id: Q9H0V9
gene_symbol: LMAN2L
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'LMAN2L (VIPL, "VIP36-like protein") is an ER-resident L-type (leguminous/ConA-like) lectin and a paralog of VIP36/LMAN2 and ERGIC-53/LMAN1. It is a single-pass type I membrane glycoprotein whose N-terminal luminal L-type lectin carbohydrate-recognition domain binds high-mannose glycans (D-mannose) and whose short cytoplasmic tail carries an RKR di-arginine ER-retention signal. Unlike the cycling lectins VIP36 and ERGIC-53, LMAN2L is predominantly a non-cycling resident of the endoplasmic reticulum, with a minor Golgi pool. It is not a glycosidase and has no catalytic activity; rather it is proposed to regulate ER export of a subset of glycoproteins and to act as a regulator of ERGIC-53, with overexpression redistributing ERGIC-53 to the ER and knockdown slowing glycoprotein secretion. LMAN2L is a neurodevelopmental disease gene: variants cause autosomal recessive (MRT52) and autosomal dominant (MRD69) intellectual developmental disorders.'
alternative_products:
- name: '1'
  id: Q9H0V9-1
- name: '2'
  id: Q9H0V9-2
  sequence_note: VSP_017940
- name: '3'
  id: Q9H0V9-3
  sequence_note: VSP_054439, VSP_054440
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: Phylogenetic (IBA) localization to the ERGIC, inherited from the cycling L-type lectins ERGIC-53/VIP36. VIPL acts in the early secretory pathway and its overexpression redistributes ERGIC-53, so an ERGIC association is plausible, though VIPL is itself predominantly ER-resident rather than a cycling ERGIC component.
    action: KEEP_AS_NON_CORE
    reason: Defensible early-secretory-pathway localization consistent with the family, but VIPL is predominantly a non-cycling ER-resident protein; the ER membrane is the core compartment.
    supported_by:
    - reference_id: PMID:12609988
      supporting_text: VIPL is a non-cycling resident protein of the ER
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic Golgi-membrane localization, consistent with the minor Golgi pool of VIPL observed experimentally.
    action: KEEP_AS_NON_CORE
    reason: VIPL is only partly found in the Golgi; the ER is its predominant and core compartment.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: VIPL localized primarily to the ER and partly to the Golgi complex
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic ER-membrane localization, fully consistent with direct experimental evidence that VIPL is a non-cycling ER-resident type I membrane protein.
    action: ACCEPT
    reason: ER membrane is the correct core compartment, supported by IDA and the UniProt subcellular location.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assignment of D-mannose binding based on the conserved L-type lectin carbohydrate-recognition domain shared with VIP36/ERGIC-53. Consistent with VIPL being a high-mannose-type lectin with the same domain organization as VIP36.
    action: ACCEPT
    reason: D-mannose binding is the defensible family-level molecular function conferred by the conserved L-type lectin CRD; consistent with the TAS annotation.
    supported_by:
    - reference_id: PMID:12609988
      supporting_text: high-mannose type I membrane glycoprotein with similar domain organization as
- 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: Phylogenetic assignment of ER-to-Golgi vesicle-mediated transport, consistent with VIPL's role in regulating ER export of glycoproteins.
    action: ACCEPT
    reason: Consistent with the experimentally supported role in ER export of a subset of glycoproteins; core biological process.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: knock-down of VIPL mRNA using siRNA significantly
- 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: Phylogenetic localization to COPII transport vesicles, inherited from cycling family members. Plausible given VIPL's transport role, but VIPL is predominantly ER-resident and direct COPII-vesicle localization is not demonstrated.
    action: KEEP_AS_NON_CORE
    reason: Plausible transport-vesicle association by homology, but not directly demonstrated for the predominantly ER-resident VIPL.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: VIPL localized primarily to the ER and partly to the Golgi complex
- 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, consistent with the minor Golgi pool of VIPL.
    action: KEEP_AS_NON_CORE
    reason: Correct minor compartment; VIPL is only partly found in the Golgi and the ER is core.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: Golgi apparatus membrane
- 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, consistent with stronger experimental (IDA) evidence.
