HIF activation by pH-dependent nucleolar sequestration of VHL.
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 preconditioning. HIF is activated by hypoxia, but undergoes degradation by the VHL (von Hippel-Lindau) tumour suppressor protein in the presence of oxygen. 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 rarely. VHL is confined to nucleoli until neutral pH conditions are reinstated. 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.
Mekhail
Karim
K
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada.
Gunaratnam
Lakshman
L
Bonicalzi
Marie-Eve
ME
Lee
Stephen
S
D000138:Acidosis / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002451:Cell Compartmentation / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D002466:Cell Nucleolus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D049452:Green Fluorescent Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D010100:Oxygen