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EMBO Rep. 2005 Apr;6(4):373-8.

VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.

Author information

1
Department of Urology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.

Abstract

Hypoxia-inducible factor (HIF)-1alpha is a short-lived protein and is ubiquitinated and degraded through the von Hippel-Lindau protein (pVHL)-E3 ubiquitin ligase pathway at normoxia. Deubiquitination, by reversing ubiquitination, has been recognized as an important regulatory step in ubiquitination-related processes. Here, we show that pVHL-interacting deubiquitinating enzyme 2, VDU2, but not VDU1, interacts with HIF-1alpha. VDU2 can specifically deubiquitinate and stabilize HIF-1alpha and, therefore, increase expression of HIF-1alpha targeted genes, such as vascular endothelial growth factor (VEGF). These findings suggest that ubiquitination of HIF-1alpha is a dynamic process and that ubiquitinated HIF-1alpha might be rescued from degradation by VDU2 through deubiquitination. Although pVHL functions as a master control for HIF-1alpha stabilization, as pVHL-E3 ligase mediates the ubiquitination of both HIF-1alpha and VDU2, the balance between the pVHL-mediated ubiquitination and VDU2-mediated deubiquitination of HIF-1alpha provides another level of control for HIF-1alpha stabilization.

PMID:
15776016
PMCID:
PMC1299287
DOI:
10.1038/sj.embor.7400377
[Indexed for MEDLINE]
Free PMC Article

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