    action: ACCEPT
    reason: Correct core compartment; redundant with IDA ER membrane.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic InterPro-based membrane localization. VIPL is a single-pass type I membrane protein, but the specific ER (and partly Golgi) membrane terms are far more informative.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-level compartment; the specific ER membrane (GO:0005789) term is the appropriate localization.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome (HuRI) capture; the GOA WITH field records MAL (P21145) as the interactor. Bare protein binding is uninformative and the partner does not reflect VIPL's lectin/ER-export function.
    action: KEEP_AS_NON_CORE
    reason: Records a real IntAct interaction (MAL) but bare protein binding is uninformative per curation guidelines; not elevated to core.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'Q9H0V9; P21145: MAL'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegenerative-disease interactome (Y2H) capture; the GOA WITH field records huntingtin HTT (P42858) as the interactor. Bare protein binding is uninformative and the partner does not reflect VIPL's core function.
    action: KEEP_AS_NON_CORE
    reason: Records a real IntAct interaction (HTT) from a disease-focused screen, but bare protein binding is uninformative; not elevated to core.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'Q9H0V9; P42858: HTT'
- term:
    id: GO:0005537
    label: D-mannose binding
  evidence_type: TAS
  original_reference_id: PMID:12609988
  qualifier: enables
  review:
    summary: TAS assignment of D-mannose binding based on VIPL being a high-mannose-type lectin with the same domain organization as VIP36 and the conserved L-type lectin CRD. The cited abstract establishes the lectin domain and high-mannose glycoprotein status but does not itself report a direct carbohydrate-binding assay for VIPL; the assignment is therefore homology/domain-based.
    action: ACCEPT
    reason: D-mannose binding is the family-level molecular function conferred by the conserved L-type lectin CRD and is consistent across TAS/IBA assignments. The cached abstract supports lectin/high-mannose-glycoprotein status but is homology/domain-based rather than a direct binding assay for VIPL; no catalytic activity is assigned.
    supported_by:
    - reference_id: PMID:12609988
      supporting_text: high-mannose type I membrane glycoprotein with similar domain organization as
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:12609988
  qualifier: located_in
  review:
    summary: Direct experimental evidence that VIPL is a non-cycling resident protein of the ER, retained by an RKR di-arginine signal. This is the core localization of VIPL.
    action: ACCEPT
    reason: Core compartment; VIPL is predominantly an ER-resident type I membrane protein, supported directly and by the UniProt subcellular location.
    supported_by:
    - reference_id: PMID:12609988
      supporting_text: VIPL is a non-cycling resident protein of the ER
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:12878160
  qualifier: located_in
  review:
    summary: Direct evidence that VIPL localizes partly to the Golgi complex in addition to its predominant ER pool.
    action: ACCEPT
    reason: Correct minor compartment; VIPL is partly found in the Golgi, consistent with the UniProt subcellular location.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: VIPL localized primarily to the ER and partly to the Golgi complex
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: NAS
  original_reference_id: PMID:12609988
  qualifier: involved_in
  review:
    summary: NAS assertion of a protein-folding role. VIPL is a lectin/transport regulator, not a folding catalyst or chaperone; any connection is to glycoprotein quality control and ER export rather than to catalysis of folding. This is a generic, over-broad assignment.
    action: MARK_AS_OVER_ANNOTATED
    reason: VIPL has no folding/chaperone activity; its function is lectin-mediated regulation of ER export, better captured by transport terms.
    supported_by:
    - reference_id: PMID:12609988
      supporting_text: VIPL is a non-cycling resident protein of the ER
- term:
    id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  evidence_type: TAS
  original_reference_id: PMID:12878160
  qualifier: involved_in
  review:
    summary: VIPL is proposed to function as an ER export receptor for a subset of glycoproteins; its knockdown slows their secretion. This ER-to-Golgi transport role is the core biological process of VIPL.
