIH). Dysregulation of IRP2 is implicated in several pathologies, including various cancers where its overexpression supports the high iron demands of tumor cells and contributes to therapeutic resistance (NIH; ResearchGate). Conversely, loss of IRP2 function is associated with microcytic hypochromic anemia and progressive neurodegeneration, as seen in both murine models and rare human cases (NIH; OUP). Recent studies have explored IRP2 as a therapeutic target, identifying experimental small-molecule inhibitors like KS-20073 that can sensitize cancer cells to radiation by inducing mitochondrial dysfunction (NIH). Additionally, IRP2 has been linked to the pathogenesis of chronic obstructive pulmonary disease (COPD) and impaired immune responses in inflammatory bowel disease (NIH; ResearchGate).

Other names

IREB2ACO3Iron regulatory protein 2IRE-BP 2Iron-responsive element-binding protein 2

Binds to iron-responsive elements (IREs) in the untranslated regions (UTRs) of target mRNAs to regulate their translation or stability, thereby controlling cellular iron levels.