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

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.