    action: ACCEPT
    reason: Core biological process; experimentally supported regulation of ER export of glycoproteins.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: Subsets of glycoproteins are thought to require lectin-like membrane receptors
- term:
    id: GO:0015031
    label: protein transport
  evidence_type: IMP
  original_reference_id: PMID:12878160
  qualifier: involved_in
  review:
    summary: siRNA knockdown of VIPL significantly slowed secretion of two glycoproteins, providing perturbation evidence that VIPL functions in the export (transport) of glycoproteins from the ER. Core biological process.
    action: ACCEPT
    reason: Core biological process directly supported by knockdown evidence; VIPL regulates ER export of a subset of glycoproteins.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: knock-down of VIPL mRNA using siRNA significantly
- term:
    id: GO:0016020
    label: membrane
  evidence_type: TAS
  original_reference_id: PMID:12609988
  qualifier: located_in
  review:
    summary: Generic membrane localization. VIPL is a single-pass type I membrane protein, but the specific ER membrane term is the appropriate, informative localization.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-level compartment; superseded by the specific ER membrane term.
    supported_by:
    - reference_id: file:human/LMAN2L/LMAN2L-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
    proposed_replacement_terms:
    - id: GO:0005789
      label: endoplasmic reticulum membrane
- term:
    id: GO:0030134
    label: COPII-coated ER to Golgi transport vesicle
  evidence_type: NAS
  original_reference_id: PMID:12878160
  qualifier: located_in
  review:
    summary: NAS assertion that VIPL associates with COPII ER-to-Golgi transport vesicles, in line with its proposed ER export receptor role. Plausible but not directly demonstrated; VIPL is predominantly ER-resident.
    action: KEEP_AS_NON_CORE
    reason: Plausible transport-vesicle association consistent with the ER export role, but not a directly demonstrated localization; kept as supporting.
    supported_by:
    - reference_id: PMID:12878160
      supporting_text: conserved carbohydrate recognition domain (CRD) as a search string
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: PMID:12609988
  title: Profile-based data base scanning for animal L-type lectins and characterization of VIPL, a novel VIP36-like endoplasmic reticulum protein.
  findings:
  - statement: VIPL is a high-mannose type I membrane glycoprotein with the same domain organization as VIP36 but, unlike VIP36 and ERGIC-53, is a non-cycling resident protein of the ER retained by an RKR di-arginine signal; overexpression redistributes ERGIC-53 to the ER, suggesting VIPL regulates ERGIC-53.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified primary characterization of VIPL. Establishes ER-resident localization, L-type lectin domain/high-mannose glycoprotein status, and the regulator-of-ERGIC-53 model. Mannose binding is inferred from the conserved CRD/homology rather than a direct binding assay in the abstract.
- id: PMID:12878160
  title: VIPL, a VIP36-like membrane protein with a putative function in the export of glycoproteins from the endoplasmic reticulum.
  findings:
  - statement: VIPL localizes primarily to the ER and partly to the Golgi; siRNA knockdown of VIPL slows secretion of two glycoproteins, suggesting VIPL functions as a lectin-type ER export receptor for a subset of glycoproteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified functional study; provides the IMP knockdown evidence and the ER/Golgi localization underpinning the ER export receptor model.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput HuRI binary interactome; source of the IPI protein binding annotation with MAL (P21145). Not informative for VIPL's specific function.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neurodegenerative-disease Y2H interactome; source of the IPI protein binding annotation with huntingtin HTT (P42858). Not informative for VIPL's core function.
- id: PMID:26566883
  title: Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes LMAN2L involvement in autosomal recessive intellectual developmental disorder MRT52 (R53Q variant). Disease relevance; not a direct source of an MF/CC/BP term.
- id: PMID:31020005
  title: Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Establishes LMAN2L involvement in autosomal dominant intellectual developmental disorder MRD69. Disease relevance; not a direct source of an MF/CC/BP term.
- id: PMID:37667433
  title: Novel compound heterozygous variants in lectin mannose-binding 2-like gene
    identified in a Chinese autosomal recessive mental retardation-52 (MRT52) patient
    with phenotype expansion.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:37667433; DOI:10.1097/CM9.0000000000002285).
