Existing Annotations Review

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

Core Functions

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:

D-mannose binding

Supporting Evidence:

PMID:20477988
bound exclusively to the high-mannose form of
PMID:23701871
lectin-glycan interaction analysis

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:

D-mannose binding

Directly Involved In:

retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum endoplasmic reticulum to Golgi vesicle-mediated transport

Cellular Locations:

endoplasmic reticulum-Golgi intermediate compartment Golgi apparatus

Supporting Evidence:

PMID:20477988
Silencing VIP36 accelerated alpha1-AT transport
file:human/LMAN2/LMAN2-uniprot.txt
transport and sorting of glycoproteins

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:15308636

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.

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.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

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.

PMID:20477988

Role of the lectin VIP36 in post-ER quality control of human alpha1-antitrypsin.

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.
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.

PMID:22016386

VIP36 protein is a target of ectodomain shedding and regulates phagocytosis in macrophage Raw 264.7 cells.

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.
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.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

Shotgun proteomics of prostatic-secretion-derived urinary exosomes detected ~900 proteins; VIP36 is one such HDA proteomics hit, reflecting presence in secreted vesicles.

PMID:23701871

Parallel quantification of lectin-glycan interaction using ultrafiltration.

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.

PMID:33796845

Exploring the landscape of ectodomain shedding by quantitative protein terminomics.

file:human/LMAN2/LMAN2-uniprot.txt

UniProt entry Q12907 (LMAN2_HUMAN), Vesicular integral-membrane protein VIP36

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.

Suggested Experiments

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.

Deep Research

Falcon

(LMAN2-deep-research-falcon.md)

Research Report: Human **LMAN2** (VIP36; UniProt **Q12907**) — Functional Annotation Falcon Edison Scientific Literature 35 citations 2 artifacts 2026-06-12T03:58:49.999170

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000028 The requested figure and table showing the VIP36 (LMAN2) cleavage site F298↓L299 and its terminomics validation are as follows: - * (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human LMAN2 (VIP36; UniProt Q12907) — Functional Annotation

1) Identity verification and scope

Target confirmed: the UniProt accession Q12907 corresponds to human LMAN2, encoding Vesicular integral-membrane protein VIP36 (VIP36/GP36b), a type I transmembrane L-type (legume-like) lectin in the early secretory pathway. This report summarizes experimentally supported function, localization, binding specificity, and recent (2023–2024 prioritized) disease/proteomics associations.

2) Key concepts and definitions (current understanding)

2.1 L-type (legume-like) lectins in the secretory pathway

LMAN2/VIP36 is part of the animal L-type lectin family, defined by a luminal carbohydrate recognition domain (CRD) structurally homologous to plant legume lectins and specialized for high-mannose N-glycan recognition in luminal secretory compartments. L-type lectins in animals are frequently membrane-anchored and implicated in protein sorting/trafficking and glycoprotein quality control rather than extracellular lectin functions. (gupta2012ltypelectinsin pages 1-2, yamamoto2014intracellularlectinsare pages 8-10)

2.2 Domain architecture and topology

VIP36 is a type I transmembrane protein with an N-terminal signal peptide, a luminal lectin CRD, a single-pass transmembrane helix, and a short cytosolic tail. Review-level summaries describe L-type cargo lectins (ERGIC-53/LMAN1 and VIP36/LMAN2) as having: (i) an N-terminal L-type lectin domain, (ii) a proline-rich/stalk region, and (iii) a region near the membrane involved in Ca2+ coordination in family members. (gupta2012ltypelectinsin pages 2-3, veronika2010theroleof pages 22-25)

2.3 Subcellular localization and cycling concepts

VIP36 localizes primarily to Golgi / pre-Golgi (ERGIC) compartments and exhibits cycling within the early secretory pathway. It has been described in cis/medial Golgi, ERGIC, and transport vesicles; under some contexts it can be detected in post-Golgi compartments and at the plasma membrane in polarized epithelial cells. This distribution is consistent with a role as a sorting receptor that binds luminal glycans in one compartment and releases them in another (e.g., driven by pH differences). (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28)

3) Molecular function and mechanism (best-supported functional model)

3.1 Primary biochemical activity: high-mannose N-glycan recognition

The primary experimentally supported biochemical function of VIP36 is binding to high-mannose N-glycans, particularly glycan determinants enriched early in the secretory pathway.

Specificity: VIP36 preferentially recognizes Man7–Man9GlcNAc2 and shows strong preference for isomers containing the D1/A-arm Manα1-2–Manα1-2–Man motif; trimming or masking terminal α1,2-mannose residues abolishes binding in biochemical assays. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11)

Environmental dependence: binding is pH sensitive, with optimal binding reported around pH ~6–6.5, aligning with early Golgi/ERGIC conditions and supporting a compartment-dependent binding/release model. (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11)

Ca2+ dependence: structural work indicates VIP36 binds one Ca2+ adjacent to the carbohydrate-binding site, supporting Ca2+-dependent ligand coordination, although some biochemical reports describe partial Ca2+ independence under certain assay conditions, indicating that Ca2+ dependence may be context- and/or method-dependent. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, gupta2012ltypelectinsin pages 12-13)

3.2 Structural determinants of glycan binding (experimental residues)

High-resolution structural summaries indicate that Ca2+ positions and/or stabilizes the binding geometry such that Asp131, Asn166, and His190 form key direct contacts with the ligand, with additional residues (e.g., Gly260, Asp261, Leu262) contributing hydrogen bonds to mannose. These details provide a mechanistic basis for the D1/A-arm preference. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28)

