MS4A6A encodes membrane-spanning 4-domains subfamily A member 6A, a CD20-like four-pass transmembrane protein in the MS4A family. It is a multi-pass membrane protein with direct experimental evidence for intracellular perinuclear/trans-Golgi localization in transfected BJAB cells, while available B-cell data argue that the protein is probably not normally expressed at the plasma membrane. MS4A6A belongs to the Alzheimer-linked MS4A gene cluster, but its intrinsic molecular activity and disease-relevant signaling mechanism remain unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005886
plasma membrane
|
IBA
GO_REF:0000033 |
MODIFY |
Summary: The family-based plasma-membrane inference is not supported by the direct MS4A6A localization paper.
Reason: Direct full-text evidence reports GFP-MS4A6A intracellular/perinuclear localization and co-localization with the trans-Golgi marker giantin, while concluding that MS4A6A is probably not normally expressed at the plasma membrane in B cells (PMID:23874341). Replace the plasma membrane inference with the directly supported trans-Golgi network localization.
Proposed replacements:
trans-Golgi network
|
|
GO:0005802
trans-Golgi network
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MS4A6A is a CD20-like multi-pass MS4A-family membrane protein with direct experimental support for perinuclear/trans-Golgi localization.
Reason: Accept because PMID:23874341 directly reports that GFP-MS4A6A is intracellular/perinuclear and co-localizes with giantin, indicating concentration in the trans-Golgi complex. This is also consistent with the PANTHER/IBA trans-Golgi network annotation.
|
|
GO:0007166
cell surface receptor signaling pathway
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: The broad receptor-signaling IBA is plausible by MS4A-family analogy but is not established for MS4A6A.
Reason: MS4A6A is CD20-like and UniProt notes possible involvement in signal transduction, but the cached direct evidence mainly supports membrane/trans-Golgi localization and low B-cell expression. No specific receptor, ligand, downstream pathway, or MS4A6A-dependent signaling assay is available here, so a cell-surface receptor signaling process is over-annotated.
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: MS4A6A is a multi-pass MS4A-family membrane protein.
Reason: Accept as a conservative localization annotation: UniProt describes MS4A6A as a membrane, multi-pass membrane protein, and PMID:23874341 localizes GFP-MS4A6A to a membrane-bound trans-Golgi compartment.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: This HuRI high-throughput interaction annotation does not define a specific MS4A6A molecular function.
Reason: Mark as over-annotated because generic protein binding from a broad binary interactome map does not explain MS4A6A biochemical activity or signaling role. More informative evidence currently supports membrane/trans-Golgi localization rather than a specific molecular function.
|
|
GO:0005802
trans-Golgi network
|
IDA
PMID:23874341 Expression of MS4A and TMEM176 Genes in Human B Lymphocytes. |
ACCEPT |
Summary: MS4A6A is a CD20-like multi-pass MS4A-family membrane protein with direct experimental support for perinuclear/trans-Golgi localization.
Reason: Accept because PMID:23874341 directly reports that GFP-MS4A6A is intracellular/perinuclear and co-localizes with giantin, indicating concentration in the trans-Golgi complex. This is also consistent with the PANTHER/IBA trans-Golgi network annotation.
|
Q: What is the intrinsic molecular activity of MS4A6A at trans-Golgi or other intracellular membranes?
Q: Does MS4A6A participate directly in receptor trafficking or signaling in myeloid cells, microglia, or other Alzheimer-relevant cell types?
Q: Under what stimuli, if any, does endogenous MS4A6A move from intracellular membranes to the plasma membrane?
Experiment: Generate validated MS4A6A antibodies or epitope-tagged endogenous knock-in cells and quantify co-localization with trans-Golgi, ER, endosomal, and plasma-membrane markers in monocytes, macrophages, and iPSC-derived microglia.
Hypothesis: Endogenous MS4A6A primarily resides in trans-Golgi or related secretory-pathway membranes rather than at the resting plasma membrane.
Type: endogenous localization assay
Experiment: Perturb MS4A6A in macrophage or microglial models and measure trafficking, surface abundance, and stimulus-induced signaling for candidate MS4A-cluster partners such as TREM2 and related immune receptors.
Hypothesis: MS4A6A influences receptor trafficking or signaling indirectly through intracellular membrane organization.
Type: loss-of-function receptor-trafficking assay
Automated deep research was attempted with just deep-research-falcon human MS4A6A --fallback perplexity-lite, but the run timed out before producing a deep-research file. This review therefore uses cached GOA publications, the UniProt record, and the PANTHER family fetch.
