Frost, Julianty 
ORCID: 0000-0001-8209-2575, Rocha, Sonia and Ciulli, Alessio
(2021)
Von Hippel-Lindau (VHL) small-molecule inhibitor binding increases stability and intracellular levels of VHL protein.
JOURNAL OF BIOLOGICAL CHEMISTRY, 297 (2).
100910-.
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Von Hippel-Lindau (VHL) small-molecule inhibitor binding increases stability and intracellular levels of VHL protein.pdf - Published version Download (1MB) | Preview |
Abstract
Von Hippel-Lindau (VHL) disease is characterized by frequent mutation of VHL protein, a tumor suppressor that functions as the substrate recognition subunit of a Cullin2 RING E3 ligase complex (CRL2<sup>VHL</sup>). CRL2<sup>VHL</sup> plays important roles in oxygen sensing by targeting hypoxia-inducible factor-alpha (HIF-α) subunits for ubiquitination and degradation. VHL is also commonly hijacked by bifunctional molecules such as proteolysis-targeting chimeras to induce degradation of target molecules. We previously reported the design and characterization of VHL inhibitors VH032 and VH298 that block the VHL:HIF-α interaction, activate the HIF transcription factor, and induce a hypoxic response, which can be beneficial to treat anemia and mitochondrial diseases. How these compounds affect the global cellular proteome remains unknown. Here, we use unbiased quantitative MS to identify the proteomic changes elicited by the VHL inhibitor compared with hypoxia or the broad-spectrum prolyl-hydroxylase domain enzyme inhibitor IOX2. Our results demonstrate that VHL inhibitors selectively activate the HIF response similar to the changes induced in hypoxia and IOX2 treatment. Interestingly, VHL inhibitors were found to specifically upregulate VHL itself. Our analysis revealed that this occurs via protein stabilization of VHL isoforms and not via changes in transcript levels. Increased VHL levels upon VH298 treatment resulted in turn in reduced levels of HIF-1α protein. This work demonstrates the specificity of VHL inhibitors and reveals different antagonistic effects upon their acute versus prolonged treatment in cells. These findings suggest that therapeutic use of VHL inhibitors may not produce overt side effects from HIF stabilization as previously thought.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cell Line, Humans, Cyclopropanes, Pyrrolidines, Thiazoles, Enzyme Inhibitors, Proteomics, Protein Binding, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, von Hippel-Lindau Disease, Protein Stability, Hypoxia |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 19 Aug 2021 07:24 |
| Last Modified: | 18 Jan 2023 21:33 |
| DOI: | 10.1016/j.jbc.2021.100910 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3133943 |
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