3.3 Cellular role: glycoprotein sorting and “glycan-maturation quality control”

VIP36 is widely framed as an intracellular cargo receptor/sorting lectin that recognizes high-mannose glycans and participates in Golgi/early secretory sorting. A prominent model is that VIP36 can bind glycoproteins that retain immature high-mannose glycans (e.g., that escaped earlier processing) and help recycle them for further glycan maturation, consistent with a quality-control role in glycosylation state. (gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 12-13)

4) Subcellular localization and trafficking (where function occurs)

4.1 Golgi/ERGIC localization and rapid retrograde cycling

VIP36 is described as predominantly Golgi/ERGIC-localized and cycling between compartments of the early secretory pathway. Quantitative FRAP measurements reported in one compiled experimental account indicate approximate half-times of ER→Golgi t1/2 ~105 ± 39 min and Golgi→ER t1/2 ~1.67 ± 0.45 min, consistent with relatively rapid retrograde movement. (veronika2010theroleof pages 25-28)

4.2 Polarized surface distribution (evidence for apical bias)

In polarized epithelial contexts, VIP36 has been reported at the plasma membrane with an apical/basolateral ratio ~7, consistent with proposed roles in polarized trafficking/sorting. (gupta2012ltypelectinsin pages 12-13)

4.3 Sorting motifs (areas of disagreement)

The cytosolic sorting logic of VIP36 is not as consistently described across sources as for ERGIC-53/LMAN1. One review describes VIP36 as lacking a canonical dilysine ER-localization motif and being mainly Golgi-localized (in contrast to ERGIC-53). (yamamoto2014intracellularlectinsare pages 8-10) In contrast, another compiled account proposes a C-terminal KRXX retrieval-like signal and reports rapid retrograde cycling consistent with COPI-mediated retrieval. (veronika2010theroleof pages 25-28) A third source discusses a short C-terminal motif (KRFY) associated with cycling in the VIP36/VIPL family, while VIPL has additional determinants for ER retention. (gupta2012ltypelectinsin pages 15-16)

Interpretation: overall evidence supports that VIP36 cycles and that its luminal lectin activity is tuned to Golgi/ERGIC conditions; however, the exact cytosolic motif logic (KRXX vs other motifs; whether “no dilysine” applies universally) is not fully reconciled within the retrieved evidence and likely depends on isoform/context and/or historical annotation differences. (veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)

5) Ectodomain shedding and extracellular detectability

5.1 Metalloprotease-sensitive ectodomain cleavage site (direct evidence)

Quantitative protein terminomics identified VIP36/LMAN2 as a metalloprotease-regulated shedding substrate with a reproducible cleavage site at F298↓L299 (reported as SVNF↓LKSP) detected across multiple cell lines, and downregulated by the broad-spectrum metalloprotease inhibitor BB-94. (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12)

The cropped figure/table evidence documenting the cleavage site and inhibitor-dependent reduction is available here. (tsumagari2021exploringthelandscape media 6d3163dc, tsumagari2021exploringthelandscape media ed8c04ed, tsumagari2021exploringthelandscape media a19a5e2b)

Implication: VIP36 can generate a soluble ectodomain fragment under metalloprotease activity, offering a mechanistic basis for detecting VIP36-derived peptides/fragments in extracellular compartments and suggesting regulated remodeling of its lectin function at membranes. (tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12)

6) Recent developments (prioritizing 2023–2024)

6.1 2024: Plasma proteomics/genetics implicate LMAN2 in kidney traits (candidate biomarker/target)

A 2024 proteome-wide association study (PWAS) integrating plasma proteomics (SOMAmer) with GWAS datasets identified LMAN2 among proteins associated with chronic kidney disease (CKD) and replicated signals in related traits (eGFR and BUN). The study used ARIC proteomics with n=7,213 European-ancestry participants and followed PWAS with Mendelian randomization (MR) and colocalization.

MR results reported: association strongest for BUN (OR 1.032, FDR 5.85×10−3); MR evidence for CKD was marginal (OR 1.283, FDR 5.63×10−2) and not significant for eGFR (OR 0.989, FDR 0.141). Colocalization did not support a shared causal cis-variant for LMAN2 with CKD/eGFR/BUN (PP4 < 0.01), weakening causal interpretation and indicating that LMAN2 is currently better viewed as an associated marker/candidate pathway component rather than a confirmed causal effector. (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)

Publication details: Xiong et al., Heliyon, Jun 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e31704. (xiong2024plasmaproteomeanalysis pages 1-2)

6.2 2023: LMAN2 responds in granulosa-cell proteome under cannabidiol stimulation

In a 2023 study of cultured human granulosa cells treated with 30 µM cannabidiol (CBD) for 24 h (n=5 biological replicates), LMAN2 (VIP36) was reported as differentially abundant with log2 fold-change = 1.23 and q = 0.04. While this does not define mechanism, it places LMAN2 among regulated proteins under conditions that induced inflammatory/secretory changes in granulosa cells. (eubler2023trpv2anovel pages 9-10)

Publication details: Eubler et al., Molecular Human Reproduction, Aug 2023. URL: https://doi.org/10.1093/molehr/gaad029. (eubler2023trpv2anovel pages 9-10)

6.3 Contextual mechanistic synthesis (expert view from authoritative reviews)

Authoritative syntheses emphasize that VIP36’s pH-dependent and high-mannose-specific recognition is well matched to the chemistry of early Golgi/ERGIC glycan maturation and positions VIP36 as a glycan-state sensor that can influence forward trafficking vs retrieval/recycling decisions for glycoproteins. (gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)

