HIF activation by pH-dependent nucleolar sequestration of VHL

Karim Mekhail, Lakshman Gunaratnam, Marie Eve Bonicalzi, Stephen Lee

Research output: Contribution to journalArticlepeer-review

196 Scopus citations


Hypoxia and acidosis occur in a wide variety of physiological and pathological settings that include muscle stress, tumour development and ischaemic disorders. A central element in the adaptive response to cellular hypoxia is HIF (hypoxia-inducible factor), a transcription factor that activates an array of genes implicated in oxygen homeostasis, tumour vascularization and ischaemic preconditioning1. HIF is activated by hypoxia, but undergoes degradation by the VHL (von Hippel-Lindau) tumour suppressor protein in the presence of oxygen2,3. Here, we demonstrate that hypoxia induction or normoxic acidosis can neutralize the function of VHL by triggering its nucleolar sequestration, a regulatory mechanism of protein function that is observed rarely4-7. VHL is confined to nucleoli until neutral pH conditions are re-instated. Nucleolar sequestration of VHL enables HIF to evade destruction in the presence of oxygen and activate its target genes. Our findings suggest that an increase in hydrogen ions elicits a transient and reversible loss of VHL function by promoting its nucleolar sequestration.

Original languageEnglish (US)
Pages (from-to)642-647
Number of pages6
JournalNature Cell Biology
Issue number7
StatePublished - Jul 2004
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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