HIF regulation by iron and oxygen levels. Under normoxic conditions, HIF-α is targeted for degradation by the VHL-containing E3 ubiquitin ligase complex. VHL recognizes HIF-α following hydroxylation of proline residues by Fe(II)- and 2-oxoglutarate-dependent dioxygenases (top). These enzymes use iron in their active sites (bottom) to activate molecular oxygen. Under conditions of low oxygen and/or iron, HIF-α cannot be hydroxylated and is spared from degradation.

Iron dependent regulation of the IRPs. In states of low iron, IRPs are capable of binding IREs in the 5′ or 3′ UTR in mRNAs of genes contributing to iron homeostasis. IRP-binding in turn blocks translation initiation or mRNA degradation, respectively. In states of high iron, IRP1 loses its IRE-binding activity following assembly of an iron sulfur cluster and conversion to a cytosolic aconitase. In contrast, IRP2 is polyubiquitinated and degraded by the proteasome under iron- and oxygen-replete conditions.

Model of FBXL5’s proposed role in cellular iron homeostasis. (A) In states of low iron bioavailability, FBXL5’s hemerythrin domain is likely destabilized, allowing for a putative E3 ubiquitin ligase to recognize a degron and promote FBXL5’s degradation. Limiting levels of FBXL5 result in IRP2 stabilization and binding to IREs. In contrast, when iron bioavailability increases, FBXL5’s hemerythrin domain forms a stable alpha helical bundle by directly binding iron and oxygen. In this state, FBXL5 is able to mask its degron and assemble into a SCF complex that promotes the polyubiquitination and degradation of IRP2. (B) Model of hemerythrin iron- and oxygen-binding site. Imidazole and carboxylate residues from conserved amino acid side chains bind a diiron center connected by a bridging oxygen atom (μ-oxo). Oxygen can be reversibly bound onto the penta-coordinate iron and forms a peroxo radical species that is stabilized by protonation and coordination to the bridging oxygen atom.

Cross-talk between pathways mediating iron and oxygen homeostasis. At the cellular level, both iron and oxygen are sensed by dioxygenases and hemerythrin to regulate HIF-α and IRP2 stability, respectively. In addition, the HIF and IRP pathways are intertwined at the level of target gene expression, as the HIF-2α 5′ UTR contains an IRE, while both HIF and IRPs mediate expression of genes involved in cellular and systemic iron homeostasis.