MS4A4A encodes membrane-spanning 4-domains subfamily A member 4A, a CD20-like four-pass transmembrane protein in the MS4A family. It is a membrane protein detected at plasma membrane, plasma membrane raft, Golgi apparatus, and endoplasmic reticulum compartments. Current evidence links MS4A4A to myeloid/macrophage biology and Alzheimer disease risk through modulation of soluble TREM2, with MS4A4A and TREM2 colocalizing at lipid rafts and MS4A4A perturbation altering sTREM2 production, but a precise intrinsic molecular activity for MS4A4A remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005886
plasma membrane
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0005794
Golgi apparatus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0016020
membrane
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0005515
protein binding
|
IPI
PMID:30833792 A protein-interaction network of interferon-stimulated genes... |
MARK AS OVER ANNOTATED |
Summary: This high-throughput interaction annotation does not define a specific MS4A4A molecular function.
Reason: Mark as over-annotated because generic protein binding from broad interactome or interferon-stimulated-gene screens is less informative than the supported membrane/raft localization and MS4A4A-sTREM2 modulation evidence (PMID:30833792, PMID:32296183).
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: This high-throughput interaction annotation does not define a specific MS4A4A molecular function.
Reason: Mark as over-annotated because generic protein binding from broad interactome or interferon-stimulated-gene screens is less informative than the supported membrane/raft localization and MS4A4A-sTREM2 modulation evidence (PMID:30833792, PMID:32296183).
|
|
GO:0005783
endoplasmic reticulum
|
IDA
PMID:31413141 The MS4A gene cluster is a key modulator of soluble TREM2 an... |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0005794
Golgi apparatus
|
IDA
PMID:31413141 The MS4A gene cluster is a key modulator of soluble TREM2 an... |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0005886
plasma membrane
|
IDA
PMID:23874341 Expression of MS4A and TMEM176 Genes in Human B Lymphocytes. |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
|
GO:0044853
plasma membrane raft
|
IDA
PMID:31413141 The MS4A gene cluster is a key modulator of soluble TREM2 an... |
ACCEPT |
Summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at plasma membrane/raft and secretory-pathway membrane compartments.
Reason: Retain as the best-supported MS4A4A biology: UniProt and GOA support a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2 colocalization on lipid rafts at the plasma membrane (PMID:31413141).
|
Q: What is the intrinsic molecular activity of MS4A4A at plasma membrane rafts and secretory-pathway membranes?
Q: Does MS4A4A directly regulate TREM2 trafficking, shedding, raft partitioning, or protease accessibility in human microglia/macrophages?
Q: Which MS4A4A interaction partners from high-throughput datasets are reproducible and biologically relevant in myeloid cells?
Experiment: Perturb MS4A4A in primary human macrophages or iPSC-derived microglia and measure TREM2 surface abundance, raft partitioning, ADAM10/ADAM17 access, and sTREM2 release.
Hypothesis: MS4A4A controls TREM2 partitioning and shedding by organizing raft-localized membrane complexes.
Type: membrane trafficking and shedding assay
Experiment: Validate candidate MS4A4A protein partners in macrophages or microglia using endogenous co-immunoprecipitation, proximity labeling, and reciprocal perturbation of sTREM2 output.
Hypothesis: High-throughput MS4A4A interactors include a smaller set of myeloid-cell-relevant membrane partners.
Type: interaction validation
Automated deep research was attempted with just deep-research-falcon human MS4A4A --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.
MS4A4A encodes a four-pass membrane protein in the MS4A/CD20-like family. UniProt describes it as a "Membrane-spanning 4-domains subfamily A member 4A" with four predicted transmembrane helices, and GOA contains only localization and generic interaction annotations. The strongest curated localization evidence places MS4A4A at plasma membrane, plasma membrane raft, Golgi apparatus, and endoplasmic reticulum.
The primary Alzheimer-relevant evidence is the 2019 MS4A/TREM2 study. It found a genome-wide significant association between an MS4A-region SNP near MS4A4A and CSF soluble TREM2, and an independent missense signal in MS4A4A [PMID:31413141 "The top SNP was rs1582763, an intergenic variant nearest MS4A4A"; PMID:31413141 "Rs6591561 (MS4A4A p.M159V) was associated with CSF sTREM2"]. The same study reports that MS4A4A expression and TREM2 biology are linked in macrophage models: "MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane" and sTREM2 increased with MS4A4A overexpression while MS4A4A silencing reduced sTREM2 [PMID:31413141 "MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane"; PMID:31413141 "sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production"].
The B-cell expression paper supports the MS4A-family context but does not establish a normal B-cell function for MS4A4A. It reports that MS4A4A was investigated because MS4A proteins can potentially hetero-oligomerize, but also found that normal B cells did not detect MS4A4A transcripts PMID:23874341. That paper remains useful for plasma-membrane localization in transfected cells but should not drive B-cell process annotations.
