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.