Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005793 endoplasmic reticulum-Golgi intermediate compartment	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER
GO:0000139 Golgi membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic Golgi-membrane localization, consistent with the minor Golgi pool of VIPL observed experimentally. Reason: VIPL is only partly found in the Golgi; the ER is its predominant and core compartment. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex
GO:0005789 endoplasmic reticulum membrane	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic ER-membrane localization, fully consistent with direct experimental evidence that VIPL is a non-cycling ER-resident type I membrane protein. Reason: ER membrane is the correct core compartment, supported by IDA and the UniProt subcellular location. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005537 D-mannose binding	IBA GO_REF:0000033	ACCEPT	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. Reason: D-mannose binding is the defensible family-level molecular function conferred by the conserved L-type lectin CRD; consistent with the TAS annotation. Supporting Evidence: PMID:12609988 high-mannose type I membrane glycoprotein with similar domain organization as
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of ER-to-Golgi vesicle-mediated transport, consistent with VIPL's role in regulating ER export of glycoproteins. Reason: Consistent with the experimentally supported role in ER export of a subset of glycoproteins; core biological process. Supporting Evidence: PMID:12878160 knock-down of VIPL mRNA using siRNA significantly
GO:0030134 COPII-coated ER to Golgi transport vesicle	IBA GO_REF:0000033	KEEP AS NON CORE	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. Reason: Plausible transport-vesicle association by homology, but not directly demonstrated for the predominantly ER-resident VIPL. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex
GO:0000139 Golgi membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer of Golgi-membrane localization from the UniProt subcellular location, consistent with the minor Golgi pool of VIPL. Reason: Correct minor compartment; VIPL is only partly found in the Golgi and the ER is core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Golgi apparatus membrane
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of ER-membrane localization from the UniProt subcellular location, consistent with stronger experimental (IDA) evidence. Reason: Correct core compartment; redundant with IDA ER membrane. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0016020 membrane	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	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. Reason: Uninformative high-level compartment; the specific ER membrane (GO:0005789) term is the appropriate localization. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	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. Reason: Records a real IntAct interaction (MAL) but bare protein binding is uninformative per curation guidelines; not elevated to core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Q9H0V9; P21145: MAL
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	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. Reason: Records a real IntAct interaction (HTT) from a disease-focused screen, but bare protein binding is uninformative; not elevated to core. Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt Q9H0V9; P42858: HTT
GO:0005537 D-mannose binding	TAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a...	ACCEPT	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. 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. Supporting Evidence: PMID:12609988 high-mannose type I membrane glycoprotein with similar domain organization as
GO:0005789 endoplasmic reticulum membrane	IDA PMID:12609988 Profile-based data base scanning for animal L-type lectins a...	ACCEPT	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. Reason: Core compartment; VIPL is predominantly an ER-resident type I membrane protein, supported directly and by the UniProt subcellular location. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER
GO:0005794 Golgi apparatus	IDA PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function...	ACCEPT	Summary: Direct evidence that VIPL localizes partly to the Golgi complex in addition to its predominant ER pool. Reason: Correct minor compartment; VIPL is partly found in the Golgi, consistent with the UniProt subcellular location. Supporting Evidence: PMID:12878160 VIPL localized primarily to the ER and partly to the Golgi complex
GO:0006457 protein folding	NAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a...	MARK AS OVER ANNOTATED	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. Reason: VIPL has no folding/chaperone activity; its function is lectin-mediated regulation of ER export, better captured by transport terms. Supporting Evidence: PMID:12609988 VIPL is a non-cycling resident protein of the ER
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport	TAS PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function...	ACCEPT	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. Reason: Core biological process; experimentally supported regulation of ER export of glycoproteins. Supporting Evidence: PMID:12878160 Subsets of glycoproteins are thought to require lectin-like membrane receptors
GO:0015031 protein transport	IMP PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function...	ACCEPT	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. Reason: Core biological process directly supported by knockdown evidence; VIPL regulates ER export of a subset of glycoproteins. Supporting Evidence: PMID:12878160 knock-down of VIPL mRNA using siRNA significantly
GO:0016020 membrane	TAS PMID:12609988 Profile-based data base scanning for animal L-type lectins a...	MARK AS OVER ANNOTATED	Summary: Generic membrane localization. VIPL is a single-pass type I membrane protein, but the specific ER membrane term is the appropriate, informative localization. Reason: Uninformative high-level compartment; superseded by the specific ER membrane term. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/LMAN2L/LMAN2L-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0030134 COPII-coated ER to Golgi transport vesicle	NAS PMID:12878160 VIPL, a VIP36-like membrane protein with a putative function...	KEEP AS NON CORE	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. Reason: Plausible transport-vesicle association consistent with the ER export role, but not a directly demonstrated localization; kept as supporting. Supporting Evidence: PMID:12878160 conserved carbohydrate recognition domain (CRD) as a search string

Core Functions

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:

D-mannose binding

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:12609988
high-mannose type I membrane glycoprotein with similar domain organization as

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:

D-mannose binding

Directly Involved In:

endoplasmic reticulum to Golgi vesicle-mediated transport protein transport

Cellular Locations:

endoplasmic reticulum membrane

Supporting Evidence:

PMID:12878160
Subsets of glycoproteins are thought to require lectin-like membrane receptors

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

PMID:12609988

Profile-based data base scanning for animal L-type lectins and characterization of VIPL, a novel VIP36-like endoplasmic reticulum protein.

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.

PMID:12878160

VIPL, a VIP36-like membrane protein with a putative function in the export of glycoproteins from the endoplasmic reticulum.

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.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:26566883

Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.

PMID:31020005

Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy.

PMID:37667433

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.

PMID:38687323

HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.

PMID:19420740

Intracellular lectins involved in folding and transport in the endoplasmic reticulum.

file:human/LMAN2L/LMAN2L-uniprot.txt

UniProt entry Q9H0V9 (LMA2L_HUMAN), VIP36-like protein (VIPL / LMAN2L)

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.

Suggested Experiments

Experiment: 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.

Experiment: Define the endogenous glycoprotein cargo whose ER export depends on VIPL using secretomics/pulse-chase in VIPL knockout versus wild-type cells.

Experiment: Test whether VIPL disease variants (R53Q; dominant MRD69 allele) perturb ERGIC-53 localization and glycoprotein secretion in patient-derived or engineered cells.

