Figure 1. Mechanism of HIF activity.

Under normoxic conditions, HIFα subunits are hydroxylated on proline residues. Hydroxylated prolines are recognised by the von Hippel-Lindau protein, ubiquinated by the E3 ubiquitin ligase, and targeted for proteosomal degradation. As oxygen levels fall, HIFα is stabilised and enters the nucleus to form a transcriptional complex with HIFβ subunits. FIH activity is maintained at lower oxygen levels than PHDs and remains active, hydroxylating asparagines. Hydroxylation of asparagines by FIH prevents association of the CBP/p300 coactivator complex with the HIFα/HIFβ transcriptional dimer. Under very low oxygen conditions, FIH becomes inactive and maximal HIF transcriptional activity is promoted.