Affinage

VPS11

Vacuolar protein sorting-associated protein 11 homolog · UniProt Q9H270

Length
941 aa
Mass
107.8 kDa
Annotated
2026-06-11
35 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS11 is a core subunit of the endolysosomal/vacuolar tethering machinery that drives delivery of proteins to the vacuole/lysosome and the maturation of late organelles across eukaryotes (PMID:2204580, PMID:12796286). First defined in yeast as a peripheral vacuolar membrane protein essential for vacuolar biogenesis and the proteolytic maturation of vacuolar hydrolases (PMID:2204580), it acts at multiple trafficking steps including the Golgi-to-prevacuolar route and, critically, the fusion of late endosomes with the vacuole/lysosome (PMID:9475722, PMID:26307567). As a shared subunit of the HOPS/CORVET complexes it carries E3 ubiquitin ligase activity, ubiquitinating substrates such as the scaffold PELP1 to modulate ERα, Wnt, and NFκB signaling (PMID:31015428). Across organisms VPS11 is required for late organelle biogenesis rather than cell fate: melanosome maturation and RPE/photoreceptor maintenance in zebrafish (PMID:21330665), and biogenesis of secretory organelles (dense granules, rhoptries, micronemes) in Toxoplasma (PMID:25640905). A central downstream function is the support of autophagic flux through autophagosome-lysosome fusion (PMID:27120463, PMID:33452836). The human VPS11 C846G mutation in the RING-H2 domain causes aberrant ubiquitination and accelerated turnover of VPS11, compromised VPS11-VPS18 complex assembly, and impaired autophagy, producing CNS hypomyelination and neuronal death; other homozygous variants cause adult-onset generalized dystonia, with patient-fibroblast lysosomal and autophagic defects rescued by wild-type VPS11 (PMID:27120463, PMID:33452836). VPS11 expression is post-transcriptionally tuned: ALKBH5-mediated m6A demethylation of VPS11 mRNA promotes its translation (PMID:39434426), and miR-542-3p targets its 3' UTR to suppress autophagy-dependent anti-mycobacterial defense (PMID:35662671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1990 High

    Established that VPS11 is required for biogenesis of the vacuole and delivery/maturation of vacuolar hydrolases, defining its foundational role in endolysosomal trafficking.

    Evidence Gene deletion, cell fractionation, and immunoblot of vacuolar hydrolase precursors in S. cerevisiae

    PMID:2204580

    Open questions at the time
    • Did not define the molecular complex or tethering mechanism
    • No mammalian ortholog characterized
  2. 1998 Medium

    Showed VPS11 acts at multiple trafficking steps, including the Golgi-to-prevacuolar step where Vps8p operates, refining where in the pathway it functions.

    Evidence Genetic epistasis (vps8/pep5 double mutants) with vacuolar hydrolase and morphology readouts in yeast

    PMID:9475722

    Open questions at the time
    • Genetic suppression does not establish direct physical interaction
    • Step-specific molecular role unresolved
  3. 2003 High

    Extended VPS11 function to fungal organelle biogenesis and linked vacuolar trafficking to hyphal morphogenesis and secreted enzyme activity.

    Evidence Gene deletion with vacuolar morphology, enzyme activity, and morphogenesis assays in C. albicans

    PMID:12796286

    Open questions at the time
    • Link between trafficking defect and morphogenesis mechanistically indirect
  4. 2011 High

    Demonstrated VPS11 is dispensable for cell fate but essential for late organelle maturation, distinguishing a biogenesis role from a developmental one.

    Evidence Zebrafish platinum mutant with phenocopy/rescue, histology, and electron microscopy of melanosomes, RPE, and photoreceptors

    PMID:21330665

    Open questions at the time
    • Molecular basis of melanosome maturation defect not defined
  5. 2013 Medium

    Connected VPS11 loss to impaired autophagic flux and cathepsin-driven cell death, implicating the lysosomal degradation pathway in VPS11 phenotypes.

