Regulation of Mammalian Iron Homeostasis

Iron is an important cofactor for a number of proteins, but levels must be maintained in a delicate balance between too low, which causes illness, and too high, which causes toxic reactions.

Cellular iron homeostasis is maintained by a number of coordinatedly-regulated gene products that mediate iron uptake, release, utilization, and storage. Expression of these genes is chiefly regulated as a function of iron availability through the actions of Iron Regulatory Proteins (IRP) 1 and 2.

However, the underlying mechanisms that sense intracellular iron levels and regulate IRP2 were poorly understood. We discovered that a key regulatory complex, containing a protein called F-box/leucine-rich-repeat (FBXL5), directly targets IRP2 for degradation when cellular iron levels are high.

We also found that FBXL5 itself is regulated, accumulating only under conditions of high iron and oxygen, by means of a hemerythrin domain that acts as an iron- and oxygen-responsive regulatory switch. These observations demonstrated a direct mechanistic link between iron sensing and cellular responses that maintain mammalian iron homeostasis, and may provide new insights for the treatment of related human diseases.

IRP diagram
Model of how iron-dependent conformational changes within the hemerythrin domain mediate cellular iron homeostasis through regulation of FBXL5 stability with concomitant control of IRP2 degradation.