21 Translational Control of Ferritin Synthesis

Abstract

REGULATION OF IRON HOMEOSTASIS
Iron is an important nutrient in mammalian cells, and the processes of uptake and sequestration of iron are highly regulated to ensure that supplies are adequate and toxicity is controlled. A major mediator of iron uptake is the transferrin receptor, a plasma membrane protein that binds serum diferric transferrin at the cell surface. Upon transferrin binding, the transferrin receptor– diferric transferrin complex is internalized in endosomes; within endosomes, iron is released from transferrin and transported into the cytosol and other compartments of the cell such as the mitochondria. When iron levels in the cell are high, toxic products generated by the reaction of iron with oxygen species can oxidize and damage cellular proteins, lipids, and nucleic acids (Halliwell and Gutteridge 1992). To protect against iron toxicity, cells synthesize ferritin, a 24-subunit spherical protein that sequesters as many as 4,500 iron atoms within precipitates in its interior (Theil 1987). Although ferritin serves a useful purpose in cells with high cytosolic iron levels, excess production of ferritin can be deleterious in iron-depleted cells because it may compete with other proteins for the limited amounts of available iron (Picard et al. 1998). Translational regulation of ferritin expression is the mechanism utilized by mammalian cells to ensure that ferritin is expressed primarily when it is needed for sequestration of excess iron (Fig. 1). Binding of cytosolic iron-sensing proteins known as iron regulatory proteins (IRPs) to a conserved RNA stem-loop element in the ferritin transcript interferes with ferritin translation in iron-depleted...