      Extends MRT52 beyond consanguineous homozygous pedigrees by reporting compound
      heterozygous LMAN2L variants (c.256C>T p.R86C; c.902del p.F301Sfs*8) in a Chinese
      proband with phenotype expansion (developmental delay, severe ID, early seizures,
      hearing loss, dystonia). Disease relevance; not a direct source of an MF/CC/BP term.
      Not in publications cache, so no verbatim supporting_text added.
- id: PMID:38687323
  title: HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein
    LMAN2L.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:38687323; DOI:10.1099/jgv.0.001980). First
      gene-specific cell-biology study to directly assay LMAN2L as an endogenous protein -
      identifies LMAN2L as a novel target of HCMV pUS2, degraded via the host E3 ligase
      TRC8 (ERAD). Plasma-membrane profiling of LMAN2L-deficient cells shows reduced
      surface integrin alpha-6 (ITGA6), supporting LMAN2L's hypothesized role in
      glycoprotein trafficking. Corroborates the ER-resident localization and ER-export
      receptor model; provides the first candidate physiological client (ITGA6).
      Not in publications cache, so no verbatim supporting_text added.
- id: PMID:19420740
  title: Intracellular lectins involved in folding and transport in the endoplasmic
    reticulum.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:19420740; DOI:10.1248/bpb.32.767). Authoritative
      review of intracellular L-type lectins (ERGIC-53/LMAN1, VIP36/LMAN2, VIPL/LMAN2L)
      in ER glycoprotein quality control and transport. Background/contextual support for
      the family-level lectin and ER-export framing; not LMAN2L-primary. Not in
      publications cache, so no verbatim supporting_text added.
- id: file:human/LMAN2L/LMAN2L-uniprot.txt
  title: UniProt entry Q9H0V9 (LMA2L_HUMAN), VIP36-like protein (VIPL / LMAN2L)
  findings:
  - statement: ER-resident (predominantly ER, partly Golgi) single-pass type I membrane L-type lectin; may regulate ER export of a subset of glycoproteins and act as a regulator of ERGIC-53; binary interactors HTT and MAL; disease gene for MRT52 and MRD69.
    reference_section_type: OTHER
core_functions:
- description: ER-resident L-type lectin whose conserved carbohydrate-recognition domain binds high-mannose glycans (D-mannose), enabling recognition of glycoprotein cargo in the early secretory pathway.
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:12609988
    supporting_text: high-mannose type I membrane glycoprotein with similar domain organization as
- description: Regulator of ER export of a subset of glycoproteins, acting as a lectin-type ER export receptor and as a regulator of ERGIC-53; knockdown slows glycoprotein secretion and overexpression redistributes ERGIC-53 to the ER.
  molecular_function:
    id: GO:0005537
    label: D-mannose binding
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:12878160
    supporting_text: Subsets of glycoproteins are thought to require lectin-like membrane receptors
  directly_involved_in:
  - id: GO:0006888
    label: endoplasmic reticulum to Golgi vesicle-mediated transport
  - id: GO:0015031
    label: protein transport
proposed_new_terms: []
suggested_questions:
- question: Does VIPL bind D-mannose / high-mannose N-glycans directly in vitro, and what is its glycan specificity relative to VIP36 and ERGIC-53?
- question: Is VIPL a positive or negative regulator of ERGIC-53-mediated ER export, and does it act by sequestering ERGIC-53 in the ER or by handing off glycoprotein cargo?
- question: How do the MRT52 (R53Q) and MRD69 disease variants alter VIPL lectin binding, ER retention, or ERGIC-53 regulation to cause intellectual disability?
suggested_experiments:
- description: Quantitative glycan-array or ITC/SPR binding assays with purified VIPL luminal CRD against high-mannose and processed N-glycans to directly establish D-mannose binding and specificity.
- description: Define the endogenous glycoprotein cargo whose ER export depends on VIPL using secretomics/pulse-chase in VIPL knockout versus wild-type cells.
- description: Test whether VIPL disease variants (R53Q; dominant MRD69 allele) perturb ERGIC-53 localization and glycoprotein secretion in patient-derived or engineered cells.