Affinage

VPS33B

Vacuolar protein sorting-associated protein 33B · UniProt Q9H267

Length
617 aa
Mass
70.6 kDa
Annotated
2026-06-11
54 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS33B is a Sec1/Munc18 (SM)-family vesicle trafficking regulator that controls protein sorting at recycling endosomes and the late endosome–lysosome interface across multiple specialized cell types (PMID:15052268, PMID:26403612). Rather than associating with the canonical CORVET/HOPS tethering complexes, it forms a distinct, stable heteromeric complex with VPS16B/VIPAS39 (VIPAR), a partnership essential for its activity and for the reciprocal stabilization of VPS16B, which is destabilized and lost when VPS33B is absent (PMID:23002115, PMID:29778605, PMID:31501156, PMID:35325493). Structurally this complex is a ~315 kDa, two-lobed bidirectional assembly with a 2:3 VPS33B:VPS16B stoichiometry, an architecture that positions a VPS33B molecule at each end to engage SNARE machinery, consistent with its physical association with SNARE proteins SEC22B and Syntaxin 12 (PMID:27319744, PMID:34905616, PMID:37062417). The complex directs cargo through Rab-dependent recycling pathways—binding Rab11a and Rab25 and the GDI2/RAB11A/RAB27A axis—to traffic diverse cargo: alpha-granule proteins in megakaryocytes, apical ABC transporters in hepatocytes, lamellar body contents in keratinocytes, and the collagen-modifying enzyme LH3 (PMID:27797340, PMID:28017832, PMID:28082148, PMID:29409756). At the late endosome–lysosome step VPS33B promotes fusion and cargo clearance, controlling delivery of endocytosed cargo for degradation, clearance of pattern-recognition-receptor-containing endosomes to limit inflammatory signaling, turnover of the LYNUS complex to restrain mTORC1 activation in regulatory T cells, and MHC class II maturation in dendritic cells (PMID:26403612, PMID:27496733, PMID:35705052, PMID:42231978). In megakaryocytes loss of VPS33B misroutes alpha-granule cargo to lysosomal degradation rather than to alpha-granule progenitor organelles, defining the recycling endosome as a key biogenesis intermediate; a competitive hand-off between Syntaxin 12 and the COMMD3/CCC retrieval complex couples endosomal entry to exit (PMID:25947942, PMID:31501156, PMID:34905616). Loss-of-function mutations in VPS33B cause ARC syndrome (arthrogryposis–renal dysfunction–cholestasis), reflecting defective vesicular sorting across megakaryocytes, hepatocytes, and skin (PMID:15052268, PMID:16123220, PMID:18347289).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2004 Medium

    Established the molecular identity of VPS33B as a Sec1-like SM-family trafficking protein and linked its loss of function to a human multisystem disorder, framing the gene as a regulator of SNARE-mediated membrane fusion.

    Evidence Positional cloning and mutation analysis in 14 ARC kindreds with sequence domain analysis

    PMID:15052268

    Open questions at the time
    • Direct biochemical demonstration of SNARE regulation not shown
    • Tissue-specific trafficking roles undefined
    • No interacting partners identified
  2. 2005 High

    Demonstrated that VPS33B is required for alpha-granule biogenesis but not secretion, providing the first concrete cellular trafficking defect underlying an ARC phenotype.

    Evidence Immunofluorescence, immunoblotting, platelet ultrastructure and aggregation assays in ARC patient cells

    PMID:16123220

    Open questions at the time
    • Molecular partners mediating granule cargo sorting unknown
    • Compartment where sorting fails not yet defined
  3. 2005 Medium

    Placed vps33b downstream of a transcriptional cascade in biliary development, connecting its trafficking function to organ morphogenesis.

    Evidence Morpholino knockdown in zebrafish, EMSA promoter binding, reporter assays

    PMID:16284120

    Open questions at the time
    • Mechanism connecting trafficking to bile duct formation unresolved
    • Mammalian relevance of transcriptional control untested
  4. 2008 Medium

    Extended the secretory trafficking defect to skin, showing lamellar granule secretion fails in VPS33B deficiency, explaining the ichthyosis component of ARC.