7) Current applications and real-world implementations

7.1 Biomarker discovery and disease association (kidney disease)

Given the PWAS/MR associations, LMAN2 is being discussed as a candidate plasma protein marker linked to CKD-related traits; however, the limited colocalization support indicates caution in interpreting LMAN2 as a drug target without further causal validation. (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)

7.2 Potential utility of soluble VIP36 fragments

Because VIP36 undergoes metalloprotease-sensitive ectodomain shedding at a specific site (F298↓L299), assays targeting shed ectodomain fragments could, in principle, serve as readouts of membrane protease activity and/or secretory-pathway remodeling, though clinical utility remains to be established. (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape media 6d3163dc)

7.3 Clinical trials

A ClinicalTrials.gov-style search performed in this run returned no clearly relevant interventional clinical trials targeting LMAN2/VIP36 specifically. (clinical-trials search result context in pqac tool state; no citeable trial context was returned)

8) Expert/authoritative pathway-level interpretation

8.1 Pathways and processes

The most coherent pathway placement for VIP36 is within secretory-pathway cargo selection and glycoprotein quality control, coupling N-glycan processing state (high mannose vs processed complex glycans) to sorting and recycling in ERGIC/cis-Golgi/TGN trafficking routes. The pH-tuned binding profile (maximal near mildly acidic Golgi conditions) provides a plausible biophysical switch for ligand engagement and release across compartments. (gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)

The retrieved reviews emphasize family context with ERGIC-53/LMAN1 and VIPL/LMAN2L, noting that paralogues differ in localization (e.g., VIPL being ER-localized) and sorting signals, reinforcing that LMAN2/VIP36 is the Golgi/ERGIC cycling lectin among close homologs. (yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)

9) Key statistics and data (compiled)

The following table consolidates quantitative parameters and recent association statistics relevant for functional annotation.

Finding	Quantitative value(s)	Experimental basis	Source (include DOI URL if available)
Glycan specificity	Prefers high-mannose Man7–9GlcNAc2 glycans; strongest recognition of D1/A-arm Manα1-2Manα1-2Man motif; trimming or glucosylation of the terminal α1,2-mannose abolishes/reduces binding; one FAC-derived affinity value is reported in review text as “7.1 × 10^8 M^-1” for immobilized VIP36 with Man7–9 glycans	Frontal affinity chromatography, competition with Man7–9 glycopeptides, glycan trimming/glucosylation perturbation, and co-crystal structural analysis of the VIP36 CRD	Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Reiterer 2010, https://doi.org/10.5451/unibas-005405317; Yamamoto 2014, https://doi.org/10.2183/pjab.90.67 (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11, gupta2012ltypelectinsin pages 10-12)
pH optimum for sugar binding	Optimal binding reported at ~pH 6.5; other assays reported ~pH 6.0; binding increases under mildly acidic conditions consistent with Golgi localization	Recombinant CRD binding assays and FAC; review synthesis of primary studies	Reiterer 2010, https://doi.org/10.5451/unibas-005405317; Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Yamamoto 2014, https://doi.org/10.2183/pjab.90.67 (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11)
Ca2+ dependence evidence	Structural evidence supports 1 Ca2+ bound adjacent to the carbohydrate-binding site; key residues Asp131, Asn166, His190 directly contact ligand; however, some biochemical studies reported binding at pH 6.0 without strict Ca2+ dependence, so evidence is mixed	X-ray crystallography of VIP36 CRD with mannosyl ligands plus biochemical glycan-binding assays	Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Reiterer 2010, https://doi.org/10.5451/unibas-005405317 (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, gupta2012ltypelectinsin pages 12-13)
Cycling kinetics	ER→Golgi t1/2 = 105 ± 39 min; Golgi→ER t1/2 = 1.67 ± 0.45 min	FRAP analysis of cycling in the early secretory pathway	Reiterer 2010, https://doi.org/10.5451/unibas-005405317 (veronika2010theroleof pages 25-28)
Localization polarity	Apical/basolateral ratio ≈ 7 in polarized cells	Cell biological localization studies in polarized epithelial cells summarized in review literature	Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7 (gupta2012ltypelectinsin pages 12-13)
Ectodomain shedding site	Cleavage at F298↓L299; local sequence reported as SVNF↓LKSP; detected across all analyzed cell lines and scored as a high-confidence metalloprotease-sensitive shedding site	Quantitative protein terminomics with metalloprotease inhibitor BB-94; cleavage-site mapping and PWM-based sheddase analysis	Tsumagari et al. 2021, https://doi.org/10.1101/2020.09.23.310102 (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12, tsumagari2021exploringthelandscape media 6d3163dc)
Recent proteomics association: granulosa cells	Log2FC = 1.23, q = 0.04, n = 5 biological replicates	Mass-spectrometry proteomics of cultured human granulosa cells treated 24 h with 30 µM CBD versus ethanol control	Eubler et al. 2023, https://doi.org/10.1093/molehr/gaad029 (eubler2023trpv2anovel pages 9-10)
Recent CKD genetics/proteomics association	PWAS identified LMAN2 among 22 CKD-associated plasma proteins; ARIC proteomics n = 7,213 European-ancestry participants; MR for BUN OR = 1.032, FDR = 5.85 × 10^-3; MR for CKD OR = 1.283, FDR = 5.63 × 10^-2; MR for eGFR OR = 0.989, FDR = 0.141; colocalization PP4 < 0.01 for CKD/eGFR/BUN	Proteome-wide association study integrating cis-pQTLs with CKD/eGFR/BUN GWAS, followed by Mendelian randomization and Bayesian colocalization	Xiong et al. 2024, https://doi.org/10.1016/j.heliyon.2024.e31704 (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 9-10, xiong2024plasmaproteomeanalysis pages 7-9)

Table: This table compiles the main experimentally supported functional parameters and the most relevant recent quantitative disease/proteomics associations for human LMAN2/VIP36. It is useful as a compact evidence summary for annotation, emphasizing what is measured directly versus what remains inferential or mixed.