    Evidence Zebrafish mutant with TUNEL, LC3B-II Western blot, and pharmacological inhibition of cathepsins/calpain and V-ATPase

    PMID:23724125

    Open questions at the time
    • Causal chain from autophagy block to cathepsin release inferred pharmacologically
    • Single lab
  6. 2015 Medium

    Pinpointed the disease C846G variant to the late endosome-to-vacuole fusion step using a functional homolog assay, mechanistically localizing the defect.

    Evidence Yeast Mup1-GFP transport assay of the homologous mutation, plus exome and homozygosity mapping

    PMID:26307567

    Open questions at the time
    • Assay in yeast surrogate, not human cells
    • Impairment characterized as moderate
  7. 2015 High

    Showed VPS11 supports secretory organelle biogenesis and parasite infectivity, broadening its organelle-maturation role to apicomplexan secretory pathways.

    Evidence Conditional knockdown with immunofluorescence localization and invasion/motility/egress assays in T. gondii

    PMID:25640905

    Open questions at the time
    • Direct tethering partners in the parasite not identified
  8. 2016 High

    Defined the molecular consequences of the human C846G RING-H2 mutation, linking disrupted VPS11-VPS18 assembly and aberrant ubiquitination to impaired autophagy and CNS hypomyelination.

    Evidence Whole exome sequencing, ubiquitination and Co-IP assays, autophagy flux assays in human cells, and zebrafish RING-H2 truncation model

    PMID:27120463

    Open questions at the time
    • Structural basis of complex destabilization not resolved
    • E3 ligase activity not directly addressed here
  9. 2019 Medium

    Identified VPS11/VPS18 as functional E3 ubiquitin ligases acting on signaling substrates, expanding VPS11 beyond membrane tethering into signal-pathway regulation.

    Evidence Overexpression and ubiquitination assays across Wnt/ERα/NFκB pathways with Co-IP of PELP1 ubiquitination

    PMID:31015428

    Open questions at the time
    • Demonstrated by overexpression; physiological context unclear
    • Direct catalytic mechanism not reconstituted
  10. 2021 Medium

    Localized VPS11 to oligodendrocyte myelin and endolysosomal vesicles, providing a cellular basis for VPS11-related hypomyelination.

    Evidence Immunocytochemistry and co-staining with MAG, MBP, PDGFRα in mouse oligodendrocytes in vitro and in vivo

    PMID:33874780

    Open questions at the time
    • No functional perturbation experiment
    • Retrograde transport role inferred from co-localization
  11. 2021 Medium

    Linked a distinct VPS11 variant to adult-onset dystonia and established the autophagic-lysosomal pathway as the disease mechanism via rescue.

    Evidence Patient fibroblast lysosomal/autophagic assays rescued by wild-type VPS11 overexpression

    PMID:33452836

    Open questions at the time
    • Single family/lab
    • Genotype-phenotype relationship to other VPS11 variants not resolved
  12. 2022 Medium

    Showed VPS11 is a post-transcriptionally regulated autophagy effector in anti-mycobacterial immunity, with miR-542-3p suppressing it to favor pathogen survival.

    Evidence Luciferase reporter, RNA pulldown/IP, VPS11 overexpression rescue, and M. tuberculosis survival/autophagy assays in macrophages

    PMID:35662671

    Open questions at the time
    • miR target site human-specific
    • Single lab
  13. 2024 Medium

    Identified m6A demethylation by ALKBH5 as a translational control mechanism for VPS11, linking VPS11-dependent autophagic flux to hepatic lipid homeostasis.

    Evidence ALKBH5 manipulation, MeRIP-qPCR on VPS11 mRNA, VPS11 overexpression rescue, and autophagy/lipid assays in hepatocytes

    PMID:39434426

    Open questions at the time
    • Reader protein decoding the m6A mark not identified
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VPS11's tethering, E3 ligase, and complex-assembly functions are mechanistically integrated, and the structural basis by which disease mutations destabilize the HOPS/CORVET core, remain unresolved.
  • No structural model of VPS11 within HOPS/CORVET
  • Catalytic E3 mechanism not reconstituted in vitro
  • Relationship between ubiquitin ligase activity and membrane tethering unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005768 endosome 2 GO:0005794 Golgi apparatus 2 GO:0005764 lysosome 1 GO:0005773 vacuole 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1
Partners
PELP1VPS18VPS8
Complex memberships
CORVETHOPS