    Evidence Ultrastructural EM of patient skin with mutation/splice analysis

    PMID:18347289

    Open questions at the time
    • Molecular step blocking lamellar granule secretion undefined
    • Partner proteins not identified
  5. 2012 High

    Identified VPS16B/VIPAS39 as the principal VPS33B partner, showing both proteins co-localize and that VIPAS39 mutations phenocopy VPS33B loss, establishing the functional complex.

    Evidence Yeast two-hybrid, mass spectrometry, co-IP, immunofluorescence, patient platelet EM

    PMID:23002115 PMID:23918659

    Open questions at the time
    • Stoichiometry and architecture of complex unknown
    • Whether complex includes CORVET/HOPS subunits unresolved
  6. 2012 Medium

    Linked VPS33B-VIPAS39 association to receptor regulation, showing the interaction stabilizes VIPAS39 and the two proteins exert opposing effects on EGFR downregulation.

    Evidence Ubiquitination/phosphorylation assays, co-IP and EGFR downregulation assays in COS-7 cells

    PMID:22677173

    Open questions at the time
    • Physiological relevance of opposing EGFR effects unclear
    • Connection to multisystem ARC phenotypes not established
  7. 2015 High

    Defined the organellar step VPS33B controls in megakaryocytes (MVB maturation/cargo entry) and in generic cells (late endosome–lysosome fusion), converging on a conserved fusion function.

    Evidence Inducible Vps33b KO mouse with immuno-EM; siRNA knockdown with cargo tracking and EM in HeLa

    PMID:25947942 PMID:26403612

    Open questions at the time
    • Direct SNARE/fusion machinery at these steps not yet identified
    • Cargo selectivity mechanism unclear
  8. 2015 High

    Showed VPS33B binds the integrin beta subunit and functions in platelet outside-in signaling and fibrinogen endocytosis, extending its role beyond granule biogenesis to receptor trafficking and cytoskeletal signaling.

    Evidence Direct binding assay, CHO overexpression, conditional KO mice, spreading/clot retraction/thrombosis assays

    PMID:26399659

    Open questions at the time
    • Structural basis of integrin binding undefined
    • How trafficking role couples to RhoA/Rac1 signaling unresolved
  9. 2016 High

    Mapped domain-specific interactions, showing VIPAS39 binds intact VPS33B while alpha-tubulin and SEC22B engage the Sec1-like domains, and that VPS33B operates within Rab11a/Rab25 and GDI2/RAB11A/RAB27A pathways.

    Evidence Co-IP, MS, pull-down in HEK293T; conditional KO mice; HSC exosome studies with rescue; LH3 trafficking rescue assays

    PMID:27319744 PMID:27797340 PMID:28017832

    Open questions at the time
    • How Rab handoffs are coordinated mechanistically unclear
    • Whether SNARE binding is direct and which SNAREs predominate per tissue undefined
  10. 2016 High

    Established cargo-selective, infection-specific function, showing VPS33B is required for maturation of PRR-containing endosomes/phagosomes and restrains inflammatory signaling, conserved from Drosophila to mammals.

    Evidence Drosophila and mammalian mutant/knockdown models, maturation assays, TLR signaling and cytokine measurements

    PMID:27496733

    Open questions at the time
    • Mechanism distinguishing microbial from non-microbial cargo unknown
    • Upstream sensors triggering selective VPS33B engagement undefined
  11. 2017 High

    Demonstrated hepatocyte apical polarity depends on VPS33B-mediated Rab11a recycling-endosome trafficking of ABC transporters, with AAV gene transfer offering partial rescue.

    Evidence Liver-specific conditional KO, bile metabolite MS, immunostaining, EM, AAV rescue

    PMID:28082148

    Open questions at the time
    • Direct VPS33B-cargo recognition mechanism unresolved
    • Durability/scalability of gene therapy untested
  12. 2018 Medium

    Clarified the complex identity: VPS33B does not associate with CORVET/HOPS but forms a small VPS33B-VIPAR complex with only transient CCC (CCDC22) contact, distinguishing it biochemically from its paralog VPS33A.

    Evidence BioID, gel filtration, comparative VPS33A/VPS33B interactome analysis

    PMID:29778605

    Open questions at the time
    • Precise stoichiometry not resolved here
    • Functional consequence of transient CCC contact undefined
  13. 2018 High

    Confirmed VPS33B-VIPAR jointly drive epidermal lamellar body biogenesis and barrier formation in mammals, validating the shared-complex model in skin.

