Affinage

VPS11

Vacuolar protein sorting-associated protein 11 homolog · UniProt Q9H270

Length
941 aa
Mass
107.8 kDa
Annotated
2026-04-28
35 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VPS11 is a core subunit of the HOPS and CORVET endolysosomal tethering complexes, functioning as a peripheral vacuolar/endosomal membrane protein essential for vesicle docking and fusion across multiple trafficking pathways including Golgi-to-prevacuolar transport, late endosome-to-lysosome fusion, autophagosome-lysosome fusion, and melanosome maturation (PMID:2204580, PMID:9475722, PMID:21330665, PMID:27120463). Beyond its tethering role, VPS11 possesses intrinsic E3 ubiquitin ligase activity through its C-terminal RING-H2 domain, enabling ubiquitination of substrates such as PELP1 to modulate Wnt, ERα, and NF-κB signaling (PMID:31015428). Disease-causing mutations in the VPS11 RING-H2 domain destabilize the protein, impair VPS11–VPS18 complex assembly, compromise autophagic flux, and reduce CNS myelination, linking VPS11 loss-of-function to leukoencephalopathy and adult-onset generalized dystonia (PMID:27120463, PMID:33452836). VPS11 expression is post-transcriptionally regulated by m6A modification of its mRNA (removed by ALKBH5) and by miR-542-3p, which suppresses VPS11 in human macrophages during mycobacterial infection to subvert autophagic clearance (PMID:39434426, PMID:35662671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1990 High

    Establishing VPS11 as a peripheral vacuolar membrane protein required for vacuolar hydrolase maturation answered the fundamental question of where and why VPS11 acts in the endomembrane system.

    Evidence Gene disruption, complementation, cell fractionation, and immunoblotting in S. cerevisiae

    PMID:2204580

    Open questions at the time
    • No interacting partners or complexes identified
    • Mechanism of membrane association unknown
    • Role limited to vacuolar hydrolase sorting; broader trafficking functions not explored
  2. 1998 Medium

    Epistasis analysis revealed that VPS11 is bifunctional, acting at both the Golgi-to-prevacuolar and vacuolar fusion steps, broadening VPS11 from a single-pathway component to a multi-step trafficking factor.

    Evidence Genetic suppressor analysis of vps8-200/pep5 double mutants in yeast with vacuolar morphology and hydrolase activity readouts

    PMID:9475722

    Open questions at the time
    • Whether VPS11 acts in distinct complexes at each step was unknown
    • Direct biochemical interaction with Vps8 not tested
  3. 2011 High

    Identification of VPS11 as essential for melanosome maturation in zebrafish extended its trafficking role to specialized lysosome-related organelles in vertebrates, separating its function from melanin biosynthesis initiation.

    Evidence Bulked segregant analysis, morpholino phenocopy, genetic rescue, TEM in zebrafish platinum mutant

    PMID:21330665

    Open questions at the time
    • Step at which melanosome biogenesis is blocked not molecularly defined
    • HOPS/CORVET complex involvement in melanosomes not directly tested
  4. 2013 Medium

    Demonstrating that Vps11 loss leads to caspase-independent, cathepsin-dependent cell death with autophagosome accumulation established that VPS11 is required for autophagic flux and lysosomal integrity in vivo.

    Evidence Pharmacological rescue (ALLM, bafilomycin A1), LC3B-II western blot, TUNEL analysis in zebrafish vps11(w66) mutant chromatophores

    PMID:23724125

    Open questions at the time
    • Whether autophagosome accumulation reflects fusion block vs. degradation block not distinguished
    • Mechanism of cathepsin release not defined
  5. 2015 High

    Functional characterization of the VPS11 C846G RING-H2 domain mutation in yeast and human cells established that this domain is critical for protein stability, VPS11–VPS18 complex integrity, autophagic activity, and CNS myelination, linking VPS11 to a leukoencephalopathy.

    Evidence Yeast Mup1-GFP transport assay; co-IP for VPS11–VPS18 assembly; autophagy flux assays in human cells; zebrafish myelination analysis; patient exome sequencing

    PMID:26307567 PMID:27120463

    Open questions at the time
    • Whether RING-H2 E3 ligase activity per se is required for tethering complex function vs. structural integrity not separated
    • Full patient phenotype-genotype correlation limited to single family
  6. 2015 High

    Conditional knockdown of Vps11 in Toxoplasma gondii demonstrated that HOPS/CORVET-mediated vesicular trafficking is essential for biogenesis of multiple secretory organelles and parasite virulence, generalizing VPS11 function across eukaryotes.

    Evidence Conditional knockdown, immunofluorescence co-localization, phenotypic assays for organelle biogenesis, invasion, and growth in T. gondii

    PMID:25640905

    Open questions at the time
    • Specific HOPS vs. CORVET contribution not separated
    • Direct physical association of TgVps11 with tethering complex subunits not biochemically demonstrated
  7. 2019 High

    Discovery that VPS11 possesses intrinsic E3 ubiquitin ligase activity via its RING-H2 domain, with the ability to ubiquitinate PELP1 and modulate Wnt, ERα, and NF-κB signaling, revealed a signaling regulatory function independent of its canonical tethering role.