10) Complementary genetics/association landscape (Open Targets)

Open Targets lists modest disease-association evidence for LMAN2 across several disease categories (e.g., metabolic syndrome, atopic eczema, allergic disease, respiratory system disease, eye disease), supported by a small set of PubMed-indexed studies (PubMed IDs provided in the Open Targets evidence rows). These associations are not mechanistic proofs of VIP36 function in those diseases but can guide hypothesis generation and prioritization. (OpenTargets Search: -LMAN2)

11) Limitations and open questions

Mechanistic cargo repertoire in human cells remains incompletely resolved in the retrieved corpus: while VIP36’s glycan specificity and cycling behavior are well supported, definitive lists of endogenous cargo proteins and direct causal effects on their secretion/processing were not fully available in the accessible texts here. (gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 10-11)
Sorting motif logic is inconsistent across summaries, with some sources emphasizing lack of canonical ER-localization motifs and others proposing KRXX/KRFY-type signals; resolving this likely requires direct sequence/isoform-specific and mutational evidence beyond what was accessible here. (veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)
Causality in CKD associations is not established: MR and colocalization analyses reduce confidence that cis-driven plasma LMAN2 is causally responsible for CKD, despite replicated associations with kidney traits. (xiong2024plasmaproteomeanalysis pages 7-9)

References (URLs and publication dates)

Gupta GS. L-Type Lectins in ER-Golgi Intermediate Compartment. In: Animal Lectins: Form, Function and Clinical Applications. Mar 2012. https://doi.org/10.1007/978-3-7091-1065-2_7 (gupta2012ltypelectinsin pages 12-13, gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 13-15)
Yamamoto K. Intracellular lectins are involved in quality control of glycoproteins. Proceedings of the Japan Academy, Series B. Feb 2014. https://doi.org/10.2183/pjab.90.67 (yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)
Suzuki T, Fujihira H. Folding and Quality Control of Glycoproteins. In: Comprehensive Glycoscience. Dec 2021. https://doi.org/10.1016/B978-0-12-409547-2.14947-9 (suzuki2021foldingandquality pages 12-14)
Tsumagari K, Chang C-H, Ishihama Y. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience (preprint DOI shown in retrieved text). Sep 2021. https://doi.org/10.1101/2020.09.23.310102 (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12, tsumagari2021exploringthelandscape media 6d3163dc)
Eubler K et al. TRPV2, a novel player in the human ovary and human granulosa cells. Molecular Human Reproduction. Aug 2023. https://doi.org/10.1093/molehr/gaad029 (eubler2023trpv2anovel pages 9-10)
Xiong Y et al. Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: A proteome-wide association study. Heliyon. Jun 2024. https://doi.org/10.1016/j.heliyon.2024.e31704 (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)