    Evidence Vps33b and Vipar KO mice, histology, immunofluorescence, EM, primary culture

    PMID:29409756

    Open questions at the time
    • Molecular cargo-loading step into lamellar bodies undefined
    • Lipid-handling mechanism not detailed
  14. 2019 High

    Resolved that the VPS33B-VPS16B complex is a discrete heterodimer-sized assembly localizing to recycling endosomes, and that without it alpha-granule cargo is misrouted to lysosomal degradation, identifying the recycling endosome as the key biogenesis intermediate.

    Evidence CRISPR KO in iPSC-derived megakaryocytes, SEC, recombinant protein, GFP-reconstitution, lysosomal inhibition

    PMID:31479177 PMID:31501156

    Open questions at the time
    • Atomic structure not yet determined here
    • Mechanism diverting cargo away from lysosome unknown
  15. 2022 High

    Defined an entry/exit hand-off, showing CCDC22 (CCC) competes with Syntaxin 12 for the VPS16B/VPS33B complex and that COMMD3-containing CCC controls alpha-granule cargo retrieval, integrating SNARE-mediated fusion with endosomal sorting.

    Evidence Co-IP, CRISPR KO of Stx12 and COMMD3/CCDC22, immunofluorescence, granule protein quantitation

    PMID:34905616 PMID:35325493

    Open questions at the time
    • Spatiotemporal regulation of the competition unresolved
    • Whether hand-off operates identically in non-platelet tissues untested
  16. 2022 High

    Revealed an immunometabolic role: VPS33B clears LYNUS-containing late endosomes/lysosomes to suppress mTORC1, sustaining regulatory T cell suppressive function and restraining glycolysis.

    Evidence Treg-specific conditional KO, mTORC1 and glycolysis assays, endolysosomal fusion assays, LYNUS co-IP, tumor models

    PMID:35705052

    Open questions at the time
    • Direct LYNUS binding interface undefined
    • Whether mTORC1 control generalizes to other cell types untested
  17. 2023 High

    Determined the bidirectional two-lobed ~315 kDa 2:3 architecture of the complex, providing the structural rationale for VPS33B engaging SNARE bundles at both ends, and mapped ARC variants that do or do not disrupt assembly.

    Evidence Recombinant expression, CD, SEC-MALS, SAXS, negative-stain EM, avidin tagging, ARC variant analysis

    PMID:37062417

    Open questions at the time
    • High-resolution structure with bound SNAREs lacking
    • Whether both lobes engage SNAREs simultaneously in vivo untested
  18. 2023 Medium

    Identified post-transcriptional control of VPS33B via METTL16-mediated m6A modification reducing transcript stability, providing a regulatory input in osteosarcoma.

    Evidence m6A and mRNA stability assays, METTL16 manipulation, VPS33B knockdown rescue

    PMID:37357526

    Open questions at the time
    • Physiological context of this regulation beyond osteosarcoma unclear
    • Downstream trafficking consequences not detailed
  19. 2026 High

    Extended VPS33B function to dendritic cell MHC class II maturation, showing its loss causes accumulation of invariant-chain intermediates and selectively impairs CD4 priming, and to renal epithelial cell-matrix adhesion.

    Evidence DC-specific and RPTEC-TERT1 CRISPR/conditional KO, MHC peptide presentation and T cell priming assays, RNA-seq, adhesion assays

