Figure 5

New roles for FIH in the regulation of the HIF response. (A) The HIF-α protein contains two independent transcriptional activation domain (N-TAD and C-TAD), the N-TAD overlaps with the CODDD. PHD enzymes hydroxylate the prolyl residue present in the N-TAD, while FIH hydroxylates the asparaginyl residue in the C-TAD. In high oxygen concentration, both PHD and FIH are active, resulting in no HIF-regulated genes activated. As the oxygen tension decreases, PHD is inactivated, resulting in expression of N-TAD-sensitive genes. In strong hypoxia, both PHD and FIH are inactivated, resulting in expression of N-TAD and C-TAD-sensitive genes[29]. (B) FIH can hydroxylate either ARD or HIF-α proteins. Sequestration of FIH by ARD inhibits HIF asparaginyl hydroxylation[27]. (C) HIF-α can be degraded via either PHD-dependent or -independent pathways. FIH hydroxylation of HIF is proposed to protect HIF degradation via the PHD-independent pathway[31].