References

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(yamamoto2014intracellularlectinsare pages 8-10): Kazuo YAMAMOTO. Intracellular lectins are involved in quality control of glycoproteins. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 90:67-82, Feb 2014. URL: https://doi.org/10.2183/pjab.90.67, doi:10.2183/pjab.90.67. This article has 38 citations.
(gupta2012ltypelectinsin pages 2-3): G. S. Gupta. L-type lectins in er-golgi intermediate compartment. Animal Lectins: Form, Function and Clinical Applications, pages 145-161, Mar 2012. URL: https://doi.org/10.1007/978-3-7091-1065-2_7, doi:10.1007/978-3-7091-1065-2_7. This article has 3 citations.
(veronika2010theroleof pages 22-25): Veronika Reiterer. The role of the lectin vip36 in the early secretory pathway. ArXiv, 2010. URL: https://doi.org/10.5451/unibas-005405317, doi:10.5451/unibas-005405317. This article has 0 citations.
(gupta2012ltypelectinsin pages 12-13): G. S. Gupta. L-type lectins in er-golgi intermediate compartment. Animal Lectins: Form, Function and Clinical Applications, pages 145-161, Mar 2012. URL: https://doi.org/10.1007/978-3-7091-1065-2_7, doi:10.1007/978-3-7091-1065-2_7. This article has 3 citations.
(veronika2010theroleof pages 25-28): Veronika Reiterer. The role of the lectin vip36 in the early secretory pathway. ArXiv, 2010. URL: https://doi.org/10.5451/unibas-005405317, doi:10.5451/unibas-005405317. This article has 0 citations.
(gupta2012ltypelectinsin pages 13-15): G. S. Gupta. L-type lectins in er-golgi intermediate compartment. Animal Lectins: Form, Function and Clinical Applications, pages 145-161, Mar 2012. URL: https://doi.org/10.1007/978-3-7091-1065-2_7, doi:10.1007/978-3-7091-1065-2_7. This article has 3 citations.
(yamamoto2014intracellularlectinsare pages 10-11): Kazuo YAMAMOTO. Intracellular lectins are involved in quality control of glycoproteins. Proceedings of the Japan Academy. Series B, Physical and Biological Sciences, 90:67-82, Feb 2014. URL: https://doi.org/10.2183/pjab.90.67, doi:10.2183/pjab.90.67. This article has 38 citations.
(gupta2012ltypelectinsin pages 15-16): G. S. Gupta. L-type lectins in er-golgi intermediate compartment. Animal Lectins: Form, Function and Clinical Applications, pages 145-161, Mar 2012. URL: https://doi.org/10.1007/978-3-7091-1065-2_7, doi:10.1007/978-3-7091-1065-2_7. This article has 3 citations.
(tsumagari2021exploringthelandscape pages 6-8): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(tsumagari2021exploringthelandscape pages 8-11): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(tsumagari2021exploringthelandscape pages 11-12): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(tsumagari2021exploringthelandscape media 6d3163dc): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(tsumagari2021exploringthelandscape media ed8c04ed): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(tsumagari2021exploringthelandscape media a19a5e2b): Kazuya Tsumagari, Chih-Hsiang Chang, and Yasushi Ishihama. Exploring the landscape of ectodomain shedding by quantitative protein terminomics. iScience, Sep 2021. URL: https://doi.org/10.1101/2020.09.23.310102, doi:10.1101/2020.09.23.310102. This article has 26 citations and is from a peer-reviewed journal.
(xiong2024plasmaproteomeanalysis pages 1-2): Yang Xiong, Tianhong Wang, Wei Wang, Yangchang Zhang, Fuxun Zhang, Jiuhong Yuan, Feng Qin, and Xianding Wang. Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: a proteome-wide association study. Heliyon, 10:e31704, Jun 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e31704, doi:10.1016/j.heliyon.2024.e31704. This article has 11 citations.
(xiong2024plasmaproteomeanalysis pages 7-9): Yang Xiong, Tianhong Wang, Wei Wang, Yangchang Zhang, Fuxun Zhang, Jiuhong Yuan, Feng Qin, and Xianding Wang. Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: a proteome-wide association study. Heliyon, 10:e31704, Jun 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e31704, doi:10.1016/j.heliyon.2024.e31704. This article has 11 citations.
(eubler2023trpv2anovel pages 9-10): Katja Eubler, Karolina M Caban, Gregory A Dissen, Ulrike Berg, Dieter Berg, Carola Herrmann, Nicole Kreitmair, Astrid Tiefenbacher, Thomas Fröhlich, and Artur Mayerhofer. Trpv2, a novel player in the human ovary and human granulosa cells. Molecular human reproduction, Aug 2023. URL: https://doi.org/10.1093/molehr/gaad029, doi:10.1093/molehr/gaad029. This article has 8 citations and is from a peer-reviewed journal.
(gupta2012ltypelectinsin pages 10-12): G. S. Gupta. L-type lectins in er-golgi intermediate compartment. Animal Lectins: Form, Function and Clinical Applications, pages 145-161, Mar 2012. URL: https://doi.org/10.1007/978-3-7091-1065-2_7, doi:10.1007/978-3-7091-1065-2_7. This article has 3 citations.
(xiong2024plasmaproteomeanalysis pages 9-10): Yang Xiong, Tianhong Wang, Wei Wang, Yangchang Zhang, Fuxun Zhang, Jiuhong Yuan, Feng Qin, and Xianding Wang. Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: a proteome-wide association study. Heliyon, 10:e31704, Jun 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e31704, doi:10.1016/j.heliyon.2024.e31704. This article has 11 citations.
(OpenTargets Search: -LMAN2): Open Targets Query (-LMAN2, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(suzuki2021foldingandquality pages 12-14): Tadashi Suzuki and Haruhiko Fujihira. Folding and quality control of glycoproteins. Comprehensive Glycoscience, pages 1-28, Dec 2021. URL: https://doi.org/10.1016/b978-0-12-409547-2.14947-9, doi:10.1016/b978-0-12-409547-2.14947-9. This article has 12 citations.

Artifacts

Edison artifact artifact-00

Citations

veronika2010theroleof pages 25-28
gupta2012ltypelectinsin pages 12-13
yamamoto2014intracellularlectinsare pages 8-10
gupta2012ltypelectinsin pages 15-16
xiong2024plasmaproteomeanalysis pages 1-2
xiong2024plasmaproteomeanalysis pages 7-9
suzuki2021foldingandquality pages 12-14
gupta2012ltypelectinsin pages 1-2
gupta2012ltypelectinsin pages 2-3
veronika2010theroleof pages 22-25
gupta2012ltypelectinsin pages 13-15
yamamoto2014intracellularlectinsare pages 10-11
tsumagari2021exploringthelandscape pages 6-8
tsumagari2021exploringthelandscape pages 8-11
tsumagari2021exploringthelandscape pages 11-12
gupta2012ltypelectinsin pages 10-12
xiong2024plasmaproteomeanalysis pages 9-10
https://doi.org/10.1016/j.heliyon.2024.e31704.
https://doi.org/10.1093/molehr/gaad029.
https://doi.org/10.1007/978-3-7091-1065-2_7;
https://doi.org/10.5451/unibas-005405317;
https://doi.org/10.2183/pjab.90.67
https://doi.org/10.5451/unibas-005405317
https://doi.org/10.1007/978-3-7091-1065-2_7
https://doi.org/10.1101/2020.09.23.310102
https://doi.org/10.1093/molehr/gaad029
https://doi.org/10.1016/j.heliyon.2024.e31704
https://doi.org/10.1016/B978-0-12-409547-2.14947-9
https://doi.org/10.1007/978-3-7091-1065-2_7,
https://doi.org/10.2183/pjab.90.67,
https://doi.org/10.5451/unibas-005405317,
https://doi.org/10.1101/2020.09.23.310102,
https://doi.org/10.1016/j.heliyon.2024.e31704,
https://doi.org/10.1093/molehr/gaad029,
https://doi.org/10.1016/b978-0-12-409547-2.14947-9,

📚 Additional Documentation

Notes

(LMAN2-notes.md)

LMAN2 (VIP36) — Gene Review Notes

UniProt: Q12907 (LMAN2_HUMAN). Gene symbol: LMAN2 (HGNC:16986), synonym C5orf8.
Protein name: Vesicular integral-membrane protein VIP36 (also Glycoprotein GP36b, Lectin
mannose-binding 2). 356 aa precursor; signal peptide 1-44; mature chain 45-356; single-pass
type I membrane protein (lumenal 45-322, TM 323-345, cytoplasmic 346-356).

