VHLprotein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1α

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