Deep Research

Falcon

(LMAN2L-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 28 citations 2 artifacts 2026-06-12T04:05:34.233529

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000028 Figure 2 on page 3 contains the requested visual information. Panels B and C show Western blot fractionation of wild-type (wt) and (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 LMAN2L (VIPL; UniProt Q9H0V9) — Functional Annotation and Current Evidence

1) Target verification (gene/protein identity)

The research target is human LMAN2L (synonym VIPL, “VIP36-like protein”), consistent across genetics, cell-biology, and infection/proteomics studies that explicitly refer to LMAN2L/VIPL as an ER-resident L-type (legume-like) intracellular lectin involved in glycoprotein handling in the early secretory pathway. This aligns with the UniProt-provided description (VIP36-like; L-type lectin/ConA-like domain superfamily; precursor/type I membrane protein). (gupta2012ltypelectinsin pages 15-16, hunter2023functionalcharacterisationof pages 91-94, casalnuovo2024characterizationofthe pages 5-9)

2) Key concepts and definitions (current understanding)

2.1 Intracellular L-type (legume-like) lectins

L-type lectins are defined by a luminal carbohydrate-recognition domain (CRD) structurally related to legume seed lectins, typically a β-sandwich that binds Ca2+ adjacent to the carbohydrate-binding site; Ca2+ helps organize binding-site residues and supports glycan binding. (gupta2012ltypelectinsin pages 13-15)

In mammalian secretory trafficking, L-type lectins include ERGIC-53/LMAN1, VIP36/LMAN2, and VIPL/LMAN2L and are proposed to recognize high-mannose N-glycans in regulated ways (compared with high-affinity plant lectins). Binding is often Ca2+-dependent and pH-sensitive, allowing capture/release across the ER→ERGIC→Golgi pH gradient. (yamamoto2009intracellularlectinsinvolved pages 5-6, yamamoto2009intracellularlectinsinvolved pages 3-5)

2.2 Cargo receptors and receptor-mediated ER export

A cargo receptor is a transmembrane protein that binds soluble secretory cargo in the ER lumen and links them to cytosolic coat machinery (e.g., COPII) for ER exit, then typically recycles via COPI. ERGIC-53 is described as a best-characterized example, with oligomerization enabling COPII-recognized sorting signals and selective export of folded cargo. (hunter2023functionalcharacterisationof pages 91-94, gupta2012ltypelectinsin pages 2-3)

2.3 LMAN2L/VIPL’s position within this framework

LMAN2L is repeatedly distinguished from cycling receptors (ERGIC-53, VIP36) by being primarily ER-resident / non-cycling, consistent with cytosolic retention signals. (hunter2023functionalcharacterisationof pages 91-94, yamamoto2009intracellularlectinsinvolved pages 5-6)

3) Molecular function of LMAN2L (VIPL): what it does and how

3.1 Proposed primary function: glycoprotein-binding lectin facilitating ER export and/or quality control

Multiple sources converge on LMAN2L as an ER-resident L-type lectin implicated in glycoprotein trafficking/export rather than enzymatic catalysis. It has been framed as a cargo receptor or “secretion chaperone” whose specific endogenous glycoprotein clients remain incompletely defined. (alkhater2019dominantlman2lmutation pages 1-3, gupta2012ltypelectinsin pages 15-16, hunter2023functionalcharacterisationof pages 91-94)

Mechanistically, LMAN2L is proposed to bind native (properly folded) glycoproteins after they exit the calnexin/calreticulin (CNX/CRT) folding cycle, thereby helping them avoid mannose trimming that would otherwise target them to ER-associated degradation (ERAD), and possibly facilitating onward transport (including potential handoff to ERGIC-53). (hunter2023functionalcharacterisationof pages 91-94)

3.2 Glycan-binding specificity and biochemical determinants

The strongest and most specific statements in the retrieved literature indicate that LMAN2L/VIPL:
- Binds high-mannose-type N-glycans, with selectivity for deglucosylated forms. (hunter2024hcmvus2coopts pages 5-7, hunter2023functionalcharacterisationof pages 91-94)
- Recognizes motifs including Manα1-2Manα1-2Man (reported from competition assays). (gupta2012ltypelectinsin pages 15-16)
- Shows Ca2+ and pH dependence, with stronger binding at neutral (ER-like) pH and weaker binding after glucosylation or mannose trimming. (hunter2023functionalcharacterisationof pages 91-94, gupta2012ltypelectinsin pages 15-16)

However, some experimental reports summarized in review text note conflicting results (e.g., failure of certain tagged constructs to detect binding to immobilized mannose/Glc/GlcNAc ligands), so glycan-binding activity is supported but not uniformly observed across assay formats. (gupta2012ltypelectinsin pages 15-16)

3.3 Subcellular localization and trafficking signals

LMAN2L is described as primarily ER-resident with some partial Golgi localization, and not cycling like ERGIC-53/VIP36. (gupta2012ltypelectinsin pages 15-16, yamamoto2009intracellularlectinsinvolved pages 5-6)

Sorting/retention motifs reported for LMAN2L/VIPL include:
- A cytosolic KRFY motif (associated with ER/ERGIC/cis-Golgi recycling signals in the L-type lectin family context). (gupta2012ltypelectinsin pages 15-16)
- An RKR ER-retention/localization motif described in its cytosolic domain (noted as a determinant of ER residency). (hunter2023functionalcharacterisationof pages 91-94, yamamoto2009intracellularlectinsinvolved pages 5-6, gupta2012ltypelectinsin pages 15-16)

3.4 Interacting partners and candidate client proteins

ERGIC-53 (LMAN1): LMAN2L has been proposed to interact with ERGIC-53; overexpression of LMAN2L can redistribute/retain ERGIC-53 in the ER, suggesting regulatory interplay in receptor-mediated export. (hunter2023functionalcharacterisationof pages 91-94, casalnuovo2024characterizationofthe pages 5-9)

Integrin trafficking (ITGA6): A key 2023–2024 development is the emergence of at least one plausible cell-surface client: ITGA6. In infection-linked and depletion experiments, surface ITGA6 was reduced in LMAN2L-deficient cells, and interactome work detected ITGB1 (ITGA6 partner) as a potential associated protein, supporting a model in which LMAN2L contributes to trafficking of specific glycoproteins to the plasma membrane. (hunter2023functionalcharacterisationof pages 121-124, hunter2024hcmvus2coopts pages 5-7)

Unbiased proteomics interaction screening (2024): A RUSH-based co-IP/MS workflow yielded 87 VIPL-associated candidate interactors/cargos after localization filtering, including proteins annotated to ER/Golgi and COPII-related components (e.g., SEC23A/SEC23B, COPB2) plus many cytoskeleton-associated proteins. This dataset is hypothesis-generating and requires orthogonal validation to separate direct interactors from indirect associations. (casalnuovo2024characterizationofthe pages 49-52, casalnuovo2024characterizationofthe pages 45-49)

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 Viral exploitation of LMAN2L: HCMV pUS2–TRC8 axis (2024)

