id: Q12907
gene_symbol: LMAN2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: LMAN2 (Vesicular integral-membrane protein VIP36; also GP36b, Lectin mannose-binding 2) is a type-I single-pass transmembrane leguminous-type (L-type) lectin of the early secretory pathway. Its lumenal L-type lectin-like (ConA-like) domain binds high-mannose N-glycans in a Ca2+-dependent manner; VIP36 is a carbohydrate-binding sorting receptor, not a glycosidase. It cycles between the endoplasmic reticulum, the ER-Golgi intermediate compartment (ERGIC) and the Golgi apparatus, where it participates in the transport, sorting and quality control of glycoproteins carrying high-mannose glycans. A characterized cargo is alpha1-antitrypsin, whose high-mannose form VIP36 binds and recycles from the Golgi back to the ER, consistent with a role in post-ER quality control. A minor pool of mature VIP36 reaches the plasma membrane, where it can be released by ectodomain shedding; in macrophages this cell-surface/shed VIP36 contributes to the regulation of phagocytosis, a secondary role distinct from its core ER-Golgi lectin function.
existing_annotations:
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: VIP36 cycles early in the secretory pathway and resides in the ERGIC; the phylogenetic ERGIC localization is concordant with experimental IDA evidence and the UniProt subcellular location.
    action: ACCEPT
    reason: Correct compartment; ERGIC residence is directly supported by experimental localization and UniProt.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate'
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: VIP36 is a single-pass Golgi apparatus membrane protein that cycles early in the secretory pathway; the phylogenetic Golgi membrane localization is correct.
    action: ACCEPT
    reason: Concordant with the UniProt Golgi apparatus membrane subcellular location.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Golgi apparatus
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: VIP36 is a single-pass type I ER membrane protein as part of its ER-ERGIC-Golgi cycling; the phylogenetic ER membrane localization is correct.
    action: ACCEPT
    reason: Concordant with the UniProt endoplasmic reticulum membrane subcellular location.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Single-pass type I
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: D-mannose binding is the core molecular function of VIP36; its L-type lectin domain binds high-mannose N-glycans. The phylogenetic assignment is concordant with experimental IMP evidence.
    action: ACCEPT
    reason: Core molecular function; VIP36 is a high-mannose-binding L-type lectin, supported experimentally and across the LMAN1/LMAN2 family.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: transport and sorting of glycoproteins
    - reference_id: PMID:20477988
      supporting_text: VIP36 binds high-mannose
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: VIP36 cycles between ER, ERGIC and Golgi and participates in ER-to-Golgi vesicle-mediated transport/sorting of high-mannose glycoproteins; conserved across the L-type lectin family.
    action: ACCEPT
    reason: Core cycling/transport role of the early-secretory-pathway lectin; concordant with Reactome COPII-mediated vesicle transport and the UniProt function.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: transport and sorting of glycoproteins
- term:
    id: GO:0030134
    label: COPII-coated ER to Golgi transport vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: As a cycling cargo receptor of the early secretory pathway, VIP36 is found in COPII-coated ER-to-Golgi transport vesicles; the phylogenetic assignment is consistent with Reactome COPII vesicle transport.
    action: ACCEPT
    reason: Correct compartment for an ER-Golgi cycling lectin; concordant with the family and the UniProt early-secretory-pathway function.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: intracellular lectin in the early
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of Golgi membrane localization from the UniProt subcellular-location vocabulary, consistent with stronger experimental and phylogenetic evidence.
    action: ACCEPT
    reason: Correct compartment; redundant with the IBA Golgi membrane and IDA Golgi apparatus annotations.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Golgi apparatus
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER membrane localization from the UniProt subcellular-location vocabulary, consistent with the experimental cycling localization.
