Affinage

VHL

von Hippel-Lindau disease tumor suppressor · UniProt P40337

Length
213 aa
Mass
24.2 kDa
Annotated
2026-06-11
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

pVHL is the oxygen-sensitive substrate-recognition subunit of a Cullin2–Elongin B/C–RING E3 ubiquitin ligase that couples oxygen and metabolic status to targeted protein degradation (PMID:11292862, PMID:24145437). Its canonical role is to bind HIFα only when a conserved proline is hydroxylated in an O2- and Fe2+-dependent manner, directing HIFα for proteasomal destruction; loss of this recognition drives constitutive HIF activity that remodels enhancer landscapes via HIF2α–HIF1β/p300 recruitment, suppresses E-cadherin, and induces a HEF1/Aurora kinase A axis promoting cilium loss (PMID:11292862, PMID:28893800, PMID:16585181, PMID:20864688). Substrate scope extends beyond HIFα to additional proline-hydroxylated and other targets, including TBK1-Pro48-OH (restraining p62/SQSTM1 phosphorylation), Beclin1-Pro54-OH (whose binding blocks VPS34–ATG14L assembly to suppress autophagy initiation), RAPTOR (inhibiting mTORC1, conserved in C. elegans), and STING (PMID:31810986, PMID:38360997, PMID:34290272, PMID:37183204). HIFα recognition is governed by an extensive regulatory layer: deubiquitination by VDU2, competing binders that occlude the substrate interface (ID2 displacing Cullin2, iASPP binding the β domain, DJ-1, RSUME), and HIF-1α lactylation that sterically blocks VHL contact (PMID:15776016, PMID:26735018, PMID:35169254, PMID:24899725, PMID:25500545, PMID:40760493). pVHL abundance and localization are themselves controlled by post-translational modification—SUMOylation at K171 stabilizes and nuclearizes it while ubiquitylation at K171/K196 (including K11 linkages added by UBE2S and degradation driven by Daam2 or viral BC-box proteins) destabilizes it (PMID:20844582, PMID:38915206, PMID:29053101, PMID:24145437). pVHL also performs HIF-independent functions: it localizes to the mitotic spindle to maintain spindle orientation, Mad2-dependent checkpoint fidelity, and chromosomal stability (PMID:19620968, PMID:24362914); undergoes SOCS1-driven K63-ubiquitylation and nuclear redistribution to support homologous recombination repair (PMID:23455319); and elevates CHCHD4 and respiratory chain subunits to sustain mitochondrial respiration (PMID:30338240). In renal epithelium, VHL loss causes replication stress whose rescue by concomitant PBRM1 loss yields fully penetrant clear-cell renal carcinoma, and saturation editing of the coding sequence has resolved pathogenic alleles—some acting through mRNA dosage rather than protein dysfunction (PMID:29229903, PMID:38969834). The HIFα-binding pocket is structurally tractable and exploitable for molecular-glue degraders that recruit neosubstrates such as CDO1 (PMID:40555806).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2001 High

    Established how pVHL achieves oxygen-sensitive substrate selection, answering how cells couple O2 availability to HIFα degradation.

    Evidence Peptide-binding and ubiquitination assays comparing hydroxylated vs. non-hydroxylated HIF peptides

    PMID:11292862

    Open questions at the time
    • Did not enumerate non-HIF substrates
    • Structural basis of the ligase assembly not resolved here
  2. 2009 High

    Revealed a HIF-independent role for pVHL in mitosis, addressing how VHL loss promotes chromosomal instability beyond hypoxia signaling.

    Evidence Spindle immunofluorescence, WT vs. disease-mutant rescue, and Mad2 epistasis in mammalian cells

    PMID:19620968

    Open questions at the time
    • Molecular mechanism of spindle/microtubule stabilization by pVHL undefined
    • How Mad2 levels are controlled by pVHL not established
  3. 2013 High

    Confirmed in vivo that VHL maintains spindle orientation and checkpoint fidelity and that its loss seeds renal carcinoma precursors, extending the in vitro mitotic findings to tissue.

    Evidence Conditional Vhl-knockout mice with ischemic injury, spindle/FISH and histopathology readouts

    PMID:24362914

    Open questions at the time
    • Causal link between aneuploidy and tumor initiation not isolated
    • Does not define the molecular spindle substrate
  4. 2013 Medium

    Defined a regulated nuclear function of VHL in DNA repair, showing how DNA breaks redirect VHL to support homologous recombination.

    Evidence SOCS1-mediated K63-ubiquitylation, nuclear fractionation, and HR repair assays

    PMID:23455319

    Open questions at the time
    • Nuclear substrate(s) of redistributed VHL unidentified
    • Single-lab finding
  5. 2013 High

    Showed VHL loss imposes replication stress that requires a second hit to permit tumor growth, explaining the genetic cooperation underlying ccRCC.