A major 2024 advance is the demonstration that human cytomegalovirus (HCMV) pUS2 targets LMAN2L for degradation by co-opting the host ERAD machinery:
- LMAN2L is downregulated early (as early as 4 hours post-infection).
- Downregulation is rescued by proteasome inhibition (MG132) but not lysosomal inhibition (leupeptin), supporting proteasome-dependent degradation.
- Deletion mapping indicates pUS2 is necessary for LMAN2L downregulation during infection.
- LMAN2L degradation is TRC8-dependent (TRC8 knockdown strongly rescues LMAN2L), consistent with US2 recruiting TRC8 to ubiquitinate substrates for dislocation and proteasomal degradation.
- Proteomics supporting data deposition: PRIDE PXD050878 (reported in the paper). (hunter2024hcmvus2coopts pages 5-7, hunter2024hcmvus2coopts pages 4-5)

The study interprets these results as consistent with LMAN2L’s hypothesized role in glycoprotein trafficking and suggests US2-mediated targeting may indirectly affect specific surface proteins, including ITGA6. (hunter2024hcmvus2coopts pages 5-7)

URL and publication date: Hunter et al., Journal of General Virology, Apr 2024. https://doi.org/10.1099/jgv.0.001980 (hunter2024hcmvus2coopts pages 5-7)

4.2 Human genetics update: compound heterozygous LMAN2L variants with expanded phenotype (2023)

A 2023 clinical report extends LMAN2L-related neurodevelopmental disease beyond homozygous consanguineous pedigrees by identifying compound heterozygous variants in a Chinese patient:
- Variants: c.256C>T (p.R86C) and c.902del (p.F301Sfs*8).
- Phenotype: global developmental delay, severe intellectual disability, seizures starting at 2 months; additional features include hearing loss and dystonia (phenotype expansion).
- Quantitative clinical details: tonic seizures lasting ~10 seconds; seizure frequency about twice per month on therapy; developmental indices <50 (mean 100).
- Diagnostic implementation: trio-WES, Sanger confirmation, ACMG classification, plus CMA noting a small duplication VUS. (zhou2023novelcompoundheterozygous pages 1-2, zhou2023novelcompoundheterozygous pages 2-3)

URL and publication date: Zhou et al., Chinese Medical Journal, Feb 2023. https://doi.org/10.1097/cm9.0000000000002285 (zhou2023novelcompoundheterozygous pages 1-2)

5) Disease associations, expert analysis, and strength of evidence

5.1 Core Mendelian disorder association: neurodevelopmental disorder with seizures (MRT52 / ID with epilepsy)

Autosomal recessive: The foundational Mendelian evidence is a 2016 consanguineous family where LMAN2L p.R53Q (c.158G>A) co-segregated with severe intellectual disability and infantile seizures until age 5, with 5 affected homozygotes and 7 unaffected relatives showing heterozygosity or non-carrier status, strongly supporting causality in that pedigree. (rafiullah2016homozygousmissensemutation pages 2-4)

Autosomal dominant: A 2019 report identified a heterozygous frameshift c.1073delT; p.(Phe358Serfs*16) that removes the ER-retention/localization motif and causes ID with remitting epilepsy in 4 affected family members. A central mechanistic interpretation is that loss of ER retention causes mislocalization and disrupts glycoprotein handling critical for neurodevelopment. (alkhater2019dominantlman2lmutation pages 1-3, alkhater2019dominantlman2lmutation pages 3-5)

Image-based evidence for mechanism (2019): Figure 2 provides direct evidence that the c.1073delT variant shifts LMAN2L into the plasma membrane fraction and produces peripheral cell-surface immunofluorescence, supporting mislocalization due to loss of ER retention. (alkhater2019dominantlman2lmutation media 119efd23)

Expert interpretation: The 2019 authors explicitly frame LMAN2L as among “glycoprotein secretion chaperone” family members and emphasize that its specific processed glycoproteins are unknown, while arguing that mislocalization or impaired glycoprotein interaction can disturb brain development and produce remitting childhood epilepsy. (alkhater2019dominantlman2lmutation pages 1-3, alkhater2019dominantlman2lmutation pages 3-5)

5.2 Psychiatric/neuropsychiatric associations (GWAS / database)

LMAN2L has been repeatedly mentioned as associated in GWAS contexts with disorders including bipolar disorder and schizophrenia in the genetics literature, but these do not establish causal mechanism in the same way as family segregation. (alkhater2019dominantlman2lmutation pages 1-3, rafiullah2016homozygousmissensemutation pages 2-4)

A disease-target association query in Open Targets lists associations for LMAN2L with autosomal dominant intellectual disability, autosomal recessive non-syndromic intellectual disability, and psychiatric phenotypes (major depressive disorder, bipolar disorder, schizophrenia), reflecting aggregated evidence links and literature mapping. (OpenTargets Search: -LMAN2L)

6) Current applications and real-world implementations

6.1 Clinical genetics/diagnostics

The most mature real-world application is rare-disease genetic diagnosis:
- LMAN2L variants are identified via whole-exome sequencing (WES) with segregation/Sanger validation in families and probands; trio-WES is used in contemporary diagnostics. (zhou2023novelcompoundheterozygous pages 1-2, rafiullah2016homozygousmissensemutation pages 2-4, alkhater2019dominantlman2lmutation pages 1-3)
- Reported inheritance spans autosomal recessive (homozygous or compound heterozygous) and autosomal dominant (ER-retention-loss frameshift) presentations, which is relevant for variant interpretation and counseling. (rafiullah2016homozygousmissensemutation pages 2-4, alkhater2019dominantlman2lmutation pages 1-3)

6.2 Infection biology and host–pathogen interaction

LMAN2L has emerging relevance as a host factor targeted by HCMV immune evasion. The pUS2–TRC8-mediated degradation of LMAN2L demonstrates a concrete host–virus interaction and provides a tool/perturbation axis for dissecting LMAN2L-dependent trafficking of specific glycoproteins. (hunter2024hcmvus2coopts pages 5-7)

6.3 Proteomics resources

The 2024 HCMV study reports proteomics deposition (PRIDE: PXD050878) supporting LMAN2L degradation and downstream surface-proteome analysis, enabling reanalysis and integration by other investigators. (hunter2024hcmvus2coopts pages 5-7, hunter2024hcmvus2coopts pages 4-5)

7) Statistics and quantitative data points from recent studies

7.1 Human genetics (cases, inheritance, phenotypes)

2016 family study: 1 consanguineous family; 5 affected homozygous p.R53Q; 7 unaffected evaluated; seizures in infancy until age 5. (rafiullah2016homozygousmissensemutation pages 2-4)
2019 dominant family study: 4 affected (father + 3 sons) with c.1073delT frameshift; seizure onset around age 6; carbamazepine-responsive with remission (weaned ~10 years, EEG normalized). (alkhater2019dominantlman2lmutation pages 1-3)
2023 case report: 1 proband, seizure onset 2 months, frequency ~2/month on therapy; developmental index <50. (zhou2023novelcompoundheterozygous pages 1-2)