    PMID:41686830 PMID:42231978

    Open questions at the time
    • Molecular step in invariant chain processing controlled by VPS33B undefined
    • Direct adhesion-pathway mechanism in renal cells not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the bidirectional VPS33B-VPS16B complex selects distinct cargo and SNARE partners across tissues, and the high-resolution structural basis for SNARE engagement, remain unresolved.
  • No co-structure of the complex with SNAREs or Rab effectors
  • Mechanism of tissue-specific cargo selectivity unknown
  • Whether both lobes function simultaneously or sequentially undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 4 GO:0005764 lysosome 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-109582 Hemostasis 3 R-HSA-168256 Immune System 3 R-HSA-9609507 Protein localization 2
Partners
CCDC22GDI2ITGB3RAB11ARAB25SEC22BSTX12VIPAS39
Complex memberships
VPS33B-VPS16B/VIPAR complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 VPS33B encodes a homolog of yeast class C vacuolar protein sorting gene Vps33 and contains a Sec1-like domain important in regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion. Loss-of-function mutations cause ARC syndrome. Positional cloning, mutation identification in 14 kindreds, sequence domain analysis Nature genetics Medium 15052268
2005 VPS33B is required for megakaryocyte and platelet alpha-granule biogenesis but not granule secretion. VPS33B colocalizes with alpha-granule markers and late endosomes/lysosomes in megakaryocytes, and VPS33B protein is absent in ARC patient fibroblasts and megakaryocytes, resulting in complete absence of alpha-granules and loss of both soluble and membrane-bound alpha-granule proteins. Immunofluorescence microscopy, immunoblotting, platelet ultrastructural analysis, platelet aggregation assays in ARC patients Blood High 16123220
2005 Zebrafish vps33b acts downstream of the hnf6/vhnf1 transcription factor pathway to regulate biliary development; vhnf1 directly binds the vps33b promoter as shown by EMSA, and vps33b knockdown causes bile duct paucity and impaired intestinal lipid absorption. Morpholino knockdown in zebrafish, EMSA, gene expression analysis, reporter assay in mammalian liver cells Development (Cambridge, England) Medium 16284120
2008 VPS33B deficiency results in failure of lamellar granule secretion at the granular-cornified cell layer boundary in skin, with lamellar granules becoming entombed in cornified cells rather than being secreted, causing ichthyosis in ARC syndrome. Ultrastructural electron microscopy of patient skin, VPS33B mutation sequencing and splice analysis Archives of dermatology Medium 18347289
2012 VPS33B interacts with VIPAS39 (SPE-39). Wild-type and disease-causing mutations in VIPAS39 and Vps33B were studied; most ARC mutations do not prevent the VIPAS39-Vps33B interaction, but all tested mutants alter subcellular localization of Vps33B to VIPAS39-positive endosomes and some fragment VIPAS39-positive endosomes. Yeast two-hybrid, co-immunoprecipitation, quantitative fluorescent microscopy Human molecular genetics Medium 23918659
2012 VPS33B binds to VPS16B (encoded by C14orf133/VIPAS39); this interaction was identified by yeast two-hybrid, mass spectrometry, and coimmunoprecipitation. VPS16B colocalizes with markers of the trans-Golgi network, late endosomes, and alpha-granules in megakaryocytic Dami cells, similar to VPS33B, and VPS16B mutations cause alpha-granule biogenesis defects identical to VPS33B mutations. Yeast two-hybrid, mass spectrometry, coimmunoprecipitation, immunofluorescence microscopy, immunoblotting, patient platelet electron microscopy Blood High 23002115
2012 Association of VPS33B with SPE-39 (VIPAS39) inhibits ubiquitination of SPE-39 following EGF stimulation, stabilizing SPE-39. Tyrosine phosphorylation of SPE-39 at Tyr-11 regulates its ubiquitination. VPS33B and SPE-39 have opposing effects on EGF receptor downregulation in EGF-stimulated cells. Ubiquitination assays, phosphorylation analysis, co-immunoprecipitation, EGF receptor downregulation assays in COS-7 cells FEBS letters Medium 22677173
2015 VPS33B deficiency in mouse megakaryocytes causes accumulation of large vacuoles and reduction in mature type-II multivesicular bodies (MVB II), with alpha-granule proteins underrepresented in MVB II and proplatelet extensions, demonstrating that VPS33B is required for protein trafficking into alpha-granule progenitor organelles and MVB maturation. Tamoxifen-inducible conditional Vps33b knockout mouse model, conventional and immuno-electron microscopy, immunofluorescence, platelet aggregation and secretion assays, tail bleeding Blood High 25947942
2015 VPS33B depletion in HeLa cells leads to accumulation of late endosomes in the perinuclear region and impairs late endosomal-lysosomal fusion, resulting in decreased delivery of endocytosed cargo to lysosomes and reduced cargo degradation. siRNA knockdown, fluorescence and electron microscopy, BSA-gold endocytosis tracking, organelle quantification Traffic (Copenhagen, Denmark) High 26403612
