Targeting of HIF-α to the von Hippel-Lindau... : Science (original) (raw)

Research: Research Articles

Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2 -Regulated Prolyl Hydroxylation

• Panu Jaakkola
• David R. Mole
• Ya-Min Tian
• Michael I. Wilson
• Janine Gielbert
• Simon J. Gaskell
• Alexander von Kriegsheim
• Holger F. Hebestreit
• Mridul Mukherji
• Christopher J. Schofield
• Patrick H. Maxwell
• Christopher W. Pugh
• Peter J. Ratcliffe

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