7.2 2023–2024 trafficking/proteomics (quantitative)

LMAN2L downregulation observed as early as 4 h post HCMV infection. (hunter2024hcmvus2coopts pages 5-7)
Deletion of US1–US11 block increases LMAN2L abundance by >20-fold (consistent with viral locus controlling its degradation). (hunter2024hcmvus2coopts pages 5-7)
TRC8 knockdown provided an approximately ~40-fold reduction (as reported) and rescued LMAN2L during infection, supporting TRC8 dependence. (hunter2024hcmvus2coopts pages 5-7)
LMAN2L depletion decreased surface ITGA6; in the 2023 thesis, ITGA6 was reproducibly ~1.5-fold downregulated upon LMAN2L depletion. (hunter2023functionalcharacterisationof pages 121-124)

8) Evidence gaps and priorities for future functional annotation

Endogenous client glycoproteins: Beyond emerging integrin evidence (ITGA6), definitive endogenous “client lists” are not yet established; unbiased interaction screens are currently hypothesis-generating. (hunter2023functionalcharacterisationof pages 121-124, casalnuovo2024characterizationofthe pages 49-52, casalnuovo2024characterizationofthe pages 45-49)
Binding specificity and structural basis for LMAN2L: Although binding to deglucosylated high-mannose motifs is reported, assay-dependent discrepancies exist, and high-resolution structures specifically for LMAN2L (vs paralogs) would clarify determinants of selectivity. (gupta2012ltypelectinsin pages 15-16)
Neurodevelopment mechanism: Genetics and mislocalization experiments support a secretion/trafficking mechanism, but direct links between LMAN2L dysfunction, specific neuronal glycoprotein secretion defects, and epilepsy remain to be experimentally mapped. (alkhater2019dominantlman2lmutation pages 1-3, alkhater2019dominantlman2lmutation pages 3-5, alkhater2019dominantlman2lmutation media 119efd23)

Summary evidence map

Category	Key findings	Evidence type	Citation id(s)	Publication year	URL
Protein identity, localization, motifs	Human LMAN2L (VIPL; UniProt Q9H0V9) is a VIP36-like, ER-resident L-type intracellular lectin/cargo-receptor family member. It is largely non-cycling relative to ERGIC-53/LMAN1 and LMAN2/VIP36. Reported cytosolic sorting motifs include KRFY and an additional RKR ER-retention/localization signal; mutation of KR can redirect VIPL to the cell surface.	Reviews/summaries of prior cell biology; mechanistic thesis synthesis	(gupta2012ltypelectinsin pages 15-16, hunter2023functionalcharacterisationof pages 91-94, casalnuovo2024characterizationofthe pages 5-9)	2012, 2023, 2024	https://doi.org/10.1007/978-3-7091-1065-2_7; https://doi.org/10.17863/cam.108565
Glycan binding and mechanistic role	VIPL/LMAN2L has been reported to recognize deglucosylated high-mannose N-glycans, especially Manα1-2Manα1-2Man motifs; binding is stronger at neutral ER-like pH and is Ca2+-dependent. Proposed role: bind native glycoproteins exiting the calnexin/calreticulin cycle, protect them from demannosylation/ERAD, and possibly hand cargo to ERGIC-53 for anterograde transport. siRNA knockdown delayed secretion of two glycoproteins. Some earlier assays failed to detect sugar binding, so this function remains supported but not fully settled.	Binding assays/competition data, knockdown experiments, mechanistic synthesis	(gupta2012ltypelectinsin pages 15-16, hunter2023functionalcharacterisationof pages 91-94)	2012, 2023	https://doi.org/10.1007/978-3-7091-1065-2_7; https://doi.org/10.17863/cam.108565
2016 clinical variant	Homozygous c.158G>A (p.R53Q) in a consanguineous Pakistani family co-segregated with severe intellectual disability and infantile epileptic seizures. Studied pedigree included 5 affected and 7 unaffected relatives; all affected were homozygous, unaffected relatives were heterozygous, supporting autosomal recessive inheritance.	Family-based WES, segregation, Sanger validation, homology modeling	(rafiullah2016homozygousmissensemutation pages 2-4)	2016	https://doi.org/10.1136/jmedgenet-2015-103179
2019 clinical variant	Heterozygous c.1073delT, p.(Phe358Serfs*16) disrupted the C-terminal KRFY ER-retention motif in a family with autosomal dominant intellectual disability and remitting epilepsy. Functional studies in HeLa cells showed mutant LMAN2L shifted from ER/light-membrane fractions to the plasma membrane; immunofluorescence showed a peripheral “shroud” consistent with surface mislocalization.	WES/segregation plus membrane fractionation and immunofluorescence	(alkhater2019dominantlman2lmutation pages 1-3, alkhater2019dominantlman2lmutation pages 3-5, alkhater2019dominantlman2lmutation media 119efd23)	2019	https://doi.org/10.1002/acn3.727
2023 clinical variant	A Chinese MRT52 proband carried compound heterozygous variants c.256C>T (p.R86C) and c.902del (p.F301Sfs*8), extending LMAN2L disease beyond homozygous cases. Phenotype included global developmental delay, severe ID, seizures beginning at 2 months, hearing loss, and dystonia; seizures occurred about twice monthly despite therapy.	Trio-WES, Sanger confirmation, ACMG classification, case report	(zhou2023novelcompoundheterozygous pages 1-2, zhou2023novelcompoundheterozygous pages 2-3)	2023	https://doi.org/10.1097/cm9.0000000000002285
2024 HCMV/ERAD finding	HCMV pUS2 targets LMAN2L for degradation through the host E3 ligase TRC8. LMAN2L was downregulated as early as 4 h post-infection, rescued by MG132 but not leupeptin, and restored in ΔUS2 infection. This supports a bona fide ER-resident role for LMAN2L and implicates it in host glycoprotein trafficking exploited by virus.	Quantitative proteomics, viral genetics, inhibitor rescue, knockdown	(hunter2024hcmvus2coopts pages 5-7, hunter2024hcmvus2coopts pages 4-5)	2024	https://doi.org/10.1099/jgv.0.001980
2024 trafficking/client evidence	In LMAN2L-deficient cells, surface ITGA6 was reproducibly reduced; 2023-2024 proteomic work also detected ITGB1 in the LMAN2L interactome, suggesting integrin-related client trafficking. Effect size reported for ITGA6 in the thesis was ~1.5-fold downregulation upon LMAN2L depletion.	Plasma-membrane profiling, CRISPR/siRNA depletion, interactome proteomics	(hunter2023functionalcharacterisationof pages 121-124, hunter2024hcmvus2coopts pages 5-7)	2023, 2024	https://doi.org/10.17863/cam.108565; https://doi.org/10.1099/jgv.0.001980
2024 proteomics interaction screening	A RUSH-based co-IP/MS study identified 87 candidate VIPL-associated proteins/cargos after localization filtering, including ER/Golgi and COPII-related proteins such as SEC23A, SEC23B, and COPB2, plus many cytoskeleton-associated proteins. Authors cautioned that these are candidate interactors/cargos requiring orthogonal validation.	RUSH live-cell trafficking, GFP-nanobody IP, mass spectrometry, imaging	(casalnuovo2024characterizationofthe pages 49-52, casalnuovo2024characterizationofthe pages 45-49)	2024	No stable journal URL available in retrieved context