What VIP36 is

VIP36/LMAN2 is a type I transmembrane leguminous-type (L-type) lectin of the early
secretory pathway. Its lumenal L-type lectin-like domain (52-276) binds carbohydrate in a
Ca2+-dependent manner [file:human/LMAN2/LMAN2-uniprot.txt "L-type lectin-like"; UniProt COFACTOR
"Binds 2 calcium ions per subunit"]. UniProt FUNCTION: "Plays a role as an intracellular lectin
in the early secretory pathway. Interacts with N-acetyl-D-galactosamine and high-mannose type
glycans and may also bind to O-linked glycans. Involved in the transport and sorting of
glycoproteins carrying high mannose-type glycans" [file:human/LMAN2/LMAN2-uniprot.txt].

It is a member of the same L-type lectin family as LMAN1/ERGIC-53 (P49257; PANTHER
PTN000259611). It is NOT a glycosidase / mannosidase — it has no catalytic activity; it is a
carbohydrate-binding cargo/sorting receptor. The CDD/InterPro signatures are lectin signatures
(cd06901 lectin_VIP36_VIPL; IPR035664 VIP36_lectin; PF03388 Lectin_leg-like).

Localization (core CC = ERGIC/Golgi/ER membrane of the early secretory pathway)

UniProt SUBCELLULAR LOCATION (from PubMed:10444376, Fullekrug et al. "VIP36 localisation to the
early secretory pathway"): "Endoplasmic reticulum-Golgi intermediate compartment membrane ...
Golgi apparatus membrane ... Endoplasmic reticulum membrane" [file:human/LMAN2/LMAN2-uniprot.txt].
It cycles early in the secretory pathway between ER/ERGIC and Golgi.

ERGIC IDA: PMID:20477988 and the localization of VIP36 to Golgi/ER cycling.
ERGIC IDA: PMID:15308636 ERGIC membrane proteomics from BFA-treated HepG2 cells —
"purification of ERGIC membranes ... enriched 110-fold over the homogenate for ERGIC-53";
VIP36 was among the cycling/cargo-receptor proteins in this ERGIC-enriched fraction.
Golgi apparatus IDA: HPA immunofluorescence (GO_REF:0000052) and PMID:20477988.

Carbohydrate / D-mannose binding (core MF)

In vitro VIP36 binds high-mannose glycans with a pH optimum ~6.5: PMID:20477988.
In the living cell VIP36 bound exclusively the high-mannose form of its cargo: PMID:20477988. This is the basis for the
D-mannose binding IMP.
Quantitative lectin-glycan binding (carbohydrate binding IDA): PMID:23701871 using "fluorescently labeled high-mannose-type glycans and recombinant intracellular
lectins."

Transport / sorting / quality control (core BP)

VIP36 functions in post-ER quality control and ER<->Golgi cycling of high-mannose glycoproteins:
- Silencing VIP36 accelerated cargo transport, arguing against a pure anterograde role and
consistent with a quality-control / retrograde recycling role: PMID:20477988.
- Retrograde Golgi-to-ER recycling (basis for GO:0006890 IMP): PMID:20477988.
- VIP36 is "postulated as a cargo receptor for Golgi-to-endoplasmic reticulum transport"
PMID:22016386.
- Reactome: COPII-mediated vesicle transport (R-HSA-204005); Cargo concentration in the ER
(R-HSA-5694530); consistent with COPII vesicle (GO:0030134) and ER-to-Golgi transport
(GO:0006888) IBA annotations.

Interactions

alpha1-antitrypsin (SERPINA1, P01009) is a glycoprotein cargo identified by YFP-fragment
complementation: source of the protein binding IPI (WITH P01009). PMID:20477988. This is a lectin-cargo
(sugar-dependent) interaction; the bare "protein binding" GO term is uninformative and the real
informative MF is the mannose/carbohydrate binding.
heat shock protein binding IPI (GO:0031072), WITH UniProtKB:P11021 (BiP / HSPA5 / GRP78):
recorded by UniProt from PMID:20477988. P11021 is the ER chaperone BiP. This is a specific,
more-informative interaction than bare protein binding but is not the defining sorting
mechanism; kept non-core. (The cached PMID:20477988 entry is abstract-only — full_text_available:
false — so the BiP interaction detail is in the full text seen by the curator, not the abstract.)

Secondary / cell-surface role (ectodomain shedding, macrophages)

A minor pool of Endo-H-resistant (late-Golgi / cell-surface) VIP36 reaches the plasma membrane
and is shed; the shed/cell-surface VIP36 regulates phagocytosis in macrophages:
- PMID:22016386
- PMID:22016386
- PMID:22016386
This is the basis for the extracellular region / plasma membrane / cell surface IDA and the
positive regulation of phagocytosis IMP/IEA. These are genuine but secondary to the core
ER-Golgi lectin/sorting function, which dominates the protein's biology. Notably the lectin
activity is dispensable for phagocytosis enhancement PMID:22016386, underscoring that this is a separate moonlighting
role rather than the core function.