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 PEP5/VPS11 (Saccharomyces cerevisiae) encodes a 117 kDa peripheral vacuolar membrane protein required for vacuolar biogenesis; pep5 deletion mutants accumulate inactive precursors of vacuolar hydrolases (PrA, PrB, CpY, alkaline phosphatase) and display vestigial vacuole morphology, establishing VPS11 as essential for protein delivery to the vacuole. Genetic complementation, gene deletion/disruption, cell fractionation, immunoblot with anti-PEP5 fusion protein antibody Genetics High 2204580
1998 Genetic epistasis in S. cerevisiae shows that the vps8-200 allele partially suppresses the vestigial vacuole phenotype and vacuolar hydrolase processing defect of pep5 (VPS11) mutants, indicating VPS11/Pep5p functions at multiple steps in vacuolar trafficking, including at the Golgi-to-prevacuolar compartment step where Vps8p acts. Genetic epistasis (double-mutant analysis), vacuolar hydrolase activity assays, vacuolar morphology assessment Genetics Medium 9475722
2003 C. albicans VPS11 is required for vacuolar biogenesis, secreted lipase and aspartyl protease activities, and yeast-to-hypha morphogenesis; vps11Δ mutants lack a vacuolar compartment and show delayed germ tube emergence and inability to form mature hyphae, indicating VPS11-mediated trafficking is necessary for hyphal growth. Gene deletion, vacuolar morphology assay, enzyme activity assays, morphogenesis induction assay Eukaryotic cell High 12796286
2011 Loss of Vps11 in zebrafish (platinum mutant, single-nucleotide insertion in vps11) does not block melanophore development, migration, or dispersion, but is essential for melanosome maturation and healthy maintenance of the RPE and photoreceptors, demonstrating a specific role for Vps11 in late organelle biogenesis rather than cell fate. Bulked segregant analysis, candidate gene sequencing, phenocopy and rescue experiments, RT-PCR, in situ hybridization, histology, immunohistochemistry, transmission electron microscopy Investigative ophthalmology & visual science High 21330665
2013 In zebrafish vps11(w66) mutants, loss of Vps11 leads to caspase-independent chromatophore death associated with increased cathepsin activity; inhibition of cathepsins/calpain (ALLM) or vacuolar H+-ATPase (Bafilomycin A1) restores normal melanophore morphology and number, and LC3B-II accumulation indicates impaired autophagic flux. This establishes Vps11 as promoting melanophore survival by inhibiting cathepsin release/activity. Zebrafish mutant analysis, TUNEL assay, caspase inhibitor treatment, Western blot for PARP-1 cleavage and LC3B-II, pharmacological inhibition (ALLM, Bafilomycin A1) PloS one Medium 23724125
2015 T. gondii Vps11 orthologue (TgVps11) is a dynamic protein that associates with Golgi endosomal-related compartments, the vacuole, and immature apical secretory organelles; conditional knockdown of TgVps11 disrupts biogenesis or proper subcellular localization of dense granules, rhoptries, and micronemes, impairing parasite motility, invasion, egress, and intracellular growth. Conditional knockdown, immunofluorescence/subcellular localization, invasion and motility assays, phenotypic analysis of secretory organelle biogenesis Cellular microbiology High 25640905
2015 The VPS11 p.Cys846Gly mutation (homologous yeast mutation tested in Mup1-GFP transport assay) causes moderate impairment of fusion of the late endosome to the vacuole, establishing that the C846G variant specifically disrupts the endosomal-vacuolar fusion step. Yeast Mup1-GFP transport assay (functional homologue assay), exome analysis, homozygosity mapping Journal of medical genetics Medium 26307567