2015 VPS33B binds directly to the integrin beta subunit. VPS33B overexpression in CHO cells potentiates alphaIIbbeta3 outside-in signaling but not inside-out signaling. Megakaryocyte/platelet-specific VPS33B conditional KO mice show impaired platelet spreading on fibrinogen, defective clot retraction, reduced platelet aggregation, and defective fibrinogen endocytosis. VPS33B acts upstream of the RhoA-ROCK-MLC and Rac1-dependent pathways. Co-immunoprecipitation/direct binding assay, CHO cell overexpression, conditional KO mouse model, platelet spreading/aggregation/clot retraction assays, FeCl3 thrombosis model, tail bleeding Circulation High 26399659
2016 VPS33B interacts with VIPAS39 (SPE-39) and with alpha-tubulin and SEC22B; pull-down experiments showed VIPAS39 binds intact VPS33B whereas alpha-tubulin and SEC22B separately interact with the Sec1-like domains of VPS33B. VPS33B deficiency disrupts redistribution of Vipas39 and Sec22b to proplatelets and interrupts co-localization of Sec22b with VWF-positive vesicles in megakaryocytes. Co-immunoprecipitation, mass spectrometry, pull-down assay, immunoblotting in HEK293T cells; conditional Vps33b KO mice; immunofluorescence microscopy The Journal of pathology Medium 27319744
2016 Drosophila and mammalian Vps33B proteins are required for maturation of phagosomes and endosomes following microbial (PRR) recognition. Vps33B deficiency specifically impairs clearance of endosomes containing internalized PRRs, resulting in enhanced and prolonged inflammatory signaling. Vps33B loss had no effect on trafficking of endosomes containing non-microbial cargo. Drosophila and mammalian Vps33B mutant/knockdown models, phagosome/endosome maturation assays, TLR signaling assays, cytokine/inflammatory mediator measurements Immunity High 27496733
2016 VPS33B controls exosome maturation and secretion in hematopoietic stem cells. VPS33B co-exists in exosomes with GDI2, VPS16B, FLOT1, and other exosome markers. Mechanistically, VPS33B interacts with the GDI2/RAB11A/RAB27A pathway to regulate trafficking of secretory proteins as exosomes. VPS33B deletion in mouse or human HSCs results in impaired exosome maturation and secretion and loss of stemness. Conditional VPS33B deletion in mouse and human HSCs, exosome purification and characterization, co-immunoprecipitation, rescue experiments with purified exosomes The Journal of clinical investigation High 27797340
2016 The p.Gly131Glu mutant VPS33B has reduced coimmunoprecipitation and colocalization with Rab11a and Rab25 and fails to rescue LH3 (lysyl hydroxylase 3) trafficking. Wild-type VPS33B interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen-modifying enzyme LH3; deficiency leads to deficient LH3-specific collagen lysine modifications. Co-immunoprecipitation, colocalization microscopy, LH3 trafficking rescue assay, collagen lysine modification analysis in patient urine and fibroblasts, VPS33B mutant construct analysis The Journal of investigative dermatology High 28017832
2017 Liver-specific Vps33b deletion in mice causes mislocalisation of ATP-binding cassette (ABC) proteins that are trafficked to the apical membrane via Rab11a-positive recycling endosomes, resulting in loss of structural and functional hepatocyte polarity. VPS33B interacts with RAB11A at recycling endosomes. Gene transfer with AAV vectors partially rescued these defects. Liver-specific conditional Vps33b KO mouse, bile/plasma metabolite analysis by mass spectrometry, immunostaining, light/transmission electron microscopy, AAV gene rescue Journal of hepatology High 28082148
2018 VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function. Vps33b and Vipar deficient mouse skin shows abnormal lamellar body morphology, disrupted localisation of lamellar body cargo, increased corneocyte thickness, decreased cornified envelope thickness, and reduced lipid deposition, causing impaired epidermal barrier. Vps33b and Vipar KO mice, histology, immunofluorescence, electron microscopy, primary cell culture Biochimica et biophysica acta. Molecular basis of disease High 29409756
2018 VPS33B does not associate with CORVET or HOPS complex subunits. Instead, VPS33B forms a distinct and small complex with VIPAR. VPS33B also interacts directly with CCDC22, a member of the CCC complex, but this interaction is transient rather than forming a stable complex. CCDC22 does not co-fractionate with VPS33B and VIPAR in gel filtration, and the VPS33B-VIPAR complex is considerably smaller than CORVET/HOPS. BioID proximity biotinylation assay, gel filtration chromatography, comparative interactome analysis of VPS33A and VPS33B Journal of molecular biology Medium 29778605
2019 The VPS33B-VPS16B complex forms a distinct small complex with the same hydrodynamic radius as the recombinant heterodimer purified from bacteria. In megakaryocyte cells, VPS33B deficiency results in alpha-granule cargo (PF4, VWF, P-selectin) degradation in lysosomes rather than delivery to alpha-granules. The VPS33B-VPS16B complex localizes to the recycling endosome, identifying the recycling endosome as a key intermediate compartment in alpha-granule biogenesis. VPS16B steady-state levels are reduced in VPS33B-KO cells, indicating VPS16B is destabilized without its partner. CRISPR/Cas9 KO in iPSC-derived immortalized megakaryocyte cells (imMKCLs), size exclusion chromatography, recombinant protein purification from bacteria, GFP-VPS33B reconstitution, cargo trafficking analysis, lysosomal inhibitor experiments Blood advances High 31501156