    Evidence In vitro ubiquitination assays, overexpression studies, signaling pathway reporters, co-IP of PELP1 ubiquitination

    PMID:31015428

    Open questions at the time
    • Endogenous-level E3 ligase activity not confirmed; findings rely on overexpression
    • Substrate specificity and physiological relevance under endogenous conditions not established
    • Whether E3 activity is separable from tethering function in vivo not tested
  8. 2021 Medium

    Localization of VPS11 to the myelin inner tongue with MAG and to PDGFRα-positive vesicles in oligodendrocytes suggested VPS11 participates in retrograde endolysosomal transport from the myelin sheath to the cell body, providing anatomical context for VPS11-associated leukoencephalopathy.

    Evidence Immunocytochemistry and immunofluorescence co-localization in mouse brain tissue and cultured oligodendrocytes

    PMID:33874780

    Open questions at the time
    • No functional KO/KD in oligodendrocytes to validate trafficking role
    • Co-localization alone does not establish direct functional interaction with MAG or PDGFRα
  9. 2021 Medium

    Demonstration that a novel VPS11 variant causes adult-onset generalized dystonia with lysosomal and autophagic abnormalities rescuable by wild-type VPS11 expanded the disease spectrum beyond leukoencephalopathy.

    Evidence Functional studies in patient fibroblasts with lysosomal/autophagic assays and rescue by wild-type VPS11 overexpression

    PMID:33452836

    Open questions at the time
    • Single family study; independent confirmation pending
    • Specific step in autophagosome–lysosome fusion that is disrupted not defined
  10. 2022 Medium

    Identification of miR-542-3p as a direct negative regulator of VPS11 mRNA in human macrophages during M. tuberculosis infection revealed a pathogen immune-evasion strategy that exploits VPS11-dependent autophagy.

    Evidence Luciferase reporter assay, RNA pulldown, RNA immunoprecipitation, VPS11 overexpression rescue in human macrophages

    PMID:35662671

    Open questions at the time
    • Species-specific (human) miRNA targeting—mouse/rat validation not possible
    • Whether other HOPS/CORVET subunits are co-regulated by miR-542-3p not tested
  11. 2024 Medium

    Showing that m6A modification of VPS11 mRNA, regulated by ALKBH5 demethylase, controls VPS11 translation and thereby autophagic flux and hepatic lipid homeostasis uncovered an epitranscriptomic layer of VPS11 regulation.

    Evidence MeRIP-qPCR, ALKBH5 knockdown/overexpression, autophagy flux assays, rescue by VPS11 overexpression in hepatocytes

    PMID:39434426

    Open questions at the time
    • Specific m6A site(s) on VPS11 mRNA not mapped
    • In vivo hepatic phenotype of VPS11 loss not directly tested
    • Reader protein mediating m6A-dependent translational regulation of VPS11 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether VPS11's E3 ligase activity is physiologically relevant at endogenous expression levels, how the RING-H2 domain's enzymatic and structural roles are balanced within the HOPS/CORVET complex, and what the complete genotype–phenotype spectrum is for VPS11 loss-of-function in the human nervous system.
  • Endogenous-level E3 ligase substrates not identified by unbiased proteomics
  • Structural basis for VPS11 within HOPS/CORVET not resolved at atomic level in human
  • Full phenotypic spectrum of human VPS11 mutations across tissues not systematically catalogued

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 4 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-9612973 Autophagy 5 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1
Partners
ALKBH5PELP1VPS18
Complex memberships
CORVET complexHOPS complex