    action: ACCEPT
    reason: Correct compartment; redundant with the IBA ER membrane annotation.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Single-pass type I
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: InterPro-based electronic assignment to the generic parent term membrane. VIP36 is a single-pass type I membrane protein, but the bare membrane term is uninformative; the specific ER/ERGIC/Golgi membrane terms are better.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative parent term; the specific early-secretory-pathway membrane compartments (GO:0005789, GO:0033116, GO:0000139) capture the localization more precisely.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Single-pass type I
- term:
    id: GO:0033116
    label: endoplasmic reticulum-Golgi intermediate compartment membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of the ERGIC membrane localization from the UniProt subcellular-location vocabulary; this is the most specific compartment term and matches the experimental evidence.
    action: ACCEPT
    reason: Correct and specific compartment; VIP36 is an ERGIC membrane protein.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate'
- term:
    id: GO:0050766
    label: positive regulation of phagocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic transfer (from mouse Lman2, UniProtKB:Q9DBH5) of a positive regulation of phagocytosis role. This reflects the secondary cell-surface/shed-ectodomain macrophage function, not the core ER-Golgi lectin function.
    action: KEEP_AS_NON_CORE
    reason: Genuine but secondary moonlighting role transferred from the mouse ortholog; not the core early-secretory-pathway sorting function.
    supported_by:
    - reference_id: PMID:22016386
      supporting_text: the amount of VIP36 precisely regulates phagocytosis
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for Golgi apparatus localization, consistent with VIP36's documented Golgi/ER cycling.
    action: ACCEPT
    reason: IDA-supported Golgi localization agrees with the UniProt Golgi apparatus membrane location and experimental cycling.
    supported_by:
    - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
      supporting_text: Golgi apparatus
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: High-throughput identification of VIP36 in urinary/prostatic exosome shotgun proteomics (~900 proteins), with no VIP36-specific functional claim. Reflects presence in secreted vesicles rather than the core ER-Golgi residence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomics-catalog localization; not informative of VIP36's core early-secretory-pathway function.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: ~900 proteins were detected
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20477988
  qualifier: enables
  review:
    summary: Records the interaction with alpha1-antitrypsin (WITH UniProtKB:P01009) identified by YFP-fragment complementation. The interaction is real and underlies the cargo/quality-control role, but the bare protein binding term is uninformative; the informative molecular function is the mannose/carbohydrate binding.
    action: KEEP_AS_NON_CORE
    reason: Captures a genuine cargo interaction but bare protein binding is uninformative; the lectin (D-mannose/carbohydrate binding) terms convey the actual molecular function.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: high-mannose form of
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: IMP
  original_reference_id: PMID:20477988
  qualifier: enables
  review:
    summary: Experimental evidence (in the living cell) that VIP36 binds exclusively the high-mannose form of its glycoprotein cargo alpha1-antitrypsin, with binding abolished by inactivating its glycosylation sites. This is the core high-mannose lectin activity of VIP36.
    action: ACCEPT
    reason: Core molecular function with direct experimental support; VIP36 binds high-mannose glycans.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: bound exclusively to the high-mannose form of
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IDA
  original_reference_id: PMID:20477988
  qualifier: located_in
  review:
    summary: Experimental localization of VIP36 to the early secretory pathway; the VIP36/alpha1-AT complex localized to Golgi and ER as it cycles through the ERGIC.
    action: ACCEPT
    reason: Directly demonstrated ERGIC/early-secretory-pathway localization, consistent with UniProt.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: VIP36 localizes to the Golgi apparatus and
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:20477988
  qualifier: located_in
  review:
    summary: Direct evidence that VIP36 localizes to the Golgi apparatus, where its lectin activity (pH optimum ~6.5) matches the Golgi luminal pH.
    action: ACCEPT
    reason: Directly demonstrated Golgi localization, concordant with the UniProt Golgi apparatus membrane location.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: VIP36 localizes to the Golgi apparatus and
- term:
    id: GO:0006890
    label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
  evidence_type: IMP
  original_reference_id: PMID:20477988
  qualifier: involved_in
  review:
    summary: VIP36 binds the high-mannose form of alpha1-antitrypsin and the complex recycles from the Golgi back to the ER; silencing VIP36 accelerates cargo transport, arguing against an anterograde role and for retrograde Golgi-to-ER recycling in post-ER quality control.