2019 A missense mutation p.Cys576Arg in VPS33B abolishes interaction with VIPAS39 in vitro, as demonstrated by co-immunoprecipitation. In vitro co-immunoprecipitation with mutant VPS33B constructs, protein expression analysis Human mutation Medium 31479177
2020 Vps33B loss-of-function in Drosophila results in hypersensitivity to infection driven by aberrant p38b MAP kinase activation downstream of PGRP-LC receptor. p38b MAPK modulates endosomal trafficking of PGRP-LC and phagocytosis of bacteria; constitutively active p38b enhances accumulation of endocytosed PGRP-LC, and p38b is required for macropinocytosis-mediated downregulation of immune receptors. Drosophila Vps33B mutant flies, p38b MAPK epistasis experiments (constitutively active/dominant negative constructs), endosomal trafficking assays, phagocytosis assays, survival assays Traffic (Copenhagen, Denmark) Medium 32677257
2022 VPS16B/VPS33B complex physically associates with Syntaxin 12 (Stx12), a SNARE protein mediating vesicle fusion at endosomes. VPS16B/VPS33B also binds CCDC22 (CCC complex). CCDC22 competes with Stx12 for binding to VPS16B/VPS33B, suggesting a hand-off mechanism between endosomal entry (Stx12-mediated fusion) and exit (CCC-mediated retrieval). COMMD3-containing CCC complex deficiency causes reduced alpha-granule numbers and loss of alpha-granule proteins, with P-selectin trafficked through the cell surface in a COMMD3-dependent manner. Co-immunoprecipitation, CRISPR/Cas9 KO of Stx12 and COMMD3/CCDC22 in megakaryocyte cells, immunofluorescence, alpha-granule protein quantitation, flow cytometry Blood High 34905616
2022 Treg-specific depletion of Vps33B in mice results in defective Treg cell suppressive function and acquisition of effector phenotype. Mechanistically, Vps33B binds the lysosomal nutrient-sensing complex (LYNUS) and promotes late endosome-lysosome fusion and clearance of LYNUS-containing late endosome/lysosomes, thereby suppressing mTORC1 activation. Vps33B deficiency causes disordered endosome-lysosome fusion, accumulation of LYNUS, elevated mTORC1 activation, and hyper-glycolytic metabolism in Treg cells. Treg-specific conditional KO mice, mTORC1 activity assays, glycolytic metabolism measurement, endolysosomal fusion assays, co-immunoprecipitation of Vps33B with LYNUS components, T cell suppression assays, tumor models Cell reports High 35705052
2022 In ARC syndrome patient platelets with VPS33B loss-of-function, VPS16B protein expression is also lost, indicating that stable expression of VPS16B in platelets and megakaryocytes is dependent on VPS33B. Immunoblotting of patient platelets, electron microscopy, genetic analysis of novel VPS33B variant Journal of thrombosis and haemostasis : JTH Medium 35325493
2023 Human VPS33B-VPS16B forms a high molecular weight complex (~315 kDa) with a VPS33B:VPS16B ratio of 2:3 and a uniquely bidirectional two-lobed structure, each lobe containing a VPS33B molecule oriented in opposite directions. This architecture allows VPS33B at each end to potentially interact with separate SNARE bundles/SNAREpins. The ARC-causing variant L30P disrupts complex formation, whereas S243F and H344D do not. Truncated VPS16B (amino acids 143-316) is sufficient to form a complex with VPS33B. Recombinant protein expression in yeast, circular dichroism, SEC-MALS, quantitative immunoblotting, small-angle X-ray scattering, negative-staining EM, avidin tagging, ARC variant expression analysis The Journal of biological chemistry High 37062417
2023 METTL16 methyltransferase induces m6A modification of VPS33B mRNA, impairing VPS33B transcript stability and reducing VPS33B protein levels. This was identified as a downstream regulatory mechanism controlling VPS33B expression in osteosarcoma. m6A modification assays, mRNA stability assays, METTL16 knockdown/overexpression, VPS33B knockdown rescue experiments Journal of cellular physiology Medium 37357526
2026 VPS33B knockout in proximal tubular epithelial cells (RPTEC-TERT1) causes a 'peeling' phenotype with altered cell-matrix adhesion and transcriptional changes in adhesion-related genes. CRISPR/Cas9 KO, brightfield imaging, immunostaining, RNA sequencing, cell detachment assays PloS one Medium 41686830
2026 VPS33B is required for optimal MHC class II antigen presentation in dendritic cells. VPS33B-deficient DCs predominantly express MHC class II loaded with invariant chain degradation intermediates rather than mature peptide-loaded complexes, impairing CD4 T cell priming while not affecting MHC class I-dependent CD8 T cell priming. DC-specific conditional KO, MHC class II peptide presentation assays, CD4 and CD8 T cell priming assays, flow cytometry, immunostaining iScience High 42231978

