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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Correct compartment; ERGIC residence is directly supported by experimental localization and UniProt. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate |
| GO:0000139 Golgi membrane | IBA GO_REF:0000033 | ACCEPT | Summary: VIP36 is a single-pass Golgi apparatus membrane protein that cycles early in the secretory pathway; the phylogenetic Golgi membrane localization is correct. Reason: Concordant with the UniProt Golgi apparatus membrane subcellular location. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Golgi apparatus |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Concordant with the UniProt endoplasmic reticulum membrane subcellular location. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Single-pass type I |
| GO:0005537 D-mannose binding | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core molecular function; VIP36 is a high-mannose-binding L-type lectin, supported experimentally and across the LMAN1/LMAN2 family. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt transport and sorting of glycoproteins PMID:20477988 VIP36 binds high-mannose |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Core cycling/transport role of the early-secretory-pathway lectin; concordant with Reactome COPII-mediated vesicle transport and the UniProt function. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt transport and sorting of glycoproteins |
| GO:0030134 COPII-coated ER to Golgi transport vesicle | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Correct compartment for an ER-Golgi cycling lectin; concordant with the family and the UniProt early-secretory-pathway function. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt intracellular lectin in the early |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of Golgi membrane localization from the UniProt subcellular-location vocabulary, consistent with stronger experimental and phylogenetic evidence. Reason: Correct compartment; redundant with the IBA Golgi membrane and IDA Golgi apparatus annotations. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Golgi apparatus |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of ER membrane localization from the UniProt subcellular-location vocabulary, consistent with the experimental cycling localization. Reason: Correct compartment; redundant with the IBA ER membrane annotation. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Single-pass type I |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. Reason: Uninformative parent term; the specific early-secretory-pathway membrane compartments (GO:0005789, GO:0033116, GO:0000139) capture the localization more precisely. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Single-pass type I |
| GO:0033116 endoplasmic reticulum-Golgi intermediate compartment membrane | IEA GO_REF:0000044 | ACCEPT | 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. Reason: Correct and specific compartment; VIP36 is an ERGIC membrane protein. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate |
| GO:0050766 positive regulation of phagocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: Genuine but secondary moonlighting role transferred from the mouse ortholog; not the core early-secretory-pathway sorting function. Supporting Evidence: PMID:22016386 the amount of VIP36 precisely regulates phagocytosis |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for Golgi apparatus localization, consistent with VIP36's documented Golgi/ER cycling. Reason: IDA-supported Golgi localization agrees with the UniProt Golgi apparatus membrane location and experimental cycling. Supporting Evidence: file:human/LMAN2/LMAN2-uniprot.txt Golgi apparatus |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | MARK AS OVER ANNOTATED | 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. Reason: Proteomics-catalog localization; not informative of VIP36's core early-secretory-pathway function. Supporting Evidence: PMID:23533145 ~900 proteins were detected |
| GO:0005515 protein binding | IPI PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | KEEP AS NON CORE | 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. Reason: Captures a genuine cargo interaction but bare protein binding is uninformative; the lectin (D-mannose/carbohydrate binding) terms convey the actual molecular function. Supporting Evidence: PMID:20477988 high-mannose form of |
| GO:0005537 D-mannose binding | IMP PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | ACCEPT | 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. Reason: Core molecular function with direct experimental support; VIP36 binds high-mannose glycans. Supporting Evidence: PMID:20477988 bound exclusively to the high-mannose form of |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IDA PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | ACCEPT | 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. Reason: Directly demonstrated ERGIC/early-secretory-pathway localization, consistent with UniProt. Supporting Evidence: PMID:20477988 VIP36 localizes to the Golgi apparatus and |
| GO:0005794 Golgi apparatus | IDA PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | ACCEPT | Summary: Direct evidence that VIP36 localizes to the Golgi apparatus, where its lectin activity (pH optimum ~6.5) matches the Golgi luminal pH. Reason: Directly demonstrated Golgi localization, concordant with the UniProt Golgi apparatus membrane location. Supporting Evidence: PMID:20477988 VIP36 localizes to the Golgi apparatus and |
| GO:0006890 retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum | IMP PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | ACCEPT | 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. Reason: Core retrograde transport / post-ER quality-control role, directly demonstrated experimentally. Supporting Evidence: PMID:20477988 Silencing VIP36 accelerated alpha1-AT transport |
| GO:0031072 heat shock protein binding | IPI PMID:20477988 Role of the lectin VIP36 in post-ER quality control of human... | KEEP AS NON CORE | 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. Reason: A genuine and reasonably specific interaction, but a peripheral partner rather than the core high-mannose-glycan sorting function; kept non-core. Supporting Evidence: PMID:20477988 post-ER quality control |
| GO:0005576 extracellular region | IDA PMID:22016386 VIP36 protein is a target of ectodomain shedding and regulat... | KEEP AS NON CORE | 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. Reason: Real but secondary localization arising from ectodomain shedding; not the core early-secretory-pathway compartment. Supporting Evidence: PMID:22016386 a soluble form of VIP36 should be released into the extracellular space |
| GO:0005886 plasma membrane | IDA PMID:22016386 VIP36 protein is a target of ectodomain shedding and regulat... | KEEP AS NON CORE | 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. Reason: Real but minor/secondary cell-surface pool linked to ectodomain shedding; not the core compartment. Supporting Evidence: PMID:22016386 VIP36 significantly accumulates on the cell surface |
| GO:0009986 cell surface | IDA PMID:22016386 VIP36 protein is a target of ectodomain shedding and regulat... | KEEP AS NON CORE | 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. Reason: Real but secondary cell-surface localization underlying the shedding/phagocytosis role; not the core compartment. Supporting Evidence: PMID:22016386 shedding of VIP36 occurs mainly on the cell surface |
| GO:0030246 carbohydrate binding | IDA PMID:23701871 Parallel quantification of lectin-glycan interaction using u... | ACCEPT | 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. Reason: Core molecular function (parent of D-mannose binding); directly measured carbohydrate-binding activity of the VIP36 lectin. Supporting Evidence: PMID:23701871 lectin-glycan interaction analysis |
| GO:0050766 positive regulation of phagocytosis | IMP PMID:22016386 VIP36 protein is a target of ectodomain shedding and regulat... | KEEP AS NON CORE | 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. Reason: Genuine experimentally supported role, but a secondary macrophage cell-surface/shedding function rather than the core early-secretory-pathway sorting function. Supporting Evidence: PMID:22016386 the amount of VIP36 precisely regulates phagocytosis |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | 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. Reason: Proteomics-catalog localization; not informative of VIP36's core early-secretory-pathway function. Supporting Evidence: PMID:19056867 profile the proteome of human urinary exosomes |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IDA PMID:15308636 Proteomics of endoplasmic reticulum-Golgi intermediate compa... | ACCEPT | 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. Reason: Directly supports ERGIC residence of VIP36, consistent with UniProt and other experimental evidence. Supporting Evidence: PMID:15308636 purification of ERGIC membranes |
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Download this section (compressed HTML)Q: 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?
Q: Is the macrophage shedding/phagocytosis role of VIP36 conserved in human macrophages and physiologically significant, given that lectin activity is dispensable for it?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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