Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2017.101 Figure 1 Regulation of HIF and the canonical arm of the NF-κB pathway through PHDs and FIH Figure 1 | Regulation of HIF and the canonical arm of the NF-κB pathway through PHDs and FIH. a | Under normoxia, prolyl hydroxylases (PHDs) and factor inhibiting hypoxia-inducible factor (FIH) hydroxylate the hypoxia-inducible factor (HIF)1α and HIF2α subunits. Prolyl hydroxylation leads to proteasomal degradation of the HIFα subunits, whereas asparaginyl hydroxylation inhibits the interaction of HIFα with the co-activators cAMP-response element binding (CREB) binding protein (CBP) and histone acetyltransferase p300 (p300). During hypoxia, the enzymatic activity of PHDs and FIH is inhibited, leading to stabilization of HIFα subunits. After translocation to the nucleus, they complex with their β subunit, recruit p300 and CBP and bind to hypoxia responsive elements (HREs) in the promoters of target genes to initiate transcription. b | PHDs prevent the activation of nuclear factor-κB (NF-κB) through their interaction with and inactivation of IkB kinases (IKKs). PHD2 hydroxylates IKKβ, whereas PHD3 blocks the interactions between IKKβ and heat shock protein 90 (HSP90) and between IKKγ and cellular inhibitor of apoptosis (cIAP1), independent of its hydroxylase activity. PHD1 is also thought to hydroxylate IKKβ, yet this has not been confirmed. FIH has been shown to hydroxylate IκBα and the NF-κB p50 subunit precursor p105, but these reactions do not affect NF-κB activation. During hypoxia, IKKs phosphorylate the NF-κB inhibitor IκBα, which results in its ubiquitylation and subsequent proteasomal degradation. Dissociation of IκBα allows the nuclear translocation of the NF-κB heterodimer and the transcription of its target genes. OH, hydroxyl group. Van Welden, S. et al. (2017) Intestinal hypoxia and hypoxia-induced signalling as therapeutic targets for IBD Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2017.101