    action: ACCEPT
    reason: Core retrograde transport / post-ER quality-control role, directly demonstrated experimentally.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: Silencing VIP36 accelerated alpha1-AT transport
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: IPI
  original_reference_id: PMID:20477988
  qualifier: enables
  review:
    summary: Records an interaction with the ER chaperone BiP/HSPA5 (WITH UniProtKB:P11021). This is a specific, more informative interaction than bare protein binding and is consistent with a post-ER quality-control context, but it represents a single binding partner rather than VIP36's defining lectin-based sorting mechanism.
    action: KEEP_AS_NON_CORE
    reason: A genuine and reasonably specific interaction, but a peripheral partner rather than the core high-mannose-glycan sorting function; kept non-core.
    supported_by:
    - reference_id: PMID:20477988
      supporting_text: post-ER quality control
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:22016386
  qualifier: located_in
  review:
    summary: A soluble form of VIP36 is released into the extracellular space by ectodomain shedding of cell-surface VIP36 in macrophages. Genuine, but reflects the secondary shedding biology rather than the core ER-Golgi residence.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary localization arising from ectodomain shedding; not the core early-secretory-pathway compartment.
    supported_by:
    - reference_id: PMID:22016386
      supporting_text: a soluble form of VIP36 should be released into the extracellular space
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:22016386
  qualifier: located_in
  review:
    summary: A minor Endo-H-resistant pool of mature VIP36 reaches the plasma membrane, where it accumulates upon inhibition of shedding. Genuine but secondary to the core ER-Golgi localization.
    action: KEEP_AS_NON_CORE
    reason: Real but minor/secondary cell-surface pool linked to ectodomain shedding; not the core compartment.
    supported_by:
    - reference_id: PMID:22016386
      supporting_text: VIP36 significantly accumulates on the cell surface
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:22016386
  qualifier: located_in
  review:
    summary: VIP36 is present on the cell surface, where its shedding occurs; this is the substrate for the shedding-dependent regulation of phagocytosis. Secondary to the core ER-Golgi localization.
    action: KEEP_AS_NON_CORE
    reason: Real but secondary cell-surface localization underlying the shedding/phagocytosis role; not the core compartment.
    supported_by:
    - reference_id: PMID:22016386
      supporting_text: shedding of VIP36 occurs mainly on the cell surface
- term:
    id: GO:0030246
    label: carbohydrate binding
  evidence_type: IDA
  original_reference_id: PMID:23701871
  qualifier: enables
  review:
    summary: Direct quantitative measurement of VIP36 lectin-glycan binding to high-mannose-type glycans, with affinity constants in agreement with ITC and frontal affinity chromatography. Supports the core carbohydrate-binding lectin function.
    action: ACCEPT
    reason: Core molecular function (parent of D-mannose binding); directly measured carbohydrate-binding activity of the VIP36 lectin.
    supported_by:
    - reference_id: PMID:23701871
      supporting_text: lectin-glycan interaction analysis
- term:
    id: GO:0050766
    label: positive regulation of phagocytosis
  evidence_type: IMP
  original_reference_id: PMID:22016386
  qualifier: involved_in
  review:
    summary: In LPS-stimulated macrophages the amount of VIP36 regulates phagocytosis, and ectodomain shedding of cell-surface VIP36 is required for this enhancement; notably the lectin activity is dispensable for it. This is a secondary moonlighting role of shed/cell-surface VIP36, distinct from its core ER-Golgi lectin function.
    action: KEEP_AS_NON_CORE
    reason: Genuine experimentally supported role, but a secondary macrophage cell-surface/shedding function rather than the core early-secretory-pathway sorting function.
    supported_by:
    - reference_id: PMID:22016386
      supporting_text: the amount of VIP36 precisely regulates phagocytosis
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput identification of VIP36 in urinary exosome proteomics (>1100 proteins), with no VIP36-specific functional claim. Reflects presence in secreted vesicles rather than core ER-Golgi residence.
