Dual regulation of HIF subunits by prolyl and asparaginyl hydroxylation

In the presence of oxygen, active hypoxia-inducible factor (HIF) hydroxylases (that is, prolyl hydroxylase domains, PHDs, and factor inhibiting HIF, FIH) downregulate and inactivate HIF1α subunits. PHDs hydroxylate a prolyl residue in the amino- and the carboxy-terminal oxygendependent degradation domains, which promotes von Hippel-Lindau-tumour-suppressor-dependent proteolysis and results in the destruction of HIF1α subunits. FIH, on the other hand, hydroxylates an asparaginyl residue in the carboxy-terminal activation domain, which blocks p300 co-activator recruitment and results in the inactivation of HIF1α-subunit transcriptional activity. In hypoxia, HIF hydroxylases are inactive and these processes are suppressed, which allows the formation of a transcriptionally active complex.