    Evidence γH2AX/replication-stress assays and combined Vhl/Pbrm1 conditional mouse knockouts

    PMID:29229903

    Open questions at the time
    • Mechanism linking VHL loss to replication stress not fully resolved
    • Whether stress is HIF-dependent unclear
  6. 2006 Medium

    Connected VHL loss to epithelial dedifferentiation by demonstrating HIF-mediated E-cadherin suppression.

    Evidence VHL re-expression in RCC lines with HIF epistasis and E-cadherin readouts

    PMID:16585181

    Open questions at the time
    • Direct HIF target mediating repression not pinned down
    • Single-lab finding
  7. 2005 Medium

    Identified deubiquitination as a counter-regulatory mechanism opposing pVHL, showing HIF-1α stability is set by a ubiquitination/deubiquitination balance.

    Evidence VDU2–HIF-1α Co-IP, in vivo deubiquitination, and VEGF reporter assays

    PMID:15776016

    Open questions at the time
    • No reconstitution of the opposing enzymatic cycle
    • Single-lab finding
  8. 2010 Medium

    Established post-translational control of pVHL itself, showing SUMOylation vs. ubiquitylation at K171/K196 dictate VHL stability and localization.

    Evidence SUMO/ubiquitin fusion constructs, fractionation, and HIFα reporter assays

    PMID:20844582

    Open questions at the time
    • Physiological triggers of K171 SUMOylation unclear
    • Single-lab finding
  9. 2010 Medium

    Defined how VHL loss drives cilium loss and motility through a HIF-induced Aurora A/HEF1 axis.

    Evidence Knockdown/overexpression in VHL-defective cells with ciliation and motility assays

    PMID:20864688

    Open questions at the time
    • Relative HIF-1 vs HIF-2 contribution not separated
    • Single-lab finding
  10. 2013 Medium

    Distinguished folding instability from catalytic loss for missense pVHL, showing chaperone-targeting drugs can restore mutant function.

    Evidence In vitro E3 ligase assays, chaperone-interaction studies, and HDAC-inhibitor rescue with xenografts

    PMID:23318261

    Open questions at the time
    • Generality across the missense mutant spectrum untested
    • Single-lab finding
  11. 2013 Medium

    Showed viral BC-box proteins hijack the Elongin B/C interface to degrade VHL, defining a competition-based route to HIF stabilization.

    Evidence Co-IP, proteasome rescue, and BC-box domain mapping with HIF reporters

    PMID:24145437

    Open questions at the time
    • Endogenous BC-box competitors not comprehensively mapped
    • Single-lab finding
  12. 2014 Medium

    Identified DJ-1 as a binder that blocks the HIF–VHL interaction, linking VHL regulation to oxidative-stress neuroprotection.

    Evidence DJ-1–VHL Co-IP, HIF-1α ubiquitination/stability, and neuroprotection assays

    PMID:24899725

    Open questions at the time
    • Binding interface on VHL not mapped
    • Single-lab finding
  13. 2014 Medium

    Established RSUME as a SUMO-dependent inhibitor of ECV complex assembly required for type-2 mutant loss-of-function.

    Evidence Co-IP, SUMOylation and ECV assembly assays, HIF ubiquitination, and xenografts

    PMID:25500545

    Open questions at the time
    • Which SUMO sites mediate the effect not fully defined
    • Single-lab finding
  14. 2016 High

    Defined a phospho-regulated competitor (ID2) that displaces Cullin2 from VHL, showing kinase signaling tunes HIF2α degradation.

    Evidence ID2–VHL Co-IP, HIF2α ubiquitination, DYRK1A/B kinase assays, Thr27 mutagenesis, and glioma xenografts

    PMID:26735018

    Open questions at the time
    • Selectivity for HIF2α over HIF1α not fully explained
    • In vivo prevalence of ID2 competition across tumors unknown
  15. 2017 Medium

    Showed VHL loss reprograms the enhancer landscape via stabilized HIF2α–HIF1β and p300 recruitment, linking VHL to chromatin-level gene deregulation in ccRCC.

    Evidence ChIP-seq for histone marks, HIF2α, and p300 across primary tumors and cell lines

    PMID:28893800

    Open questions at the time
    • Causal contribution of individual enhancers to tumorigenesis untested
    • Single-lab finding
  16. 2017 Medium

    Identified Daam2 as a non-mutational driver of VHL degradation in glioma.

    Evidence Daam2–VHL Co-IP, ubiquitination, stability, and tumor growth assays

    PMID:29053101

    Open questions at the time
    • E3 ligase mediating Daam2-driven VHL ubiquitination not defined here
    • Single-lab finding
  17. 2018 Medium

    Defined a HIF-independent role for pVHL in sustaining mitochondrial respiration via CHCHD4.

    Evidence VHL re-expression and HIF-2α knockdown with OCR and respiratory-subunit measurements

    PMID:30338240

    Open questions at the time
    • Mechanism by which pVHL elevates CHCHD4 unresolved
    • Single-lab finding
  18. 2019 Medium

    Extended VHL substrate logic to TBK1 via Pro48 hydroxylation, showing VHL loss hyperactivates TBK1 to stabilize p62 and drive proliferation.