Proteomics-only localizations (non-core / over-annotation)

extracellular exosome (GO:0070062) HDA from urinary/prostatic exosome shotgun proteomics
[PMID:23533145; PMID:19056867] — large-scale proteomic catalogs (~900-1132 proteins), no
VIP36-specific functional claim; reflects presence in secreted vesicles, not core residence.
membrane (GO:0016020) IEA (InterPro IPR005052) — bare "membrane" is uninformative; the protein
is specifically an ER/ERGIC/Golgi single-pass membrane protein.

Cofactor / metal

Lectin domain binds 2 Ca2+ per subunit as a structural cofactor required for carbohydrate
binding [file:human/LMAN2/LMAN2-uniprot.txt COFACTOR "Binds 2 calcium ions per subunit"]; multiple
Ca2+-binding residues (162, 164, 166, 193). UniProt keyword "Metal-binding" / GO:0046872 metal ion
binding (IEA) is a structural attribute, not the core function. (No metal/calcium binding row is
present in the GOA TSV stub, so no annotation is reviewed for it.)

Summary of review decisions

Core MF: D-mannose binding (GO:0005537), carbohydrate binding (GO:0030246) — ACCEPT.
Core CC: ERGIC (GO:0005793), ERGIC membrane (GO:0033116), Golgi membrane (GO:0000139),
Golgi apparatus (GO:0005794), ER membrane (GO:0005789), COPII vesicle (GO:0030134) — ACCEPT.
Core BP: ER-to-Golgi vesicle-mediated transport (GO:0006888), retrograde Golgi-to-ER transport
(GO:0006890) — ACCEPT.
heat shock protein binding (GO:0031072), protein binding (GO:0005515) — KEEP_AS_NON_CORE.
positive regulation of phagocytosis (GO:0050766, IMP + IEA) — KEEP_AS_NON_CORE (secondary
macrophage role); IEA ortholog one MARK_AS_OVER_ANNOTATED.
extracellular region/plasma membrane/cell surface (22016386 IDA) — KEEP_AS_NON_CORE (shedding).
extracellular exosome (HDA), membrane (IEA) — MARK_AS_OVER_ANNOTATED.

Falcon deep-research findings (incorporated 2026-06)

Specific ectodomain-shedding cleavage site (mechanism for the existing cell-surface/shedding role):
quantitative protein terminomics maps VIP36/LMAN2 as a metalloprotease-regulated shedding substrate
cleaved at F298 down-arrow L299 (SVNF/LKSP), reproducible across multiple cell lines and
suppressed by the broad-spectrum metalloprotease inhibitor BB-94 [PMID:33796845 (Tsumagari et al.,
iScience 2021) "Exploring the landscape of ectodomain shedding by quantitative protein terminomics";
DOI 10.1016/j.isci.2021.102476]. This refines the mechanistic basis of the previously curated
cell-surface/plasma-membrane/extracellular-region IDA and the shedding-dependent phagocytosis role
(PMID:22016386). Added as MEDIUM-relevance reference; no annotation change (shedding already
KEEP_AS_NON_CORE).
Glycan-binding specificity detail (Falcon synthesis of prior reviews; consistent with existing
D-mannose/carbohydrate binding annotations): VIP36 prefers high-mannose Man7-9GlcNAc2 with strongest
recognition of the D1/A-arm Man-alpha-1,2-Man-alpha-1,2-Man motif; binding is pH-sensitive (optimum
~pH 6.0-6.5, matching early-Golgi/ERGIC lumen) and structurally Ca2+-assisted (residues Asp131,
Asn166, His190 contact ligand). Reinforces the existing core MF; reviews (Gupta 2012, Yamamoto 2014,
Reiterer 2010 thesis) are not PubMed-cached primary sources — notes-only, not added to YAML.
Disease/association context (Falcon; non-causal, not gene function): 2024 plasma-proteome PWAS
(Xiong et al., Heliyon) associates LMAN2 with CKD-related traits (BUN/eGFR), but colocalization
PP4 < 0.01 does NOT support a shared causal cis-variant, so LMAN2 is at best an associated marker;
2023 granulosa-cell proteomics (Eubler et al.) reports LMAN2 as differentially abundant under
cannabidiol. Both are association/proteomics only and do not inform VIP36 molecular function;
notes-only, not added to YAML.

Pn Notes

(LMAN2-pn-notes.md)

LMAN2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q12907
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/LMAN2/LMAN2-ai-review.yaml
AIGR review HTML: missing - genes/human/LMAN2/LMAN2-ai-review.html
Gene notes: present - genes/human/LMAN2/LMAN2-notes.md
GOA TSV: present - genes/human/LMAN2/LMAN2-goa.tsv
UniProt record: present - genes/human/LMAN2/LMAN2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/LMAN2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/LMAN2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/LMAN2/LMAN2-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 16; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 3

PN Consistency Summary

Consistency: Deep research ↔ review ↔ PN annotation consistent. LMAN2/VIP36 is correctly an L-type (ConA-like) lectin cargo/sorting receptor (D-mannose binding GO:0005537, carbohydrate binding GO:0030246) — NOT a mannosidase, matching the PN "Lectin chaperone" type. Distinctive feature well captured: retrograde Golgi→ER recycling (GO:0006890) in post-ER QC of alpha1-antitrypsin, plus a secondary shed-ectodomain/phagocytosis role kept non-core.
PN story / NEW pressure: No NEW GO pressure; functions are captured (IMP D-mannose binding, retrograde transport, ER-Golgi cycling). Falcon shedding cleavage-site detail (PMID:33796845) refines the already-non-core shedding role only. Conclude: already captured.
Evidence alignment: PN dossier is mapping-only (no titles). Review evidence PubMed-verified and centered on PMID:20477988 (the key functional paper), 23701871, 22016386, 15308636. No bibliographic conflict; divergence is conceptual (group term vs. lectin function).
Verdict: Review strong and PN-consistent (lectin, not mannosidase; distinct retrograde-QC angle). Inherited group→GO:0006487 projection is an over-reach for VIP36.

