VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha.
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.
Pubmed ID: 15776016 RIS Download
Animals | COS Cells | Cercopithecus aethiops | Endopeptidases | Enzyme-Linked Immunosorbent Assay | Gene Expression Regulation | HeLa Cells | Humans | Hypoxia-Inducible Factor 1, alpha Subunit | Immunoblotting | Luciferases | Reverse Transcriptase Polymerase Chain Reaction | Transcription Factors | Tumor Suppressor Proteins | Ubiquitin Thiolesterase | Ubiquitin-Protein Ligases | Ubiquitins | Von Hippel-Lindau Tumor Suppressor Protein