    Evidence VHL–TBK1 Co-IP, hydroxylation/phosphorylation assays, and xenografts

    PMID:31810986

    Open questions at the time
    • Whether TBK1 is ubiquitinated/degraded by VHL or only sequestered unclear
    • Single-lab finding
  19. 2020 High

    Placed VHL in a developmental Daam2–VHL–Nedd4 axis controlling oligodendrocyte differentiation and myelination, with Nedd4 stabilizing VHL via K63 ubiquitination.

    Evidence Proteomics, Co-IP, conditional KO mice, K63 ubiquitination assays, and human MS lesion analysis

    PMID:32792353

    Open questions at the time
    • Downstream VHL substrate in oligodendrocytes not defined
    • How the axis integrates with HIF signaling unclear
  20. 2021 Medium

    Identified RAPTOR as a VHL substrate, linking VHL to mTORC1 restraint with cross-species conservation.

    Evidence VHL–RAPTOR Co-IP, ubiquitination, mTORC1 activity assays, and C. elegans vhl-1 genetics

    PMID:34290272

    Open questions at the time
    • Whether RAPTOR recognition requires hydroxylation not established
    • Single-lab finding
  21. 2021 Medium

    Revealed a negative feedback in which VHL–HIFα interface inhibitors paradoxically stabilize VHL protein.

    Evidence Quantitative MS proteomics and cycloheximide-chase stability assays after VH298 treatment

    PMID:34174286

    Open questions at the time
    • Mechanism coupling substrate engagement to VHL turnover not resolved
    • Single-lab finding
  22. 2022 Medium

    Established STING as a VHL E3 substrate and demonstrated VHL-recruiting PROTAC degradation depending on STING trafficking.

    Evidence PROTAC degradation, ER-retention mutagenesis, Co-IP, and innate immune signaling assays

    PMID:37183204

    Open questions at the time
    • Whether STING recognition is hydroxylation-dependent not defined
    • Single-lab finding
  23. 2022 Medium

    Identified iASPP as a β-domain competitor that blocks HIF-1α degradation even in VHL-wild-type tumors.

    Evidence iASPP–VHL Co-IP, β-domain mapping, ubiquitination competition, and xenografts

    PMID:35169254

    Open questions at the time
    • Regulation of iASPP–VHL binding in normoxia unclear
    • Single-lab finding
  24. 2024 High

    Defined the autophagy-suppressing function of VHL through binding hydroxylated Beclin1 to block VPS34–ATG14L assembly.

    Evidence VHL–Beclin1 Co-IP, PHD1 hydroxylation, Pro54 mutagenesis, VPS34 pull-down, and autophagy flux assays

    PMID:38360997

    Open questions at the time
    • Whether Beclin1 is also ubiquitinated/degraded vs. only sequestered not fully addressed
    • In vivo autophagy consequences in VHL-disease tissue not characterized
  25. 2024 Medium

    Showed metabolite-driven lactylation of HIF-1α sterically blocks VHL binding without affecting prolyl hydroxylation, defining a metabolism-coupled escape from degradation.

    Evidence MS lactylation mapping, mutagenesis, K48 ubiquitination, VHL Co-IP, and ChIP

    PMID:40760493

    Open questions at the time
    • Enzymes catalyzing/removing HIF-1α lactylation not defined here
    • Single-lab finding
  26. 2024 Medium

    Showed UBE2S adds K11-linked polyubiquitin to VHL K171/K196 independently of an E3, degrading VHL and indirectly stabilizing HIF-1α in HCC.

    Evidence Co-IP, K11-specific ubiquitination, VHL stability, and glycolysis assays

    PMID:38915206

    Open questions at the time
    • How an E2 acts E3-independently on VHL mechanistically unresolved
    • Single-lab finding
  27. 2024 High

    Built a comprehensive functional variant map distinguishing ccRCC- from pheochromocytoma-associated alleles and revealing mRNA-dosage mechanisms of pathogenicity.

    Evidence Saturation genome editing of 2,268 variants with functional selection and mRNA quantification

    PMID:38969834

    Open questions at the time
    • Mechanistic basis of phenotype-specific allele effects not fully explained
    • Functional scores derived in selected cell systems
  28. 2025 High

    Demonstrated the HIF1α-binding pocket on pVHL can be redirected by a molecular-glue degrader to recruit and degrade neosubstrates such as CDO1, providing a structural basis for VHL-based degraders.

