From the Guidelines
The Iron Response Element Binding Protein (IRP) functions as a critical regulator of cellular iron homeostasis by binding to iron-responsive elements (IRE) in regulated messenger RNAs (mRNA) of cellular iron importers, exporters, and storage genes, thereby determining the size of the labile iron pool (LIP) 1. The IRP system, involving two IRPs (IRP1 and IRP2), plays a crucial role in maintaining cellular iron homeostasis by regulating the translation of key genes involved in iron metabolism, including transferrin receptor 1 (TfR1), ferroportin, and ferritin 1. Key aspects of IRP function include:
- Stimulating the translation of TfR1 mRNA and inhibiting the translation of ferroportin and ferritin mRNA under conditions of cellular iron starvation, thereby facilitating cellular iron uptake and preventing iron storage and export 1
- Inhibiting further iron uptake and stimulating iron storage and export when cellular iron levels are adequate 1 The IRP system works in conjunction with other regulatory mechanisms, such as the hepcidin-ferroportin axis and the hypoxia-inducible factor (HIF) system, to maintain systemic and cellular iron homeostasis 1. Overall, the IRP system is essential for maintaining appropriate iron levels in cells, preventing both iron deficiency and toxicity, and ensuring proper iron utilization and storage.
From the Research
Function of Iron Response Element Binding Protein (IRP)
The Iron Response Element Binding Protein (IRP) plays a crucial role in regulating iron metabolism in cells. The main function of IRP is to bind to iron-responsive elements (IREs) in the untranslated regions of target mRNAs, thereby controlling mRNA translation or stability 2, 3.
Regulation of IRP Binding
IRP binding to IRE is regulated by cellular iron levels. When cells are deprived of iron, IRP binds to IRE, and if IRE is located at the 5'UTR, IRP binding inhibits translation initiation. In contrast, if IRE is located at the 3'UTR, IRP binding stabilizes mRNA and prevents it from degradation 2.
Physiological Functions of IRP
IRP1 and IRP2 have distinct physiological functions, with IRP1 emerging as a key regulator of erythropoiesis and iron absorption, and IRP2 dominating the control of iron uptake and heme biosynthesis in erythroid progenitor cells 4.
Collaboration with Other Proteins
IRP1 collaborates with other proteins, such as FBXL5, to maintain cellular iron homeostasis. FBXL5 targets IRP1 and IRP2 for degradation, and its expression is induced when the cytosolic iron-sulfur cluster assembly (CIA) system is impaired 5.
Importance of IRP in Cell Growth
The IRP/IRE system is essential for cell growth, and disruption of this system can lead to impaired cell viability. Iron supplementation can reverse this growth defect, and phosphorylation of IRP1 at Ser-138 is required for iron rescue 5.
Key Features of IREs
IREs are characterized by a specific RNA sequence and structure, with a highly conserved stem-loop structure. Currently available programs to predict IREs have limitations, but improved software tools, such as SIREs, can predict IREs with higher sensitivity and accuracy 6.
- IRP binds to IREs in target mRNAs to regulate iron metabolism
- IRP binding is regulated by cellular iron levels
- IRP1 and IRP2 have distinct physiological functions
- IRP1 collaborates with FBXL5 to maintain cellular iron homeostasis
- The IRP/IRE system is essential for cell growth and viability 2, 3, 4, 5, 6