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nature genetics 243 15052268
2005 Requirement of VPS33B, a member of the Sec1/Munc18 protein family, in megakaryocyte and platelet alpha-granule biogenesis. Blood 118 16123220
2016 Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis. The Journal of clinical investigation 76 27797340
2012 The VPS33B-binding protein VPS16B is required in megakaryocyte and platelet α-granule biogenesis. Blood 65 23002115
2019 VPS33B interacts with NESG1 to modulate EGFR/PI3K/AKT/c-Myc/P53/miR-133a-3p signaling and induce 5-fluorouracil sensitivity in nasopharyngeal carcinoma. Cell death & disease 57 30944308
2005 Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6. Development (Cambridge, England) 50 16284120
2015 VPS33B regulates protein sorting into and maturation of α-granule progenitor organelles in mouse megakaryocytes. Blood 44 25947942
2017 Vps33b is crucial for structural and functional hepatocyte polarity. Journal of hepatology 41 28082148
2008 Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B. Archives of dermatology 37 18347289
2016 Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification. The Journal of investigative dermatology 36 28017832
2015 Vps33B is required for delivery of endocytosed cargo to lysosomes. Traffic (Copenhagen, Denmark) 36 26403612
2015 Characterization of a Novel Integrin Binding Protein, VPS33B, Which Is Important for Platelet Activation and In Vivo Thrombosis and Hemostasis. Circulation 32 26399659
2009 Clinical characteristics and VPS33B mutations in patients with ARC syndrome. Journal of pediatric gastroenterology and nutrition 32 19274792
2018 VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function. Biochimica et biophysica acta. Molecular basis of disease 30 29409756
2006 VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. The Journal of pediatrics 30 16492441
2016 ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination. Immunity 29 27496733
2016 Vps33b regulates Vwf-positive vesicular trafficking in megakaryocytes. The Journal of pathology 28 27319744
2020 VPS33B modulates c-Myc/p53/miR-192-3p to target CCNB1 suppressing the growth of non-small cell lung cancer. Molecular therapy. Nucleic acids 24 33425490
2018 Proteomic and Biochemical Comparison of the Cellular Interaction Partners of Human VPS33A and VPS33B. Journal of molecular biology 23 29778605
2013 Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes. Human molecular genetics 23 23918659
2022 Syntaxin 12 and COMMD3 are new factors that function with VPS33B in the biogenesis of platelet α-granules. Blood 21 34905616
2019 VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer. International journal of cancer 21 31125123
2000 Cloning, mapping and expression analysis of VPS33B, the human orthologue of rat Vps33b. Cytogenetics and cell genetics 21 10894945
2019 Mechanism of platelet α-granule biogenesis: study of cargo transport and the VPS33B-VPS16B complex in a model system. Blood advances 20 31501156
2019 Novel missense mutation in VPS33B is associated with isolated low gamma-glutamyltransferase cholestasis: Attenuated, incomplete phenotype of arthrogryposis, renal dysfunction, and cholestasis syndrome. Human mutation 19 31479177
2019 Metabolomics and Lipidomics Reveal the Effect of Hepatic Vps33b Deficiency on Bile Acids and Lipids Metabolism. Frontiers in pharmacology 17 30967781
2023 METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m6 A-dependent manner. Journal of cellular physiology 16 37357526
2022 Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation. Cell reports 16 35705052
2020 A Novel Mutation of VPS33B Gene Associated with Incomplete Arthrogryposis-Renal Dysfunction-Cholestasis Phenotype. Case reports in genetics 14 33029437
