Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O-2-regulated prolyl hydroxylation

Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a ce ntral role in the regulation of gene expression by oxygen. In oxygenated an d iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechani sm that involves ubiquitylation by the von Hippel-Lindau tumor suppressor ( pVHL) E3 Ligase complex. This process is suppressed by hypoxia and iron che lation, allowing transcriptional activation. Here we show that the interact ion between human pVHL and a specific domain of the HIF-1 alpha subunit is regulated through hydroxylation of a proline residue (HIF-1 alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests th at HIF-PH functions directly as a cellular oxygen sensor.