MS4A6A encodes membrane-spanning 4-domains subfamily A member 6A, a CD20-like four-pass transmembrane protein in the MS4A family. UniProt describes the protein as a membrane, multi-pass membrane protein with four predicted transmembrane helices, and the local PANTHER fetch places it in PTHR23320:SF135, within the MS4A/CD20-like family.
The full-text B-cell expression and localization paper provides the strongest direct evidence for compartment assignment. It states that the study cloned human MS4A6A as a GFP fusion for BJAB localization assays PMID:23874341. In those assays, GFP-MS4A6A did not behave like CD20 or MS4A4A at the plasma membrane; instead, "GFP-MS4A6A and GFP-MS4A7 were localized intracellularly in the perinuclear space" and "Both GFP-MS4A6A and GFP-MS4A7 co-localized with giantin, indicating that they were concentrated in the trans-Golgi complex" [PMID:23874341 "GFP-MS4A6A and GFP-MS4A7 were localized intracellularly in the perinuclear space"; PMID:23874341 "Both GFP-MS4A6A and GFP-MS4A7 co-localized with giantin, indicating that they were concentrated in the trans-Golgi complex"].
The same paper argues against treating MS4A6A as a normal plasma-membrane CD20 partner in B cells. It reports that "MS4A6A and MS4A7 transcripts were detected in most B-cell samples but at two to four orders of magnitude lower than MS4A1 (CD20)" and concludes that "MS4A6A and MS4A7 transcripts were detected in most normal B samples but at very low levels and the corresponding proteins are probably not normally expressed at the plasma membrane" [PMID:23874341 "MS4A6A and MS4A7 transcripts were detected in most B-cell samples but at two to four orders of magnitude lower than MS4A1 (CD20)"; PMID:23874341 "MS4A6A and MS4A7 transcripts were detected in most normal B samples but at very low levels and the corresponding proteins are probably not normally expressed at the plasma membrane"].
For curation, retain membrane and trans-Golgi network annotations as the best-supported functional surface. Treat the plasma-membrane IBA as a likely over-propagated family inference and propose replacement with trans-Golgi network, which is already directly supported by IDA evidence. Treat the broad cell surface receptor signaling pathway IBA as over-annotated because no resolved MS4A6A receptor/signaling mechanism is established in the cached evidence. The generic protein binding annotation from the HuRI binary interactome paper should also be marked over-annotated: PMID:32296183 is a valuable high-throughput interactome resource, but for MS4A6A it does not define an informative molecular function beyond a single binary interaction.
The second-pass audit confirmed the existing MS4A6A review and manual reference metadata. No annotation action changes were needed: MS4A6A remains curated as an intracellular/trans-Golgi multi-pass MS4A-family membrane protein, with plasma-membrane and receptor-signaling family transfers treated as over-propagated relative to the direct cached localization evidence.
id: Q9H2W1
gene_symbol: MS4A6A
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'MS4A6A encodes membrane-spanning 4-domains subfamily A member 6A, a
CD20-like four-pass transmembrane protein in the MS4A family. It is a multi-pass
membrane protein with direct experimental evidence for intracellular perinuclear/trans-Golgi
localization in transfected BJAB cells, while available B-cell data argue that the
protein is probably not normally expressed at the plasma membrane. MS4A6A belongs
to the Alzheimer-linked MS4A gene cluster, but its intrinsic molecular activity
and disease-relevant signaling mechanism remain unresolved.'
alternative_products:
- name: 1 (3.1)
id: Q9H2W1-1
- name: 2 (3.2)
id: Q9H2W1-2
sequence_note: VSP_007381, VSP_007382
- name: '3'
id: Q9H2W1-3
sequence_note: VSP_007383, VSP_007384
- name: '4'
id: Q9H2W1-4
sequence_note: VSP_041191, VSP_041192
- name: '5'
id: Q9H2W1-5
sequence_note: VSP_056732, VSP_007381, VSP_007382
existing_annotations:
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: The family-based plasma-membrane inference is not supported by the
direct MS4A6A localization paper.
action: MODIFY
reason: Direct full-text evidence reports GFP-MS4A6A
intracellular/perinuclear localization and co-localization with the
trans-Golgi marker giantin, while concluding that MS4A6A is probably not
normally expressed at the plasma membrane in B cells (PMID:23874341).