    Evidence Protein array screening, docking/MD, X-ray crystallography of the ternary VHL–CDO1–degrader complex, and cellular degradation

    PMID:40555806

    Open questions at the time
    • Generalizability to other neosubstrates not established
    • In vivo efficacy not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how the many competing substrates and regulators of pVHL are prioritized in vivo and whether non-HIF substrates require proline hydroxylation as a universal recognition rule.
  • No unifying model integrating spindle, repair, mitochondrial, and ligase functions
  • Substrate recognition determinants beyond hydroxyproline not generalized
  • Tissue-specific substrate hierarchy unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2 R-HSA-73894 DNA Repair 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953897 Cellular responses to stimuli 1 R-HSA-9612973 Autophagy 1
Partners
BECN1CUL2DAAM2ELOBELOCHIF1AID2TBK1
Complex memberships
CRL2VHL (pVHL–Elongin B/C–Cullin2–RING E3 ligase)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 pVHL binds to a short HIF-derived peptide only when a conserved proline residue is hydroxylated; proline hydroxylation requires molecular oxygen and Fe2+, establishing pVHL as the oxygen-sensitive substrate-recognition component of an E3 ubiquitin ligase that targets HIFα for proteasomal destruction. Peptide-binding assay with hydroxylated vs. non-hydroxylated HIF-derived peptides; functional ubiquitination assay Science High 11292862
2009 pVHL localizes to the mitotic spindle in mammalian cells; its functional inactivation causes spindle misorientation via unstable astral microtubules, reduced Mad2 levels leading to spindle checkpoint weakening, and chromosomal instability. Restoration of wild-type pVHL (but not microtubule-stabilization-defective VHL disease mutants) rescued spindle misorientation. Immunofluorescence localization to mitotic spindle; VHL re-expression rescue experiments; Mad2 knockdown/overexpression epistasis; analysis of VHL disease mutants; aneuploidy scoring in human renal cancer Nature Cell Biology High 19620968
2005 VHL-interacting deubiquitinating enzyme 2 (VDU2), but not VDU1, interacts with HIF-1α and specifically deubiquitinates and stabilizes it, counteracting pVHL-mediated ubiquitination, thereby increasing HIF-1α target gene expression (e.g., VEGF). Co-immunoprecipitation (VDU2–HIF-1α interaction); in vivo deubiquitination assay; reporter gene assays for VEGF expression EMBO Reports Medium 15776016
2006 pVHL directly associates with and positively regulates tumor suppressor p53 by inhibiting Mdm2-mediated ubiquitination of p53 and by recruiting p53-modifying enzymes; VHL-deleted RCC cells show attenuated DNA-damage response that is restored by pVHL re-expression. Co-immunoprecipitation (pVHL–p53 interaction); ubiquitination assays; cell-cycle and apoptosis assays in VHL-null vs. pVHL-restored RCC cells Cell Cycle Medium 16969113
2006 VHL inactivation suppresses E-cadherin expression through HIF activation; HIF activation is both necessary and sufficient to suppress E-cadherin in renal cancer cells, and VHL re-expression in VHL-defective RCC lines restores E-cadherin. VHL re-expression in RCC4 and RCC10 cell lines; HIF activation experiments; E-cadherin expression assays by western blot/immunostaining Cancer Research Medium 16585181
2010 VHL inactivation induces HEF1/NEDD9 and Aurora kinase A via HIF-1 and HIF-2 stabilization; Aurora kinase A promotes primary cilium regression via HDAC-dependent tubulin depolymerization, and HEF1 at the centrosome enhances this effect. Suppression of this pathway improved primary cilium formation and reduced cell motility in VHL-defective cells. Gene expression analysis; knockdown/overexpression experiments in VHL-defective renal cancer cells; cilium formation assays; cell motility assays Journal of the American Society of Nephrology Medium 20864688
2013 SOCS1 promotes K63-ubiquitylation of VHL in response to DNA double-strand breaks (DSBs), causing nuclear redistribution of VHL; loss of VHL or VHL mutations that compromise K63-ubiquitylation attenuates homologous recombination repair and increases persistence of DSBs. Co-immunoprecipitation; ubiquitination assays (K63-specific); DNA damage assays (γH2AX foci, comet assay); nuclear fractionation; HR repair assay Oncogene Medium 23455319
2010 VHL undergoes ubiquitylation at lysine residues 171 and 196, which destabilizes VHL and promotes cytoplasmic localization; SUMOylation at K171 (mediated by PIASy) blocks ubiquitylation, increases VHL stability, and promotes nuclear redistribution. Mutation of K171 and K196 to arginine abrogates VHL's inhibitory function on HIFα transcriptional activity. VHL-SUMO1/ubiquitin fusion proteins; subcellular fractionation; reporter assays for HIFα transcriptional activity; tube formation assay PLoS ONE Medium 20844582
