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

Abstract

Hypoxia-inducible factor (HIF)-1α 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-1α. VDU2 can specifically deubiquitinate and stabilize HIF-1α and, therefore, increase expression of HIF-1α targeted genes, such as vascular endothelial growth factor (VEGF). These findings suggest that ubiquitination of HIF-1α is a dynamic process and that ubiquitinated HIF-1α might be rescued from degradation by VDU2 through deubiquitination. Although pVHL functions as a master control for HIF-1α stabilization, as pVHL-E3 ligase mediates the ubiquitination of both HIF-1α and VDU2, the balance between the pVHL-mediated ubiquitination and VDU2-mediated deubiquitination of HIF-1α provides another level of control for HIF-1α stabilization. ©2005 European Molecular Biology Organization.