Table: This table condenses the main experimentally supported findings for human LMAN2L/VIPL, spanning identity, localization, glycan-binding biology, disease variants, and the most relevant 2023-2024 mechanistic studies. It is useful as a quick-reference evidence map linking each claim to specific cited contexts and source URLs.

Key cited sources (URLs, dates)

Hunter LM et al. Apr 2024. Journal of General Virology. “HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.” https://doi.org/10.1099/jgv.0.001980 (hunter2024hcmvus2coopts pages 5-7)
Zhou C et al. Feb 2023. Chinese Medical Journal. “Novel compound heterozygous variants in LMAN2L…” https://doi.org/10.1097/cm9.0000000000002285 (zhou2023novelcompoundheterozygous pages 1-2)
Alkhater RA et al. Mar 2019. Annals of Clinical and Translational Neurology. “Dominant LMAN2L mutation…” https://doi.org/10.1002/acn3.727 (alkhater2019dominantlman2lmutation pages 1-3)
Rafiullah et al. (epub details in retrieved text) 2016. Journal of Medical Genetics. “Homozygous missense mutation in LMAN2L…” https://doi.org/10.1136/jmedgenet-2015-103179 (rafiullah2016homozygousmissensemutation pages 2-4)
Yamamoto K. May 2009. Biological & Pharmaceutical Bulletin. “Intracellular lectins involved in folding and transport in the endoplasmic reticulum.” https://doi.org/10.1248/bpb.32.767 (yamamoto2009intracellularlectinsinvolved pages 5-6)
Gupta GS. Mar 2012. Book chapter. “L-Type Lectins in ER-Golgi Intermediate Compartment.” https://doi.org/10.1007/978-3-7091-1065-2_7 (gupta2012ltypelectinsin pages 13-15)

References

(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.
(hunter2023functionalcharacterisationof pages 91-94): Functional Characterisation of Protein Degradation during Human Cytomegalovirus Infection This article has 0 citations.
(casalnuovo2024characterizationofthe pages 5-9): S Casalnuovo. Characterization of the protein vip36 and vipl and identification of their interaction partners. Unknown journal, 2024.
(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.
(yamamoto2009intracellularlectinsinvolved pages 5-6): Kazuo Yamamoto. Intracellular lectins involved in folding and transport in the endoplasmic reticulum. Biological & pharmaceutical bulletin, 32 5:767-73, May 2009. URL: https://doi.org/10.1248/bpb.32.767, doi:10.1248/bpb.32.767. This article has 29 citations and is from a peer-reviewed journal.
(yamamoto2009intracellularlectinsinvolved pages 3-5): Kazuo Yamamoto. Intracellular lectins involved in folding and transport in the endoplasmic reticulum. Biological & pharmaceutical bulletin, 32 5:767-73, May 2009. URL: https://doi.org/10.1248/bpb.32.767, doi:10.1248/bpb.32.767. This article has 29 citations and is from a peer-reviewed journal.
(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.
(alkhater2019dominantlman2lmutation pages 1-3): Reem A. Alkhater, Peixiang Wang, Alessandra Ruggieri, Lori Israelian, Susan Walker, Stephen W. Scherer, Mary Lou Smith, and Berge A. Minassian. Dominant lman2l mutation causes intellectual disability with remitting epilepsy. Annals of Clinical and Translational Neurology, 6:807-811, Mar 2019. URL: https://doi.org/10.1002/acn3.727, doi:10.1002/acn3.727. This article has 14 citations and is from a peer-reviewed journal.
(hunter2024hcmvus2coopts pages 5-7): Leah M. Hunter, Joanne Kite, Alice Fletcher-Etherington, Katie Nightingale, Luis Nobre, Robin Antrobus, Ceri A. Fielding, Richard J. Stanton, and Michael P. Weekes. Hcmv us2 co-opts trc8 to degrade the endoplasmic reticulum-resident protein lman2l. Apr 2024. URL: https://doi.org/10.1099/jgv.0.001980, doi:10.1099/jgv.0.001980. This article has 4 citations and is from a peer-reviewed journal.
(hunter2023functionalcharacterisationof pages 121-124): Functional Characterisation of Protein Degradation during Human Cytomegalovirus Infection This article has 0 citations.
(casalnuovo2024characterizationofthe pages 49-52): S Casalnuovo. Characterization of the protein vip36 and vipl and identification of their interaction partners. Unknown journal, 2024.
(casalnuovo2024characterizationofthe pages 45-49): S Casalnuovo. Characterization of the protein vip36 and vipl and identification of their interaction partners. Unknown journal, 2024.
(hunter2024hcmvus2coopts pages 4-5): Leah M. Hunter, Joanne Kite, Alice Fletcher-Etherington, Katie Nightingale, Luis Nobre, Robin Antrobus, Ceri A. Fielding, Richard J. Stanton, and Michael P. Weekes. Hcmv us2 co-opts trc8 to degrade the endoplasmic reticulum-resident protein lman2l. Apr 2024. URL: https://doi.org/10.1099/jgv.0.001980, doi:10.1099/jgv.0.001980. This article has 4 citations and is from a peer-reviewed journal.
(zhou2023novelcompoundheterozygous pages 1-2): Cong Zhou, Xing Wei, Yuanyuan Xiao, Shanling Liu, and Jing Wang. 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. Chinese Medical Journal, 136:2107-2109, Feb 2023. URL: https://doi.org/10.1097/cm9.0000000000002285, doi:10.1097/cm9.0000000000002285. This article has 2 citations and is from a peer-reviewed journal.
(zhou2023novelcompoundheterozygous pages 2-3): Cong Zhou, Xing Wei, Yuanyuan Xiao, Shanling Liu, and Jing Wang. 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. Chinese Medical Journal, 136:2107-2109, Feb 2023. URL: https://doi.org/10.1097/cm9.0000000000002285, doi:10.1097/cm9.0000000000002285. This article has 2 citations and is from a peer-reviewed journal.
(rafiullah2016homozygousmissensemutation pages 2-4): Rafiullah Rafiullah, Muhammad Aslamkhan, Nagarajan Paramasivam, Christian Thiel, Ghulam Mustafa, Stefan Wiemann, Matthias Schlesner, Rebecca C Wade, Gudrun A Rappold, and Simone Berkel. Homozygous missense mutation in the lman2l gene segregates with intellectual disability in a large consanguineous pakistani family. Journal of Medical Genetics, 53:138-144, Nov 2016. URL: https://doi.org/10.1136/jmedgenet-2015-103179, doi:10.1136/jmedgenet-2015-103179. This article has 25 citations and is from a domain leading peer-reviewed journal.
(alkhater2019dominantlman2lmutation pages 3-5): Reem A. Alkhater, Peixiang Wang, Alessandra Ruggieri, Lori Israelian, Susan Walker, Stephen W. Scherer, Mary Lou Smith, and Berge A. Minassian. Dominant lman2l mutation causes intellectual disability with remitting epilepsy. Annals of Clinical and Translational Neurology, 6:807-811, Mar 2019. URL: https://doi.org/10.1002/acn3.727, doi:10.1002/acn3.727. This article has 14 citations and is from a peer-reviewed journal.
(alkhater2019dominantlman2lmutation media 119efd23): Reem A. Alkhater, Peixiang Wang, Alessandra Ruggieri, Lori Israelian, Susan Walker, Stephen W. Scherer, Mary Lou Smith, and Berge A. Minassian. Dominant lman2l mutation causes intellectual disability with remitting epilepsy. Annals of Clinical and Translational Neurology, 6:807-811, Mar 2019. URL: https://doi.org/10.1002/acn3.727, doi:10.1002/acn3.727. This article has 14 citations and is from a peer-reviewed journal.
(OpenTargets Search: -LMAN2L): Open Targets Query (-LMAN2L, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