2016 The VPS11 C846G (c.2536T>G) missense mutation in humans causes aberrant ubiquitination and accelerated turnover of VPS11 protein, compromised VPS11-VPS18 complex assembly, and impaired autophagic activity; zebrafish with truncated RING-H2 domain show significant reduction in CNS myelination and extensive neuronal death in hindbrain and midbrain. Whole exome sequencing, ubiquitination assays, VPS11-VPS18 co-immunoprecipitation, autophagy flux assays in human cells, zebrafish genetic model with histology PLoS genetics High 27120463
2019 Vps11 and Vps18, as common subunits of HOPS/CORVET complexes, function as E3 ubiquitin ligases; overexpression of Vps11/Vps18 perturbs ubiquitination in signal transduction pathways including Wnt, estrogen receptor α (ERα), and NFκB; specifically, Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs activation of ERα by c-Src. Overexpression, ubiquitination assays, signaling pathway readouts (Wnt, ERα, NFκB), co-immunoprecipitation for PELP1 ubiquitination Nature communications Medium 31015428
2021 VPS11 is strongly expressed in mouse oligodendrocytes and specifically localizes with Myelin Associated Glycoprotein (MAG) in the inner tongue of myelin; Vps11 co-localizes with PDGFRα in round vesicles of OPCs/oligodendrocytes in vitro and in vivo, suggesting a role in retrograde endolysosomal transport from the myelin inner tongue to the oligodendrocyte perikaryon. Immunocytochemistry, immunofluorescent co-staining with MAG, MBP, neurofilament, and PDGFRα markers, in vitro and in vivo co-localization ASN neuro Medium 33874780
2021 A novel homozygous VPS11 variant causes adult-onset generalized dystonia; functional studies on patient-derived fibroblasts show marked lysosomal and autophagic abnormalities that are rescued by overexpression of wild-type VPS11, establishing the autophagic-lysosomal pathway as the mechanistic basis of VPS11-related disease. Patient fibroblast functional studies (lysosomal/autophagic assays), wild-type VPS11 rescue experiment Annals of neurology Medium 33452836
2014 Knockdown of Vps11 in human cells increases retrograde Golgi transport of Shiga toxin (Stx) and ricin, and also increases Stx toxicity and ricin toxicity; Vps11 knockdown also restores reduced Gb3 (globotriaosylceramide) glycolipid levels caused by moesin depletion, establishing that Vps11 regulates retrograde toxin transport and glycolipid degradation. siRNA knockdown, Shiga toxin and ricin retrograde transport assays, toxicity assays, Gb3 level measurement Communicative & integrative biology Low 24778763
2024 ALKBH5, an m6A RNA demethylase, alleviates hepatic lipid deposition by removing m6A modification on VPS11 mRNA to promote its translation; overexpression of VPS11 reverses FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes by restoring autophagosome-lysosome fusion (autophagic flux). Overexpression and knockdown of ALKBH5, methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), RNA-seq, VPS11 overexpression rescue, autophagy flux assays (LC3B, p62/SQSTM1), lipid accumulation assays The FEBS journal Medium 39434426
2022 miR-542-3p targets the 3' UTR of human VPS11 mRNA (seed sequence absent in mice/rats), reducing VPS11 expression in macrophages infected with M. tuberculosis; VPS11 overexpression antagonizes the miR-542-3p-mediated promotion of M. tuberculosis survival by restoring autophagic flux, establishing VPS11 as a key autophagy regulator in anti-mycobacterial defense. Luciferase reporter assay, RNA pulldown, RNA immunoprecipitation, VPS11 overexpression in macrophages, M. tuberculosis survival assay, autophagy flux assays Microbial pathogenesis Medium 35662671