Replace the plasma membrane inference with the directly supported
trans-Golgi network localization.
proposed_replacement_terms:
- id: GO:0005802
label: trans-Golgi network
additional_reference_ids:
- PMID:23874341
- term:
id: GO:0005802
label: trans-Golgi network
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: MS4A6A is a CD20-like multi-pass MS4A-family membrane protein with
direct experimental support for perinuclear/trans-Golgi localization.
action: ACCEPT
reason: Accept because PMID:23874341 directly reports that GFP-MS4A6A is
intracellular/perinuclear and co-localizes with giantin, indicating
concentration in the trans-Golgi complex. This is also consistent with the
PANTHER/IBA trans-Golgi network annotation.
additional_reference_ids:
- PMID:23874341
- term:
id: GO:0007166
label: cell surface receptor signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: The broad receptor-signaling IBA is plausible by MS4A-family
analogy but is not established for MS4A6A.
action: MARK_AS_OVER_ANNOTATED
reason: MS4A6A is CD20-like and UniProt notes possible involvement in signal
transduction, but the cached direct evidence mainly supports
membrane/trans-Golgi localization and low B-cell expression. No specific
receptor, ligand, downstream pathway, or MS4A6A-dependent signaling assay
is available here, so a cell-surface receptor signaling process is
over-annotated.
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: MS4A6A is a multi-pass MS4A-family membrane protein.
action: ACCEPT
reason: 'Accept as a conservative localization annotation: UniProt describes MS4A6A
as a membrane, multi-pass membrane protein, and PMID:23874341 localizes GFP-MS4A6A
to a membrane-bound trans-Golgi compartment.'
additional_reference_ids:
- PMID:23874341
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: This HuRI high-throughput interaction annotation does not define a
specific MS4A6A molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: Mark as over-annotated because generic protein binding from a broad
binary interactome map does not explain MS4A6A biochemical activity or
signaling role. More informative evidence currently supports
membrane/trans-Golgi localization rather than a specific molecular
function.
- term:
id: GO:0005802
label: trans-Golgi network
evidence_type: IDA
original_reference_id: PMID:23874341
qualifier: located_in
review:
summary: MS4A6A is a CD20-like multi-pass MS4A-family membrane protein with
direct experimental support for perinuclear/trans-Golgi localization.
action: ACCEPT
reason: Accept because PMID:23874341 directly reports that GFP-MS4A6A is
intracellular/perinuclear and co-localizes with giantin, indicating
concentration in the trans-Golgi complex. This is also consistent with the
PANTHER/IBA trans-Golgi network annotation.
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:23874341
title: Expression of MS4A and TMEM176 Genes in Human B Lymphocytes.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached full text directly supports MS4A6A expression testing
and GFP-MS4A6A trans-Golgi localization, and cautions against normal
plasma-membrane localization in B cells.
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Cached full text describes the HuRI binary interactome
reference map; for MS4A6A it supports only a generic high-throughput
protein-interaction annotation.
core_functions:
- description: Four-pass MS4A-family membrane protein localization, with
strongest direct evidence for intracellular perinuclear/trans-Golgi
localization and no resolved intrinsic molecular activity.
supported_by:
- reference_id: PMID:23874341
supporting_text: MS4A is a family of tetraspanning membrane proteins
- reference_id: PMID:23874341
supporting_text: GFP-MS4A6A and GFP-MS4A7 were localized intracellularly in
the perinuclear space
- reference_id: PMID:23874341
supporting_text: Both GFP-MS4A6A and GFP-MS4A7 co-localized with giantin,
indicating that they were concentrated in the trans-Golgi complex
locations:
- id: GO:0005802
label: trans-Golgi network
- id: GO:0016020
label: membrane
suggested_questions:
- question: What is the intrinsic molecular activity of MS4A6A at trans-Golgi or
other intracellular membranes?
- question: Does MS4A6A participate directly in receptor trafficking or
signaling in myeloid cells, microglia, or other Alzheimer-relevant cell
types?
- question: Under what stimuli, if any, does endogenous MS4A6A move from
intracellular membranes to the plasma membrane?
suggested_experiments:
- hypothesis: Endogenous MS4A6A primarily resides in trans-Golgi or related
secretory-pathway membranes rather than at the resting plasma membrane.
description: Generate validated MS4A6A antibodies or epitope-tagged endogenous
knock-in cells and quantify co-localization with trans-Golgi, ER, endosomal,
and plasma-membrane markers in monocytes, macrophages, and iPSC-derived
microglia.
experiment_type: endogenous localization assay
- hypothesis: MS4A6A influences receptor trafficking or signaling indirectly
through intracellular membrane organization.
description: Perturb MS4A6A in macrophage or microglial models and measure
trafficking, surface abundance, and stimulus-induced signaling for candidate
MS4A-cluster partners such as TREM2 and related immune receptors.
experiment_type: loss-of-function receptor-trafficking assay