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Citations

gupta2012ltypelectinsin pages 13-15
hunter2023functionalcharacterisationof pages 91-94
gupta2012ltypelectinsin pages 15-16
zhou2023novelcompoundheterozygous pages 1-2
rafiullah2016homozygousmissensemutation pages 2-4
hunter2023functionalcharacterisationof pages 121-124
yamamoto2009intracellularlectinsinvolved pages 5-6
casalnuovo2024characterizationofthe pages 5-9
yamamoto2009intracellularlectinsinvolved pages 3-5
gupta2012ltypelectinsin pages 2-3
casalnuovo2024characterizationofthe pages 49-52
casalnuovo2024characterizationofthe pages 45-49
zhou2023novelcompoundheterozygous pages 2-3
https://doi.org/10.1099/jgv.0.001980
https://doi.org/10.1097/cm9.0000000000002285
https://doi.org/10.1007/978-3-7091-1065-2_7;
https://doi.org/10.17863/cam.108565
https://doi.org/10.1136/jmedgenet-2015-103179
https://doi.org/10.1002/acn3.727
https://doi.org/10.17863/cam.108565;
https://doi.org/10.1248/bpb.32.767
https://doi.org/10.1007/978-3-7091-1065-2_7
https://doi.org/10.1007/978-3-7091-1065-2_7,
https://doi.org/10.1248/bpb.32.767,
https://doi.org/10.1002/acn3.727,
https://doi.org/10.1099/jgv.0.001980,
https://doi.org/10.1097/cm9.0000000000002285,
https://doi.org/10.1136/jmedgenet-2015-103179,

📚 Additional Documentation

Notes

(LMAN2L-notes.md)

LMAN2L (VIPL / VIP36-like protein), human — review notes

UniProt: Q9H0V9 (LMA2L_HUMAN). Gene symbol LMAN2L (HGNC:19263); synonym VIPL.
348 aa precursor; signal peptide 1-44; lumenal L-type lectin-like domain (49-274);
single-pass type I membrane protein (TM 314-336); short cytoplasmic tail (337-348)
ending in a C-terminal RKR di-arginine / KRFY ER-retention/retrieval motif.

Family / identity

LMAN2L is an L-type (leguminous-type, ConA-like) lectin family member, a paralog of
LMAN2/VIP36 and related to LMAN1/ERGIC-53. It was identified by profile-based database
scanning for animal L-type lectins and named VIPL ("VIP36-Like")
PMID:12609988.
It is ubiquitously expressed and evolutionarily older than VIP36
PMID:12609988.

Subcellular localization — ER-resident (key distinction from VIP36)

Unlike VIP36 and ERGIC-53 (which cycle in the early secretory pathway), VIPL is a
non-cycling resident protein of the ER
PMID:12609988.
ER retention depends on a cytoplasmic RKR di-arginine signal
PMID:12609988;
UniProt records loss of ER retention on RKR->SSS mutagenesis (MUTAGEN 344..346).
A second study found VIPL "localized primarily to the ER and partly to the Golgi complex"
PMID:12878160,
consistent with the UniProt subcellular location ("Predominantly found in the endoplasmic
reticulum. Partly found in the Golgi"). Supports CC = ER membrane (IDA, core) and Golgi
apparatus (IDA, accepted, minor pool).

Molecular function — D-mannose/lectin binding (by homology/domain, not directly shown)

VIPL is a high-mannose type I membrane glycoprotein with the same domain organization as
VIP36 PMID:12609988.
The carbohydrate recognition domain (CRD) was used as the search string to identify it
PMID:12878160.
Neither cached abstract directly demonstrates D-mannose binding by VIPL itself; the
D-mannose binding (GO:0005537) assignment rests on the conserved L-type lectin CRD /
PROSITE L_LECTIN_LIKE profile and homology to VIP36 (whose mannose binding is
characterized). UniProt carbohydrate-binding residues (93, 128, 161-163, 188, 258-260) and
Ca2+ sites are annotated by PROSITE-ProRule (ECO:0000255), i.e. by similarity. Therefore
the TAS/IBA D-mannose binding annotations are best treated as KEEP_AS_NON_CORE /
homology-based rather than a directly demonstrated core MF. Avoid assigning any
mannosidase/glycosidase or catalytic activity — VIPL has no catalytic activity; it is a
lectin/regulator.

Biological process — regulation of ER export of glycoproteins; regulator of ERGIC-53 (CORE)

UniProt FUNCTION: "May be involved in the regulation of export from the endoplasmic
reticulum of a subset of glycoproteins. May function as a regulator of ERGIC-53."
(ECO:0000269|PubMed:12878160).