    action: MARK_AS_OVER_ANNOTATED
    reason: Proteomics-catalog localization; not informative of VIP36's core early-secretory-pathway function.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: profile the proteome of human urinary exosomes
- term:
    id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  evidence_type: IDA
  original_reference_id: PMID:15308636
  qualifier: located_in
  review:
    summary: VIP36 was identified among cycling/cargo-receptor proteins in ERGIC membranes purified (enriched ~110-fold over ERGIC-53) from brefeldin A-treated HepG2 cells, supporting its ERGIC localization.
    action: ACCEPT
    reason: Directly supports ERGIC residence of VIP36, consistent with UniProt and other experimental evidence.
    supported_by:
    - reference_id: PMID:15308636
      supporting_text: purification of ERGIC membranes
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:15308636
  title: Proteomics of endoplasmic reticulum-Golgi intermediate compartment (ERGIC)
    membranes from brefeldin A-treated HepG2 cells identifies ERGIC-32, a new cycling
    protein that interacts with human Erv46.
  findings:
  - statement: ERGIC membranes purified from brefeldin A-treated HepG2 cells (enriched ~110-fold over ERGIC-53) contain established and putative cargo receptors of the early secretory pathway, including VIP36, identified by mass spectrometry.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERGIC proteomics study; supports VIP36 ERGIC localization (IDA). Title foregrounds ERGIC-32 but VIP36 is among the cargo receptors in the ERGIC-enriched fraction.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: Large-scale LC-MS/MS profiling of human urinary exosomes catalogued >1100 proteins; VIP36 is one such proteomics hit (HDA), reflecting presence in secreted vesicles rather than a functional localization.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics catalog; supports only an over-annotated extracellular exosome localization.
- id: PMID:20477988
  title: Role of the lectin VIP36 in post-ER quality control of human alpha1-antitrypsin.
  findings:
  - statement: VIP36 is an L-type lectin that localizes to the Golgi and cycles early in the secretory pathway, binding high-mannose glycans in vitro with a pH optimum of 6.5.
    reference_section_type: ABSTRACT
  - statement: VIP36 binds exclusively the high-mannose form of alpha1-antitrypsin; the complex localizes to Golgi and ER and recycles from the Golgi back to the ER, and silencing VIP36 accelerates alpha1-AT transport, consistent with a post-ER quality-control rather than anterograde role.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key functional paper establishing VIP36's high-mannose binding (D-mannose binding IMP), ERGIC/Golgi localization, retrograde Golgi-to-ER recycling, and the alpha1-AT (protein binding IPI) / BiP (heat shock protein binding IPI) interactions. Cached entry is abstract-only.
- id: PMID:22016386
  title: VIP36 protein is a target of ectodomain shedding and regulates phagocytosis
    in macrophage Raw 264.7 cells.
  findings:
  - statement: VIP36 (a lectin-domain transmembrane protein postulated as a cargo receptor for Golgi-to-ER transport) is subject to ectodomain shedding mainly on the cell surface, and the amount of VIP36 regulates phagocytosis in macrophages in a shedding-dependent manner.
    reference_section_type: ABSTRACT
  - statement: VIP36 localizes mainly to the ER and Golgi; only the Endo-H-resistant cell-surface glycoform is shed, and lectin activity is dispensable for the enhancement of phagocytosis.
    reference_section_type: DISCUSSION
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Source of the cell-surface / plasma membrane / extracellular region IDA and the positive regulation of phagocytosis IMP. Establishes the secondary shedding/macrophage role; confirms ER-Golgi as the main localization.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings:
  - statement: Shotgun proteomics of prostatic-secretion-derived urinary exosomes detected ~900 proteins; VIP36 is one such HDA proteomics hit, reflecting presence in secreted vesicles.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput exosome proteomics catalog; supports only an over-annotated extracellular exosome localization.