2013 Adenoviral Gam1 protein, via its BC-box domain competing with VHL for Elongin B/C binding, induces VHL proteasomal degradation through a CRL-dependent mechanism, leading to HIF-1α stabilization; cellular BC-box proteins and SOCS domain-containing viral proteins can similarly drive VHL degradation. Co-immunoprecipitation; proteasome inhibitor rescue experiments; HIF-1α reporter assays; domain mapping with BC-box mutants PNAS Medium 24145437
2014 DJ-1 (PARK7) interacts with VHL protein and negatively regulates VHL's ubiquitination activity toward HIF-1α by inhibiting the HIF–VHL interaction; DJ-1 deficiency leads to lowered HIF-1α levels under hypoxia and oxidative stress, and HIF-1α accumulation rescues DJ-1-deficient neurons from toxicity. Co-immunoprecipitation (DJ-1–VHL); HIF-1α ubiquitination and stability assays; HIF-1α accumulation assays in knockout models; neuroprotection assays Journal of Neuroscience Medium 24899725
2016 ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin 2, and impairs HIF2α ubiquitylation and degradation. DYRK1A/B phosphorylation of ID2 at Thr27 (stimulated by PHD1/EGLN2 in normoxia) blocks the ID2–VHL interaction, preserving HIF2α ubiquitylation. Co-immunoprecipitation (ID2–VHL complex); ubiquitination assays for HIF2α; kinase assays (DYRK1A/B phosphorylation of ID2); phospho-site mutagenesis; glioma xenograft models Nature High 26735018
2013 Missense mutant pVHL retains E3 ligase function (including HIFα degradation) but is unstable due to misfolding and imbalance of chaperonin binding; HDAC inhibitors stabilize missense pVHL by modulating the HDAC-Hsp90 chaperone axis, restoring activity comparable to wild-type protein. In vitro E3 ligase assays; chaperone interaction studies; HDACI treatment with protein stability measurements; xenograft tumor growth assays Cell Reports Medium 23318261
2014 RSUME physically interacts with pVHL, sumoylates it, and negatively regulates assembly of the pVHL–Elongin–Cullin (ECV) complex, thereby inhibiting HIF-1α and HIF-2α ubiquitination and degradation; RSUME is required for the loss-of-function of type 2 pVHL mutants. Co-immunoprecipitation (RSUME–pVHL); SUMOylation assays; ECV assembly assays; HIF ubiquitination assays; HIF stability reporter; xenograft assay Oncogene Medium 25500545
2017 Daam2 associates with VHL and facilitates its ubiquitination and proteasomal degradation, providing a non-mutational mechanism of VHL suppression in glioma; inverse correlation between Daam2 and VHL expression was found across cancers including glioma. Co-immunoprecipitation (Daam2–VHL); ubiquitination assays; VHL protein stability measurements; tumor growth assays eLife Medium 29053101
2017 VHL loss stabilizes HIF2α–HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 to acquire active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes, driving enhancer/superenhancer deregulation without overtly affecting preexisting promoter–enhancer interactions. ChIP-seq (H3K27ac, H3K4me1, HIF2α, p300); chromatin profiling in 10 primary tumor/normal pairs and 9 cell lines; VHL loss-of-function genetic models Cancer Discovery Medium 28893800
2018 pVHL re-expression in pVHL-defective renal carcinoma cells elevates CHCHD4 (a mitochondrial intermembrane space protein import component) and respiratory chain subunits (NDUFB10, mtCO-2, COX IV), enhancing oxygen consumption rate; this effect is distinct from HIF-α regulation and is also recapitulated by HIF-2α knockdown. VHL re-expression in 786O and RCC10 cells; oxygen consumption rate measurements; western blot for respiratory chain subunits; metabolic profiling; mitochondrial morphology analysis Frontiers in Oncology Medium 30338240
2019 TBK1 hydroxylation on Proline 48 triggers VHL binding (as well as phosphatase PPM1B binding), leading to decreased TBK1 phosphorylation; in the absence of VHL, TBK1 is hyperactivated and phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Co-immunoprecipitation (VHL–TBK1); hydroxylation assays; phosphorylation assays; VHL loss-of-function studies; xenograft models Cancer Discovery Medium 31810986
2021 VHL interacts with RAPTOR (regulatory-associated protein of mTOR) and increases RAPTOR degradation by ubiquitination, thereby inhibiting mTORC1 signaling; loss of vhl-1 in C. elegans increases mTORC1 activity, supporting evolutionary conservation of this mechanism. Co-immunoprecipitation (VHL–RAPTOR); ubiquitination assays; mTORC1 activity assays; C. elegans vhl-1 loss-of-function genetics Scientific Reports Medium 34290272
2020 The E3 ligase VHL interacts with Daam2, and their mutual antagonism regulates oligodendrocyte differentiation during development; the E3 ubiquitin ligase Nedd4 stabilizes VHL via K63-linked ubiquitination. This Daam2-VHL-Nedd4 axis is required for developmental myelination and remyelination after white matter injury. Proteomic analysis of Daam2–VHL complex; co-immunoprecipitation; conditional knockout mouse models; K63 ubiquitination assays; demyelination mouse models; human MS lesion analysis Genes & Development High 32792353