Two complementary lines of evidence:
- Overexpression of VIPL redistributes ERGIC-53 to the ER, suggesting VIPL is a regulator
of ERGIC-53 PMID:12609988.
- siRNA knock-down of VIPL slows secretion of two glycoproteins, indicating an ER export
receptor role PMID:12878160.

This supports the core BP framing: regulation of ER export of a subset of glycoproteins /
ER-to-Golgi transport. The IMP (PMID:12878160, protein transport GO:0015031) and TAS
(PMID:12878160, ER-to-Golgi vesicle-mediated transport GO:0006888) annotations are core.
Note that "lectin-like membrane receptors" are thought to be required for efficient export
of glycoprotein subsets from the ER PMID:12878160.

protein folding (GO:0006457 NAS)

NAS assertion (PMID:12609988). VIPL is not a folding enzyme/chaperone; any role is in
glycoprotein quality-control/sorting context, not catalysis of folding. Over-annotation —
mark as MARK_AS_OVER_ANNOTATED / non-core.

Protein interactions

UniProt INTERACTION block lists two binary partners:
- HTT (P42858) — huntingtin; from the neurodegenerative-disease interactome
PMID:32814053 (Y2H ND-focused screen). MalaCards/disease context but uninformative for core MF.
- MAL (P21145) — myelin and lymphocyte protein; from HuRI binary interactome PMID:32296183.

These yield bare "protein binding" (GO:0005515 IPI) annotations. Per guidelines, avoid bare
protein binding as core → KEEP_AS_NON_CORE. (GOA WITH/FROM fields: PMID:32296183 -> MAL P21145;
PMID:32814053 -> HTT P42858.)

Disease

Intellectual developmental disorder, autosomal recessive 52 (MRT52; MIM:616887): homozygous
missense R53Q segregating in a consanguineous Pakistani family
PMID:26566883, no effect on general protein glycosylation (UniProt VARIANT R53Q note).
Intellectual developmental disorder, autosomal dominant 69 (MRD69; MIM:617863): dominant
LMAN2L mutation causing intellectual disability with remitting epilepsy PMID:31020005.

Disease links are not directly used to assign MF/CC/BP GO terms here but underscore the
gene's importance in neurodevelopment.

Summary of action plan for annotations

D-mannose binding (TAS 12609988; IBA): KEEP_AS_NON_CORE (homology/CRD-based, not directly shown).
ER membrane (IDA 12609988; IBA, IEA): ACCEPT (ER-resident, core CC).
Golgi apparatus (IDA 12878160), Golgi membrane (IBA, IEA): ACCEPT/KEEP_AS_NON_CORE (minor Golgi pool).
ERGIC (IBA GO:0005793): ACCEPT (early secretory pathway, consistent localization).
protein folding (NAS 12609988): MARK_AS_OVER_ANNOTATED.
ER-to-Golgi vesicle-mediated transport (TAS 12878160; IBA), protein transport (IMP 12878160): ACCEPT (core BP).
COPII vesicle (NAS 12878160; IBA GO:0030134): KEEP_AS_NON_CORE.
generic membrane (GO:0016020 IEA, TAS): MARK_AS_OVER_ANNOTATED (ER/Golgi membrane more informative).
protein binding (IPI 32296183, 32814053): KEEP_AS_NON_CORE.

Falcon deep-research findings (incorporated 2026-06)

The Falcon (Edison Scientific) deep-research report for LMAN2L (28 citations) was reviewed against the existing COMPLETE review. The core experimental references it cites are already in the review: the two primary VIPL characterizations (PMID:12609988, PMID:12878160), the disease papers (Rafiullah 2016 = PMID:26566883; Alkhater 2019 = PMID:31020005; Zhou 2023 = PMID:37667433), the Yamamoto 2009 lectin review (PMID:19420740), and the HCMV/TRC8 paper (Hunter et al. 2024 = PMID:38687323). None of these are cached in publications/, so no verbatim supporting_text could be added. No new resolvable gene-specific PMIDs were found; no YAML reference changes were made.

(Gene-specific; from already-cited Hunter 2024, PMID:38687323) First emerging candidate physiological client: surface integrin alpha-6 (ITGA6) is reduced in LMAN2L-deficient cells, consistent with a role in trafficking specific glycoproteins to the plasma membrane [DOI:10.1099/jgv.0.001980, Hunter et al. 2024 "surface ITGA6 was reduced in LMAN2L-deficient cells"]. The Hunter 2024 reference_review in the YAML already records this; reinforces the existing ER-export-receptor BP framing but does not warrant a new annotation (single thesis/paper-level, candidate-stage).
(Gene-specific; from Hunter 2024, PMID:38687323) HCMV pUS2 co-opts the host E3 ligase TRC8 to degrade LMAN2L via ERAD; LMAN2L is downregulated as early as 4 h post-infection, rescued by MG132 (proteasome) but not leupeptin (lysosome), and TRC8 knockdown rescues it. This corroborates the bona fide ER-resident localization. Already captured in the existing reference_review for PMID:38687323; no annotation change.
(Gene-specific, UNVERIFIABLE source) A 2024 thesis (Casalnuovo, "Characterization of the protein VIP36 and VIPL and identification of their interaction partners") reports a RUSH-based co-IP/MS screen yielding ~87 candidate VIPL interactors/cargos, including COPII components (SEC23A/SEC23B, COPB2). NOT PubMed-indexed (thesis, no PMID); hypothesis-generating only; not added to references.
(Gene-specific, UNVERIFIABLE source) A 2023 Cambridge thesis (Hunter, DOI:10.17863/cam.108565) provides the ~1.5-fold ITGA6 downregulation figure and the secretion-chaperone/handoff-to-ERGIC-53 mechanistic synthesis. Thesis, no PMID; not added as a reference (the peer-reviewed Hunter 2024 paper already covers the HCMV/ITGA6 results).
(Family/paralog-inferred) Glycan-binding details (deglucosylated high-mannose, Manα1-2Manα1-2Man motif, Ca2+/neutral-pH dependence) and the KRFY/RKR ER-retention motifs are drawn largely from the Gupta 2012 book chapter (DOI:10.1007/978-3-7091-1065-2_7, not PubMed-indexed) and Yamamoto 2009 review — family/paralog-level, consistent with the existing homology-based D-mannose-binding (KEEP_AS_NON_CORE per notes) and ER-retention framing. The chapter also notes assay-dependent discrepancies (some tagged constructs failed to detect sugar binding), reinforcing that direct VIPL glycan binding remains unsettled. Not added as a reference (no PMID).
(Database-level only, not promoted) Falcon cites OpenTargets GWAS/association links (bipolar disorder, schizophrenia, major depressive disorder, plus the established ID disorders). Aggregated association evidence, hypothesis-generating; the Mendelian ID disorders (MRT52/MRD69) are already captured via PMID:26566883/31020005/37667433. No new references or annotations.
Net effect on review: none to the YAML. Falcon's gene-specific advances (ITGA6 client, HCMV/TRC8 degradation) trace to PMID:38687323, which is already a reference with a reference_review noting these points; remaining new content is thesis/book-chapter material that does not resolve to PMIDs. Existing dispositions stand.