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Nucleotide sequence of the lantibiotic Pep5 biosynthetic gene cluster and functional analysis of PepP and PepC. Evidence for a role of PepC in thioether formation. European journal of biochemistry 119 7556197
1989 Pep5, a new lantibiotic: structural gene isolation and prepeptide sequence. Archives of microbiology 98 2764678
1996 Engineering of a novel thioether bridge and role of modified residues in the lantibiotic Pep5. Applied and environmental microbiology 96 8593044
1990 Biosynthesis of the lantibiotic Pep5. Isolation and characterization of a prepeptide containing dehydroamino acids. European journal of biochemistry 80 2253617
2016 A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects. PLoS genetics 61 27120463
2003 Candida albicans VPS11 is required for vacuole biogenesis and germ tube formation. Eukaryotic cell 59 12796286
1996 The biosynthesis of the lantibiotics epidermin, gallidermin, Pep5 and epilancin K7. Antonie van Leeuwenhoek 54 8775972
1994 Producer immunity towards the lantibiotic Pep5: identification of the immunity gene pepI and localization and functional analysis of its gene product. Applied and environmental microbiology 54 8085827
2004 Localization and functional analysis of PepI, the immunity peptide of Pep5-producing Staphylococcus epidermidis strain 5. Applied and environmental microbiology 50 15184120
2015 Toxoplasma gondii Vps11, a subunit of HOPS and CORVET tethering complexes, is essential for the biogenesis of secretory organelles. Cellular microbiology 44 25640905
1994 Construction of an expression system for engineering of the lantibiotic Pep5. Applied and environmental microbiology 44 7811073
1990 Isolation and characterization of PEP5, a gene essential for vacuolar biogenesis in Saccharomyces cerevisiae. Genetics 44 2204580
2015 Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients. Journal of medical genetics 43 26307567
1999 Molecular analysis of expression of the lantibiotic pep5 immunity phenotype. Applied and environmental microbiology 37 9925587
2019 Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling. Nature communications 34 31015428
2006 Bacteriocins Pep5 and epidermin inhibit Staphylococcus epidermidis adhesion to catheters. Current microbiology 33 16586024
2011 The loss of vacuolar protein sorting 11 (vps11) causes retinal pathogenesis in a vertebrate model of syndromic albinism. Investigative ophthalmology & visual science 29 21330665
2021 A Novel Homozygous VPS11 Variant May Cause Generalized Dystonia. Annals of neurology 26 33452836
2016 The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement. Journal of inherited metabolic disease 26 27473128
2013 Maintenance of melanophore morphology and survival is cathepsin and vps11 dependent in zebrafish. PloS one 20 23724125
2018 A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs. G3 (Bethesda, Md.) 19 29945969
2006 Reduced expression of vps11 causes less pigmentation in medaka, Oryzias latipes. Pigment cell research 14 17083489
1998 Genetic interaction with vps8-200 allows partial suppression of the vestigial vacuole phenotype caused by a pep5 mutation in Saccharomyces cerevisiae. Genetics 11 9475722
2022 Vision and sensorimotor defects associated with loss of Vps11 function in a zebrafish model of genetic leukoencephalopathy. Scientific reports 9 35241734
2024 The two-component regulatory systems GraRS and SrrAB mediate Staphylococcus aureus susceptibility to Pep5 produced by clinical isolate of Staphylococcus epidermidis. Applied and environmental microbiology 6 38832774
2022 Multi-Layered PLGA-PEI Nanoparticles Functionalized with TKD Peptide for Targeted Delivery of Pep5 to Breast Tumor Cells and Spheroids. International journal of nanomedicine 6 36444195
2019 Melanosome maturation proteins Oca2, Mitfa and Vps11 are differentially required for cisplatin resistance in zebrafish melanocytes. Experimental dermatology 6 30977151
2024 The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux. The FEBS journal 5 39434426
2019 Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of the Trypanosoma cruzi Life Cycle and Blocks Parasite Infectivity. Antimicrobial agents and chemotherapy 5 30833431
2014 Vps11, a subunit of the tethering complexes HOPS and CORVET, is involved in regulation of glycolipid degradation and retrograde toxin transport. Communicative & integrative biology 5 24778763
2022 Pep5-based antitumor peptides containing multifunctional fragments with enhanced activity and synergistic effect. European journal of medicinal chemistry 3 35452935
2021 Characterization of the Expression of Vacuolar Protein Sorting 11 (Vps11) in Mammalian Oligodendrocytes. ASN neuro 3 33874780
2022 Overexpression of VPS11 antagonizes the promoting effect of miR-542-3p on Mycobacterium tuberculosis survival in macrophages by regulating autophagy. Microbial pathogenesis 2 35662671
2026 Pep5-Cpp, a Cyclin D2-Derived Antimicrobial. Molecules (Basel, Switzerland) 0 41752412
2025 Confirmation of biallelic VPS11 variants as a cause of complex dystonic syndrome. Clinical parkinsonism & related disorders 0 41551069

Missed literature

Know a paper Affinage missed for VPS11? Flag it for the maintainers and the community.

No submissions yet.