- id: PMID:23701871
  title: Parallel quantification of lectin-glycan interaction using ultrafiltration.
  findings:
  - statement: Using an ultrafiltration assay with fluorescently labeled high-mannose-type glycans, VIP36 carbohydrate-binding affinity constants were measured and agreed with values from ITC and frontal affinity chromatography.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Quantitative biophysical support for VIP36 carbohydrate (high-mannose) binding (carbohydrate binding IDA).
- id: PMID:33796845
  title: Exploring the landscape of ectodomain shedding by quantitative protein terminomics.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: 'PubMed-verified (PMID:33796845, Tsumagari et al., iScience 2021, DOI
      10.1016/j.isci.2021.102476). Quantitative protein terminomics identifies VIP36/LMAN2 as a
      metalloprotease-regulated ectodomain-shedding substrate with a reproducible cleavage site at
      F298 down-arrow L299 (SVNF/LKSP) detected across multiple cell lines and reduced by the
      broad-spectrum metalloprotease inhibitor BB-94. Provides the specific cleavage-site mechanism
      underlying the previously curated cell-surface shedding role (PMID:22016386). Not cached; no
      supporting_text added. Identified via Falcon deep research.'
- id: file:human/LMAN2/LMAN2-uniprot.txt
  title: UniProt entry Q12907 (LMAN2_HUMAN), Vesicular integral-membrane protein VIP36
  findings:
  - statement: Intracellular L-type lectin of the early secretory pathway that interacts with high-mannose-type glycans and is involved in the transport and sorting of high-mannose glycoproteins; single-pass type I membrane protein of the ERGIC, Golgi and ER membranes; binds 2 calcium ions per subunit as a structural cofactor.
    reference_section_type: OTHER
core_functions:
- description: High-mannose-binding L-type lectin (carbohydrate-recognition / D-mannose binding) acting as the carbohydrate-binding module that recognizes high-mannose N-glycans on secretory glycoproteins.
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  supported_by:
  - reference_id: PMID:20477988
    supporting_text: bound exclusively to the high-mannose form of
  - reference_id: PMID:23701871
    supporting_text: lectin-glycan interaction analysis
- description: ER-ERGIC-Golgi cycling cargo receptor that sorts and recycles high-mannose glycoproteins, mediating retrograde Golgi-to-ER transport in post-ER quality control (e.g., of alpha1-antitrypsin).
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  locations:
  - id: GO:0005793
    label: endoplasmic reticulum-Golgi intermediate compartment
  - id: GO:0005794
    label: Golgi apparatus
  supported_by:
  - reference_id: PMID:20477988
    supporting_text: Silencing VIP36 accelerated alpha1-AT transport
  - reference_id: file:human/LMAN2/LMAN2-uniprot.txt
    supporting_text: transport and sorting of glycoproteins
  directly_involved_in:
  - id: GO:0006890
    label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
  - id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
proposed_new_terms: []
suggested_questions:
- question: Beyond alpha1-antitrypsin, what is the broader endogenous high-mannose glycoprotein cargo repertoire of VIP36, and how is cargo selection coordinated with the LMAN1/ERGIC-53 lectin system?
- question: Is the macrophage shedding/phagocytosis role of VIP36 conserved in human macrophages and physiologically significant, given that lectin activity is dispensable for it?
suggested_experiments:
- description: Map the endogenous VIP36 glycoprotein interactome by glyco-proteomics of VIP36 pull-downs (wild type vs carbohydrate-binding-site mutant) to define the high-mannose cargo set and distinguish sugar-dependent from sugar-independent partners.
- description: Use pulse-chase and ER/Golgi trafficking assays in VIP36-knockout cells to quantify the contribution of VIP36 to retrograde Golgi-to-ER recycling and post-ER quality control of high-mannose glycoproteins.
- description: Identify the macrophage-specific sheddase for VIP36 and test, in primary human macrophages, whether the shed ectodomain or the membrane-retained fragment mediates the effect on phagocytosis.