2024 VHL suppresses autophagy by directly binding to Beclin1 after PHD1-mediated hydroxylation of Beclin1 on Pro54; this binding inhibits the Beclin1–VPS34 complex association with ATG14L, blocking autophagy initiation. Non-hydroxylatable Beclin1-P54A abrogates VHL-mediated autophagy inhibition. Co-immunoprecipitation (VHL–Beclin1); PHD1 hydroxylation assays; Pro54 site-directed mutagenesis; VPS34 complex pull-down; autophagy flux assays; xenograft tumor models The EMBO Journal High 38360997
2022 VHL acts as a bona fide E3 ligase for STING in renal cell carcinoma; VHL-recruiting STING PROTACs further promote VHL-dependent STING degradation, and locking STING on the endoplasmic reticulum via mutagenesis blocks its translocation to the proteasome and prevents degradation. PROTAC-mediated degradation assays; STING localization mutagenesis (ER retention); co-immunoprecipitation; downstream innate immune signaling assays Cellular and Molecular Life Sciences Medium 37183204
2024 Lactylation of HIF-1α at K644 (mouse) or K12 (human/pig) reduces K48-linked ubiquitination and proteasomal degradation by sterically hindering VHL binding without affecting prolyl hydroxylation of HIF-1α; lactylated HIF-1α retains increased transcriptional activity (elevated VEGFA, GLUT1 promoter occupancy). Mass spectrometry identification of lactylation sites; site-directed mutagenesis; K48 ubiquitination assays; VHL co-immunoprecipitation with lactylated vs. non-lactylated HIF-1α; structural modeling; chromatin immunoprecipitation Cell Communication and Signaling Medium 40760493
2024 UBE2S promotes K11-linkage polyubiquitination of VHL at lysine residues 171 and 196 independently of E3 ligase activity, mediating VHL proteasomal degradation and indirectly stabilizing HIF-1α to promote glycolysis in hepatocellular carcinoma. Co-immunoprecipitation; ubiquitination assays (K11-specific); VHL stability measurements; glycolysis assays; HIF-1α protein level analysis Clinical and Molecular Hepatology Medium 38915206
2022 iASPP directly binds to the β domain of VHL (the region involved in HIF-1α binding), blocking VHL's binding to and degradation of HIF-1α under normoxia, thereby promoting angiogenesis and glycolysis in VHL wild-type tumors. Co-immunoprecipitation (iASPP–VHL); domain mapping (β domain); HIF-1α ubiquitination and stability assays; in vitro binding competition assays; tumor xenograft models Oncogene Medium 35169254
2021 VHL inhibitor VH298 stabilizes VHL protein isoforms (without changing transcript levels), which in turn reduces HIF-1α protein levels, demonstrating a negative feedback mechanism where VHL inhibitor-mediated blocking of the VHL–HIF-α interaction paradoxically increases VHL protein abundance. Quantitative mass spectrometry proteomics; VHL stability assays (cycloheximide chase); transcript level analysis; HIF-1α western blot after VH298 treatment Journal of Biological Chemistry Medium 34174286
2013 VHL loss alone causes DNA replication stress and DNA damage accumulation in renal epithelial cells, constraining proliferation; concomitant loss of PBRM1 rescues VHL-induced replication stress and allows proliferation. Combined deletion of Vhl and Pbrm1 in mouse kidney is sufficient for fully-penetrant, multifocal carcinoma development. DNA damage markers (γH2AX); replication stress assays; conditional mouse knockout (Vhl, Pbrm1, or both); histopathological analysis of kidney tumors Nature Communications High 29229903
2013 Tumor suppressor VHL is required for proper spindle orientation and mitotic checkpoint fidelity in vivo: Vhl-deficient kidney cells after ischemic injury demonstrate spindle misorientation and aneuploidy (lagging chromosomes, indicating checkpoint impairment) within days, followed by ccRCC precursor lesion development at 4 months. Ischemic kidney injury model; conditional Vhl knockout mice; immunofluorescence for spindle orientation; FISH for aneuploidy; histopathological analysis Cancer Research High 24362914
2024 Saturation genome editing of VHL's entire coding sequence quantified functional effects of 2,268 VHL single-nucleotide variants; function scores identified a core set of pathogenic alleles driving ccRCC, distinguished from pheochromocytoma-associated alleles, and revealed that some variants impact VHL function through mRNA dosage effects rather than protein dysfunction. Saturation genome editing (base editing + selection); mRNA quantification; comparison across isogenic cell lines; functional score calculation Nature Genetics High 38969834
2025 A small molecule binds the HIF1α-binding pocket on pVHL and functions as a molecular glue degrader, recruiting the neosubstrate cysteine dioxygenase 1 (CDO1) into the VHL–Cullin–RING E3 ligase complex for selective ubiquitin-dependent degradation; X-ray crystal structure of the ternary VHL–CDO1–degrader complex was solved. Protein array screening; mutagenesis; protein–protein docking + molecular dynamics; X-ray crystallography of ternary complex; cellular degradation assays Nature Chemical Biology High 40555806