Pn Notes

(LMAN2L-pn-notes.md)

LMAN2L PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9H0V9
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/LMAN2L/LMAN2L-ai-review.yaml
AIGR review HTML: missing - genes/human/LMAN2L/LMAN2L-ai-review.html
Gene notes: present - genes/human/LMAN2L/LMAN2L-notes.md
GOA TSV: present - genes/human/LMAN2L/LMAN2L-goa.tsv
UniProt record: present - genes/human/LMAN2L/LMAN2L-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/LMAN2L.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/LMAN2L.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/LMAN2L/LMAN2L-deep-research-falcon.md

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 9; KEEP_AS_NON_CORE: 7; MARK_AS_OVER_ANNOTATED: 3

PN Consistency Summary

Consistency: Deep research ↔ review ↔ PN annotation consistent. VIPL is an L-type lectin, NOT a glycosidase — matching the "Lectin chaperone" type. Distinctive vs its cycling paralogs: it is a non-cycling ER-resident (RKR retention) regulator of ER export / regulator of ERGIC-53 (core BP GO:0006888, GO:0015031). D-mannose binding accepted as a homology/CRD-based MF (no direct binding assay for VIPL itself — review states this clearly). No contradictions.
PN story / NEW pressure: No NEW GO pressure. ER-export-receptor / ERGIC-53-regulator role is captured by transport terms; a candidate physiological client (ITGA6, via PMID:38687323) is noted but single-paper/candidate-stage and the review correctly did not mint a term. Conclude: already captured.
Evidence alignment: PN dossier is mapping-only. Review evidence centers on PMID:12609988 and PMID:12878160 (PubMed-verified primary papers) plus disease PMIDs (26566883, 31020005, 37667433) and HCMV/TRC8 (38687323). No bibliographic conflict; divergence is conceptual (group biosynthesis term vs. lectin/ER-export function).
Verdict: Review strong and PN-consistent (ER-resident lectin/export regulator, not a mannosidase). Inherited group→GO:0006487 projection is an over-reach.

Full Consistency Review

UniProt: Q9H0V9 (VIP36-like protein / VIPL) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE, thorough (two primary characterizations + disease + 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. VIPL is an L-type lectin, NOT a glycosidase — matching the "Lectin chaperone" type. Distinctive vs its cycling paralogs: it is a non-cycling ER-resident (RKR retention) regulator of ER export / regulator of ERGIC-53 (core BP GO:0006888, GO:0015031). D-mannose binding accepted as a homology/CRD-based MF (no direct binding assay for VIPL itself — review states this clearly). No contradictions.
PN story / NEW pressure: No NEW GO pressure. ER-export-receptor / ERGIC-53-regulator role is captured by transport terms; a candidate physiological client (ITGA6, via PMID:38687323) is noted but single-paper/candidate-stage and the review correctly did not mint a term. Conclude: already captured.
Mapping strategy: Group→GO:0006487 (new_to_goa) over-reaches as for the other lectins — VIPL reads/exports high-mannose glycoproteins; it does not perform N-linked glycosylation. Additionally, VIPL is predominantly ER-resident (not a classic ERGIC cycler), so even the family-level "N-glycosylation system" framing fits it least well. PN node correct to leave "Lectin chaperone" unmapped; projected term should not propagate.
Evidence alignment: PN dossier is mapping-only. Review evidence centers on PMID:12609988 and PMID:12878160 (PubMed-verified primary papers) plus disease PMIDs (26566883, 31020005, 37667433) and HCMV/TRC8 (38687323). No bibliographic conflict; divergence is conceptual (group biosynthesis term vs. lectin/ER-export function).
Verdict: Review strong and PN-consistent (ER-resident lectin/export regulator, not a mannosidase). Inherited group→GO:0006487 projection is an over-reach.
Recommended edits: [MAP] Do not propagate GO:0006487 (protein N-linked glycosylation) to LMAN2L/VIPL — it is an ER-resident high-mannose lectin / ER-export regulator, not an N-glycosylation enzyme; flag the "N-glycosylation system" group node as over-broad (and a poor fit for a non-cycling ER resident).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/LMAN2L/LMAN2L-ai-review.yaml
PN workbook rows: 1

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

UniProt: Q9H0V9
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: 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.

LMAN2L

Gene Description

Existing Annotations Review

Core Functions

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research Report: Human LMAN2L (VIPL; UniProt Q9H0V9) — Functional Annotation and Current Evidence

1) Target verification (gene/protein identity)

2) Key concepts and definitions (current understanding)

2.1 Intracellular L-type (legume-like) lectins

2.2 Cargo receptors and receptor-mediated ER export

2.3 LMAN2L/VIPL’s position within this framework

3) Molecular function of LMAN2L (VIPL): what it does and how

3.1 Proposed primary function: glycoprotein-binding lectin facilitating ER export and/or quality control

3.2 Glycan-binding specificity and biochemical determinants

3.3 Subcellular localization and trafficking signals

3.4 Interacting partners and candidate client proteins

4) Recent developments and latest research (prioritizing 2023–2024)

4.1 Viral exploitation of LMAN2L: HCMV pUS2–TRC8 axis (2024)

4.2 Human genetics update: compound heterozygous LMAN2L variants with expanded phenotype (2023)

5) Disease associations, expert analysis, and strength of evidence

5.1 Core Mendelian disorder association: neurodevelopmental disorder with seizures (MRT52 / ID with epilepsy)

5.2 Psychiatric/neuropsychiatric associations (GWAS / database)

6) Current applications and real-world implementations

6.1 Clinical genetics/diagnostics

6.2 Infection biology and host–pathogen interaction

6.3 Proteomics resources

7) Statistics and quantitative data points from recent studies

7.1 Human genetics (cases, inheritance, phenotypes)

7.2 2023–2024 trafficking/proteomics (quantitative)

8) Evidence gaps and priorities for future functional annotation

Summary evidence map

Key cited sources (URLs, dates)

Artifacts

Citations

📚 Additional Documentation

Notes

LMAN2L (VIPL / VIP36-like protein), human — review notes

Family / identity

Subcellular localization — ER-resident (key distinction from VIP36)

Molecular function — D-mannose/lectin binding (by homology/domain, not directly shown)

Biological process — regulation of ER export of glycoproteins; regulator of ERGIC-53 (CORE)

protein folding (GO:0006457 NAS)

Protein interactions

Disease

Summary of action plan for annotations

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

LMAN2L 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