Figure 1.

Different levels of iron and oxygen promote the proteasomal degradation of key regulatory proteins of iron and oxygen metabolism.

Notes: When iron and oxygen are plentiful, PHD-dependent hydroxylation targets for proteasomal degradation HIF-α, whereas FBXL5 accumulates, binds, and targets to degradation of IRP2 and CITED2. Conversely, the lack of iron and/or oxygen leads to FBXL5 ubiquitination and degradation by the proteasome, thus allowing IRP2 to function as a regulator of iron homeostasis. HERC2 is responsible for the basal proteasomal degradation of FBXL5 at the steady state, but whether its activity is modulated by changes in iron and oxygen availability has not been defined (dotted arrows). Moreover, HERC2 induces iron-dependent proteasomal degradation of NCOA4, thus, preventing ferritin destruction in the autophagosome.

Abbreviations: HIF, hypoxia inducible factors; IRP, iron regulatory protein.