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science (New York, N.Y.) 3948 11292862
1994 Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature genetics 1506 7915601
1994 Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proceedings of the National Academy of Sciences of the United States of America 1360 7937876
2004 Role of VHL gene mutation in human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 752 15611513
2015 VHL, the story of a tumour suppressor gene. Nature reviews. Cancer 621 25533676
2012 The VHL/HIF axis in clear cell renal carcinoma. Seminars in cancer biology 322 22705278
2010 VHL and HIF signalling in renal cell carcinogenesis. The Journal of pathology 258 20225241
2020 Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nature communications 244 32948771
2006 Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer research 229 16585181
1998 The VHL tumour-suppressor gene paradigm. Trends in genetics : TIG 192 9820032
2022 Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders. Chemical Society reviews 171 35983982
2022 A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nature communications 170 36216795
2005 VHL protein-interacting deubiquitinating enzyme 2 deubiquitinates and stabilizes HIF-1alpha. EMBO reports 168 15776016
2010 Alterations in VHL as potential biomarkers in renal-cell carcinoma. Nature reviews. Clinical oncology 145 20368728
2009 The VHL tumor suppressor: master regulator of HIF. Current pharmaceutical design 144 19671042
2017 VHL Deficiency Drives Enhancer Activation of Oncogenes in Clear Cell Renal Cell Carcinoma. Cancer discovery 135 28893800
2006 The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney international 135 16531988
2008 The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell death and differentiation 131 18219317
2009 VHL loss causes spindle misorientation and chromosome instability. Nature cell biology 130 19620968
2019 Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs. Bioorganic & medicinal chemistry 113 30826187
2002 Endemic polycythemia in Russia: mutation in the VHL gene. Blood cells, molecules & diseases 109 11987242
2016 An ID2-dependent mechanism for VHL inactivation in cancer. Nature 105 26735018
2009 Treatment of kidney cancer: insights provided by the VHL tumor-suppressor protein. Cancer 104 19402056
2017 The VHL Tumor Suppressor Gene: Insights into Oxygen Sensing and Cancer. Transactions of the American Clinical and Climatological Association 100 28790514
2018 VHL and Hypoxia Signaling: Beyond HIF in Cancer. Biomedicines 98 29562667
2019 TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss. Cancer discovery 94 31810986
2017 Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. Nature communications 85 29229903
2021 Loss of Von Hippel-Lindau (VHL) Tumor Suppressor Gene Function: VHL-HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC). International journal of molecular sciences 81 34575959
2012 Renal tubular HIF-2α expression requires VHL inactivation and causes fibrosis and cysts. PloS one 76 22299048
2013 Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO molecular medicine 75 23606570
2017 The HIF and other quandaries in VHL disease. Oncogene 72 28925400
2011 Role of VHL gene mutation in human renal cell carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 71 22125026
2019 HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Science signaling 70 31575731
2014 Sporadic hemangioblastomas are characterized by cryptic VHL inactivation. Acta neuropathologica communications 67 25589003
2009 CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma. Molecular cancer 66 19493342
2012 Systemic VHL gene functions and the VHL disease. FEBS letters 65 22673568
2010 VHL inactivation induces HEF1 and Aurora kinase A. Journal of the American Society of Nephrology : JASN 57 20864688
2009 Genotype-phenotype correlations in VHL exon deletions. American journal of medical genetics. Part A 57 19764026
2021 VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives. European journal of medicinal chemistry 54 34656901
2007 Molecular pathology of eyes with von Hippel-Lindau (VHL) Disease: a review. Retina (Philadelphia, Pa.) 51 17218907
2011 JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma. Oncogene 49 22020339
2006 The positive regulation of p53 by the tumor suppressor VHL. Cell cycle (Georgetown, Tex.) 47 16969113
2013 Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. Cell reports 46 23318261
2010 VHL disease. Best practice & research. Clinical endocrinology & metabolism 46 20833332
2010 Ubiquitin/SUMO modification regulates VHL protein stability and nucleocytoplasmic localization. PloS one 45 20844582
2006 Ubiquitin pathway in VHL cancer syndrome. Neoplasia (New York, N.Y.) 45 16925945
2001 Clinical management of Von Hippel-Lindau (VHL) disease. The Netherlands journal of medicine 45 11705642
2023 A beginner's guide to current synthetic linker strategies towards VHL-recruiting PROTACs. Bioorganic & medicinal chemistry 44 37224698
2024 Saturation genome editing maps the functional spectrum of pathogenic VHL alleles. Nature genetics 41 38969834
2013 K63-ubiquitylation of VHL by SOCS1 mediates DNA double-strand break repair. Oncogene 40 23455319
2014 Regulation of the VHL/HIF-1 pathway by DJ-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 24899725
2023 Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design. ChemMedChem 37 36749883
2015 Pharmacological HIF2α inhibition improves VHL disease-associated phenotypes in zebrafish model. The Journal of clinical investigation 36 25866969
2020 The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma. Frontiers in endocrinology 35 33329393