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Yeast PEP5/VPS11 gene product is a peripheral vacuolar membrane protein of ~107 kDa required for vacuolar hydrolase maturation; loss-of-function causes accumulation of inactive precursors to vacuolar hydrolases and vestigial vacuole morphology. Gene deletion/disruption, complementation, cell fractionation, immunoblot with anti-PEP5 antibodies Genetics High 2204580
1998 Genetic epistasis in yeast shows that VPS11/PEP5 functions both at the Golgi-to-prevacuolar compartment step (where Vps8p acts) and more proximally at the vacuole; the vps8-200 allele partially suppresses the pep5 vestigial vacuole phenotype, restoring mature vacuolar hydrolases, indicating VPS11 is bifunctional across multiple transport pathways to the vacuole. Genetic epistasis/suppressor analysis; double-mutant phenotypic characterization of vacuolar morphology and hydrolase activity Genetics Medium 9475722
2016 The human VPS11 C846G missense mutation in the RING-H2 domain causes aberrant ubiquitination and accelerated turnover of VPS11 protein, compromised VPS11-VPS18 complex assembly, impaired autophagic activity in human cells, and reduced CNS myelination in zebrafish with truncated RING-H2 domain. Exome sequencing for variant identification; immunoblot for protein stability; co-immunoprecipitation for VPS11-VPS18 complex assembly; autophagy flux assay in human cells; zebrafish vps11 mutant CNS myelination analysis PLoS genetics High 27120463
2015 The yeast homolog of the human VPS11 C846G mutation (p.Cys846Gly) shows moderate impairment of fusion of the late endosome to the vacuole, as demonstrated by the Mup1-GFP transport assay in mutant yeast. Mup1-GFP transport assay in Saccharomyces cerevisiae homologous mutant Journal of medical genetics Medium 26307567
2019 Vps11 (and Vps18), as common subunits of the HOPS/CORVET complexes, possess intrinsic E3 ubiquitin ligase activity; overexpression perturbs ubiquitination in signal transduction pathways including Wnt, ERα, and NFκB; specifically, Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs ERα activation by c-Src. Overexpression experiments, ubiquitination assays, signaling pathway readouts (Wnt, ERα, NFκB reporters), co-immunoprecipitation of PELP1 ubiquitination Nature communications High 31015428
2015 Toxoplasma gondii Vps11 (ortholog of human VPS11) is a component of HOPS and CORVET tethering complexes; it associates dynamically with Golgi endosomal-related compartments, the vacuole, and immature apical secretory organelles; conditional knockdown disrupts biogenesis of dense granules, rhoptries, and micronemes, impairing parasite motility, invasion, egress, and intracellular growth. Conditional knockdown (regulatable expression), immunofluorescence/co-localization, phenotypic analysis of organelle biogenesis and parasite function Cellular microbiology High 25640905
2011 Loss of zebrafish Vps11 (platinum mutant) results in absence of mature melanosomes and gradual loss of RPE integrity; Vps11 is essential for melanosome maturation but not for initiation of melanin biosynthesis or normal retinal development, establishing its role in late-stage vesicular trafficking in pigment cells. Bulked segregant analysis, candidate gene sequencing, phenocopy by morpholino, rescue experiments, histology, immunohistochemistry, transmission electron microscopy Investigative ophthalmology & visual science High 21330665
2013 In zebrafish vps11(w66) mutants, loss of Vps11 leads to caspase-independent, cathepsin-dependent chromatophore death; increased autophagosome marker LC3B-II accumulation and premature chromatophore death are rescued by cathepsin/calpain inhibitor ALLM or bafilomycin A1 (V-ATPase inhibitor), indicating Vps11 promotes melanophore survival by suppressing aberrant cathepsin release/activity. TUNEL analysis, caspase inhibitor treatment, western blot for PARP-1 cleavage and LC3B, pharmacological rescue with ALLM and bafilomycin A1 PloS one Medium 23724125
2014 Knockdown of Vps11 (core subunit of HOPS and CORVET) in human cells increases retrograde transport of Shiga toxin and ricin to the Golgi, increases their toxicity, and restores reduced Gb3 glycolipid levels caused by moesin depletion, placing Vps11 as a negative regulator of retrograde toxin transport and glycolipid degradation. siRNA knockdown, retrograde transport assays for Shiga toxin and ricin, cytotoxicity assays, Gb3 level measurement Communicative & integrative biology Medium 24778763
2021 VPS11 protein is strongly expressed in mouse oligodendrocytes and localizes with Myelin Associated Glycoprotein (MAG) in the inner tongue of myelin; co-localization with PDGFRα in round vesicles of OPCs/oligodendrocytes in vitro and in vivo suggests VPS11 participates in retrograde endolysosomal transport from the myelin inner tongue to the oligodendrocyte perikaryon. Immunocytochemistry, immunofluorescent co-localization (Vps11/MAG, Vps11/MBP, Vps11/neurofilament, Vps11/PDGFRα) in mouse tissue and cultured cells ASN neuro Medium 33874780
2021 A novel homozygous VPS11 variant associated with adult-onset generalized dystonia causes marked lysosomal and autophagic abnormalities in patient fibroblasts; these abnormalities are rescued by overexpression of wild-type VPS11 protein, confirming a loss-of-function mechanism. Functional studies in patient fibroblasts: lysosomal and autophagic assays; rescue by wild-type VPS11 overexpression Annals of neurology Medium 33452836
2024 ALKBH5, an m6A demethylase, removes m6A modification from VPS11 mRNA to promote its translation; loss of ALKBH5 reduces VPS11 protein levels, impairing autophagic flux (autophagosome-lysosome fusion) and promoting hepatic lipid accumulation; VPS11 overexpression reverses lipid accumulation in ALKBH5-silenced hepatocytes. RNA-sequencing, methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR), stable overexpression/knockdown, autophagy flux assays (LC3B, p62), rescue by VPS11 overexpression The FEBS journal Medium 39434426
2022 miR-542-3p targets the 3' UTR of human VPS11 mRNA (seed sequence absent in mouse/rat), reducing VPS11 expression in human macrophages upon M. tuberculosis infection; VPS11 overexpression antagonizes miR-542-3p-mediated promotion of mycobacterial survival by restoring autophagy. Luciferase reporter assay, RNA pulldown, RNA immunoprecipitation, VPS11 overexpression in human macrophages, autophagy 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 33 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 8 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
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
2024 The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux. The FEBS journal 3 39434426
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