Full Consistency Review

UniProt: Q12907 (Vesicular integral-membrane protein VIP36) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE, thorough (detailed notes + Falcon).
PN placement: ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone ; PN-node mapping: type "Lectin chaperone" no_mapping; group "N-glycosylation system" mapped→GO:0006487 (protein N-linked glycosylation, ok_for_propagation, new_to_goa); class/branch no_mapping.
Consistency: Deep research ↔ review ↔ PN annotation consistent. LMAN2/VIP36 is correctly an L-type (ConA-like) lectin cargo/sorting receptor (D-mannose binding GO:0005537, carbohydrate binding GO:0030246) — NOT a mannosidase, matching the PN "Lectin chaperone" type. Distinctive feature well captured: retrograde Golgi→ER recycling (GO:0006890) in post-ER QC of alpha1-antitrypsin, plus a secondary shed-ectodomain/phagocytosis role kept non-core.
PN story / NEW pressure: No NEW GO pressure; functions are captured (IMP D-mannose binding, retrograde transport, ER-Golgi cycling). Falcon shedding cleavage-site detail (PMID:33796845) refines the already-non-core shedding role only. Conclude: already captured.
Mapping strategy: Same over-reach as LMAN1 — group→GO:0006487 over-reaches for VIP36, a glycan-reader/sorter that neither installs nor trims N-glycans. new_to_goa would introduce an unsupported biosynthesis assertion. The review's own BP terms (GO:0006888, GO:0006890) are transport/QC, conceptually disjoint from GO:0006487. PN node correctly leaves "Lectin chaperone" unmapped; the inherited group term should not propagate.
Evidence alignment: PN dossier is mapping-only (no titles). Review evidence PubMed-verified and centered on PMID:20477988 (the key functional paper), 23701871, 22016386, 15308636. No bibliographic conflict; divergence is conceptual (group term vs. lectin function).
Verdict: Review strong and PN-consistent (lectin, not mannosidase; distinct retrograde-QC angle). Inherited group→GO:0006487 projection is an over-reach for VIP36.
Recommended edits: [MAP] Do not propagate GO:0006487 (protein N-linked glycosylation) to LMAN2/VIP36 — it is a high-mannose glycan-reading sorting receptor (transport/retrograde QC), not an N-linked-glycosylation enzyme; flag the "N-glycosylation system" group node as over-broad.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/LMAN2/LMAN2-ai-review.yaml
PN workbook rows: 1

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

UniProt: Q12907
In branches: ER
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Glycoproteostasis|N-glycosylation system|Lectin chaperone
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [group] ER proteostasis|Glycoproteostasis|N-glycosylation system
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006487 protein N-linked glycosylation]
  rationale: This PN group captures the ER N-glycosylation machinery that installs and processes N-linked glycans during proteostasis. GO protein N-linked glycosylation is the best current propagation target in the local cache.
- [class] ER proteostasis|Glycoproteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

GO:0006487 protein N-linked glycosylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=ER proteostasis|Glycoproteostasis|N-glycosylation system

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

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.

LMAN2

Gene Description

Existing Annotations Review

Core Functions

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.

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).

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human LMAN2 (VIP36; UniProt Q12907) — Functional Annotation

1) Identity verification and scope

2) Key concepts and definitions (current understanding)

2.1 L-type (legume-like) lectins in the secretory pathway

2.2 Domain architecture and topology

2.3 Subcellular localization and cycling concepts

3) Molecular function and mechanism (best-supported functional model)

3.1 Primary biochemical activity: high-mannose N-glycan recognition

3.2 Structural determinants of glycan binding (experimental residues)

3.3 Cellular role: glycoprotein sorting and “glycan-maturation quality control”

4) Subcellular localization and trafficking (where function occurs)

4.1 Golgi/ERGIC localization and rapid retrograde cycling

4.2 Polarized surface distribution (evidence for apical bias)

4.3 Sorting motifs (areas of disagreement)

5) Ectodomain shedding and extracellular detectability

5.1 Metalloprotease-sensitive ectodomain cleavage site (direct evidence)

6) Recent developments (prioritizing 2023–2024)

6.1 2024: Plasma proteomics/genetics implicate LMAN2 in kidney traits (candidate biomarker/target)

6.2 2023: LMAN2 responds in granulosa-cell proteome under cannabidiol stimulation

6.3 Contextual mechanistic synthesis (expert view from authoritative reviews)

7) Current applications and real-world implementations

7.1 Biomarker discovery and disease association (kidney disease)

7.2 Potential utility of soluble VIP36 fragments

7.3 Clinical trials

8) Expert/authoritative pathway-level interpretation

8.1 Pathways and processes

8.2 Distinguishing LMAN2 (VIP36) from related family members

9) Key statistics and data (compiled)

10) Complementary genetics/association landscape (Open Targets)

11) Limitations and open questions

References (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

LMAN2 (VIP36) — Gene Review Notes

What VIP36 is

Localization (core CC = ERGIC/Golgi/ER membrane of the early secretory pathway)

Carbohydrate / D-mannose binding (core MF)

Transport / sorting / quality control (core BP)

Interactions

Secondary / cell-surface role (ectodomain shedding, macrophages)

Proteomics-only localizations (non-core / over-annotation)

Cofactor / metal

Summary of review decisions

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

LMAN2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Glycoproteostasis | N-glycosylation system | Lectin chaperone

Projected GO annotations (1)

Note

📄 View Raw YAML