2007 The HIF/VHL pathway: from oxygen sensing to innate immunity. American journal of respiratory cell and molecular biology 35 17932373
2006 Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas. Annals of the New York Academy of Sciences 35 17102089
2024 Structure-Guided Design and Optimization of Covalent VHL-Targeted Sulfonyl Fluoride PROTACs. Journal of medicinal chemistry 32 38478885
2013 Renal cell carcinoma with smooth muscle stroma lacks chromosome 3p and VHL alterations. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 24201123
2023 Development of VHL-recruiting STING PROTACs that suppress innate immunity. Cellular and molecular life sciences : CMLS 31 37183204
2020 Evaluation, diagnosis and surveillance of renal masses in the setting of VHL disease. World journal of urology 31 32936333
2002 Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter. Journal of medical genetics 31 12114475
2013 BC-box protein domain-related mechanism for VHL protein degradation. Proceedings of the National Academy of Sciences of the United States of America 30 24145437
2009 Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations. PloS one 30 19340311
2021 Von Hippel-Lindau (VHL) small-molecule inhibitor binding increases stability and intracellular levels of VHL protein. The Journal of biological chemistry 29 34174286
2020 The Daam2-VHL-Nedd4 axis governs developmental and regenerative oligodendrocyte differentiation. Genes & development 29 32792353
2022 The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis. Genes 28 35205407
2021 VHL suppresses RAPTOR and inhibits mTORC1 signaling in clear cell renal cell carcinoma. Scientific reports 28 34290272
2021 Relationship between visceral adipose tissue and genetic mutations (VHL and KDM5C) in clear cell renal cell carcinoma. La Radiologia medica 27 33400184
2018 Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism. Molecular cancer therapeutics 27 29720560
2024 Impact of Linker Composition on VHL PROTAC Cell Permeability. Journal of medicinal chemistry 26 39693386
2023 Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders. European journal of medicinal chemistry 26 38199162
2013 Tumor suppressor VHL functions in the control of mitotic fidelity. Cancer research 26 24362914
2025 Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition. Cell communication and signaling : CCS 24 40760493
2022 Selective Wee1 degradation by PROTAC degraders recruiting VHL and CRBN E3 ubiquitin ligases. Bioorganic & medicinal chemistry letters 24 35231578
2020 Prevalence and clinical significance of VHL mutations and 3p25 deletions in renal tumor subtypes. Oncotarget 24 32076485
2007 The role of VHL in the regulation of E-cadherin: a new connection in an old pathway. Cell cycle (Georgetown, Tex.) 24 17245122
2025 A small-molecule VHL molecular glue degrader for cysteine dioxygenase 1. Nature chemical biology 23 40555806
2018 VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function. Frontiers in oncology 23 30338240
2008 Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics. Cell cycle (Georgetown, Tex.) 23 18818511
2018 Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia. The Journal of clinical endocrinology and metabolism 22 29373688
2024 UBE2S promotes glycolysis in hepatocellular carcinoma by enhancing E3 enzyme-independent polyubiquitination of VHL. Clinical and molecular hepatology 21 38915206
2018 Immune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch. Protein & cell 21 30413999
2017 Daam2 driven degradation of VHL promotes gliomagenesis. eLife 21 29053101
2016 Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions. The Journal of pathology 21 27126173
2024 VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation. The EMBO journal 20 38360997
2014 RSUME inhibits VHL and regulates its tumor suppressor function. Oncogene 20 25500545
2012 Targeting HIF2α translation with Tempol in VHL-deficient clear cell renal cell carcinoma. Oncotarget 20 23178531
2006 VHL and p53: tumor suppressors team up to prevent cancer. Molecular cell 20 16713574
2005 Determination of vhl gene mutations in sporadic renal cell carcinoma. European urology 20 16387411
2024 Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs. Communications medicine 19 38755248
2019 Rb1/Rbl1/Vhl loss induces mouse subretinal angiomatous proliferation and hemangioblastoma. JCI insight 19 31613797
2017 Management Strategies and Outcomes for VHL-related Craniospinal Hemangioblastomas. Journal of kidney cancer and VHL 19 28868236
2017 Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate. Oncotarget 17 28036268
2018 Consequences of VHL Loss on Global DNA Methylome. Scientific reports 16 29463811
2005 Molecular targets from VHL studies into the oxygen-sensing pathway. Current cancer drug targets 16 16101382
2022 iASPP is essential for HIF-1α stabilization to promote angiogenesis and glycolysis via attenuating VHL-mediated protein degradation. Oncogene 15 35169254
2022 VHL mosaicism: the added value of multi-tissue analysis. NPJ genomic medicine 15 35304467
2018 Small activating RNA induced expression of VHL gene in renal cell carcinoma. The international journal of biochemistry & cell biology 15 29425832
2014 Mutational status of VHL gene and its clinical importance in renal clear cell carcinoma. Virchows Archiv : an international journal of pathology 15 25027579
2019 VHL Synthetic Lethality Signatures Uncovered by Genotype-Specific CRISPR-Cas9 Screens. The CRISPR journal 14 31436504

Missed literature

Know a paper Affinage missed for VHL? Flag it for the maintainers and the community.

No submissions yet.