2020 VPS33B suppresses lung adenocarcinoma metastasis and chemoresistance to cisplatin. Genes & diseases 14 33997178
2019 A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival. JIMD reports 13 31240160
2014 Identification of novel mutations in the VPS33B gene involved in arthrogryposis, renal dysfunction, and cholestasis syndrome. Clinical genetics 12 24917129
2023 The Sec1-Munc18 protein VPS33B forms a uniquely bidirectional complex with VPS16B. The Journal of biological chemistry 11 37062417
2014 ARC syndrome with high GGT cholestasis caused by VPS33B mutations. World journal of gastroenterology 10 24782640
2018 Novel VPS33B mutation in a patient with autosomal recessive keratoderma-ichthyosis-deafness syndrome. American journal of medical genetics. Part A 9 30561130
2021 Hepatic Vps33b deficiency aggravates cholic acid-induced cholestatic liver injury in male mice. Acta pharmacologica Sinica 8 34253877
2019 A Novel VPS33B Variant Identified by Exome Sequencing in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome. Pediatric gastroenterology, hepatology & nutrition 8 31777725
2014 Two novel VPS33B mutations in a patient with arthrogryposis, renal dysfunction and cholestasis syndrome in mainland China. World journal of gastroenterology 7 24415890
2022 Platelet VPS16B is dependent on VPS33B expression, as determined in two siblings with arthrogryposis, renal dysfunction, and cholestasis syndrome. Journal of thrombosis and haemostasis : JTH 6 35325493
2021 VPS33B interacts with NESG1 to suppress cell growth and cisplatin chemoresistance in ovarian cancer. Cancer science 6 33788346
2017 A Novel VPS33B Mutation in a Patient with Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome. Pediatric dermatology 4 28544027
2012 Inhibitory effect of SPE-39 due to tyrosine phosphorylation and ubiquitination on the function of Vps33B in the EGF-stimulated cells. FEBS letters 4 22677173
2017 [Clinical features and VPS33B mutations in a family affected by arthrogryposis, renal dysfunction, and cholestasis syndrome]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 3 29046204
2025 VPS33B-dependent exosomes modulate cellular senescence of mesenchymal stem cells via an autocrine signaling pathway. Experimental gerontology 2 40383211
2022 Two novel mutations in VPS33B gene cause a milder ARC syndrome with prolonged survival in a 12-year-old patient: Case report. Frontiers in pediatrics 2 36568436
2022 Mild Phenotype of Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome 1 Caused by a Novel VPS33B Variant. Frontiers in genetics 1 35281816
2022 Two novel mutations in the VPS33B gene in a Chinese patient with arthrogryposis, renal dysfunction and cholestasis syndrome 1: A case report. World journal of clinical cases 1 36338198
2021 A New Aberration in the VPS33B Gene Leads to Full-Symptom ARCS1. The American journal of case reports 1 34531360
2021 Vps33B in Dendritic Cells Regulates House Dust Mite-Induced Allergic Lung Inflammation. Journal of immunology (Baltimore, Md. : 1950) 1 34732466
2020 Hypersensitivity of Vps33B mutant flies to non-pathogenic infections is dictated by aberrant activation of p38b MAP kinase. Traffic (Copenhagen, Denmark) 1 32677257
2026 A VPS33B CRISPR knockout study: In vitro evidence of an adhesion defect. PloS one 0 41686830
2026 VPS33B regulates MHC class II antigen presentation in dendritic cells to drive CD4 T cell immunity. iScience 0 42231978
2025 A novel homozygous splice-site variant in VPS33B identified as a cause of bleeding. Journal of thrombosis and haemostasis : JTH 0 41138802
2024 [Rare VPS33B gene mutation combined with GP1BA mutation causes severe decrease in plasma VWF levels: a case report and literature review]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 39134495

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