For curation, retain the subcellular-localization annotations as the high-confidence functional surface: MS4A4A is a multi-pass membrane protein at plasma membrane/raft and secretory pathway compartments. The generic protein binding annotations from high-throughput interactome studies should be marked over-annotated rather than accepted as a core molecular function. There is good evidence that MS4A4A modulates sTREM2 in macrophage models, but GOA does not contain a precise molecular-function or biological-process term for this; treat it as a suggested question/experiment rather than inventing a new GO annotation.
The second-pass audit confirmed the existing MS4A4A review and manual reference metadata. No annotation action changes were needed: MS4A4A remains curated conservatively as a four-pass membrane/raft and secretory-pathway protein with TREM2/sTREM2 modulation as the main unresolved functional question, while generic high-throughput protein-binding annotations remain over-annotated.
id: Q96JQ5
gene_symbol: MS4A4A
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: 'MS4A4A encodes membrane-spanning 4-domains subfamily A member 4A, a
CD20-like four-pass transmembrane protein in the MS4A family. It is a membrane protein
detected at plasma membrane, plasma membrane raft, Golgi apparatus, and endoplasmic
reticulum compartments. Current evidence links MS4A4A to myeloid/macrophage biology
and Alzheimer disease risk through modulation of soluble TREM2, with MS4A4A and
TREM2 colocalizing at lipid rafts and MS4A4A perturbation altering sTREM2 production,
but a precise intrinsic molecular activity for MS4A4A remains unresolved.'
alternative_products:
- name: '1'
id: Q96JQ5-1
- name: '2'
id: Q96JQ5-2
sequence_note: VSP_007380
existing_annotations:
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0016020
label: membrane
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:30833792
qualifier: enables
review:
summary: This high-throughput interaction annotation does not define a
specific MS4A4A molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: Mark as over-annotated because generic protein binding from broad
interactome or interferon-stimulated-gene screens is less informative than
the supported membrane/raft localization and MS4A4A-sTREM2 modulation
evidence (PMID:30833792, PMID:32296183).
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: This high-throughput interaction annotation does not define a
specific MS4A4A molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: Mark as over-annotated because generic protein binding from broad
interactome or interferon-stimulated-gene screens is less informative than
the supported membrane/raft localization and MS4A4A-sTREM2 modulation
evidence (PMID:30833792, PMID:32296183).
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: PMID:31413141
qualifier: located_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0005794
label: Golgi apparatus
evidence_type: IDA
original_reference_id: PMID:31413141
qualifier: located_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:23874341
qualifier: located_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
- term:
id: GO:0044853
label: plasma membrane raft
evidence_type: IDA
original_reference_id: PMID:31413141
qualifier: located_in
review:
summary: MS4A4A is a multi-pass MS4A-family membrane protein observed at
plasma membrane/raft and secretory-pathway membrane compartments.
action: ACCEPT
reason: 'Retain as the best-supported MS4A4A biology: UniProt and GOA support
a four-pass membrane protein, and the AD/sTREM2 study reports MS4A4A and TREM2
colocalization on lipid rafts at the plasma membrane (PMID:31413141).'
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: MEDIUM
correctness: VERIFIED
review_notes: Cached full text supports MS4A family/tetraspanning context
and MS4A4A expression analysis; useful for family context and localization
but not a normal B-cell function.
- id: PMID:30833792
title: A protein-interaction network of interferon-stimulated genes extends
the innate immune system landscape.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Cached abstract describes a high-throughput
interferon-stimulated-gene interaction network; supports only generic
interaction evidence.
- id: PMID:31413141
title: The MS4A gene cluster is a key modulator of soluble TREM2 and
Alzheimer's disease risk.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Cached full text directly supports MS4A4A/TREM2 colocalization
at plasma membrane lipid rafts, MS4A4A perturbation effects on sTREM2, and
the AD-risk/sTREM2 genetic context.
- 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 a broad binary interactome
reference map; supports only generic interaction evidence.
core_functions:
- description: Four-pass MS4A-family membrane localization at plasma
membrane/raft and secretory-pathway compartments, with disease-relevant
evidence for TREM2/sTREM2 modulation in macrophage models but no resolved
intrinsic molecular activity.
supported_by:
- reference_id: PMID:23874341
supporting_text: MS4A is a family of tetraspanning membrane proteins
- reference_id: PMID:31413141
supporting_text: MS4A4A and TREM2 colocalized on lipid rafts at the plasma
membrane
- reference_id: PMID:31413141
supporting_text: silencing of MS4A4A reduced sTREM2 production
locations:
- id: GO:0005886
label: plasma membrane
- id: GO:0044853
label: plasma membrane raft
- id: GO:0005794
label: Golgi apparatus
- id: GO:0005783
label: endoplasmic reticulum
suggested_questions:
- question: What is the intrinsic molecular activity of MS4A4A at plasma
membrane rafts and secretory-pathway membranes?
- question: Does MS4A4A directly regulate TREM2 trafficking, shedding, raft
partitioning, or protease accessibility in human microglia/macrophages?
- question: Which MS4A4A interaction partners from high-throughput datasets are
reproducible and biologically relevant in myeloid cells?
suggested_experiments:
- hypothesis: MS4A4A controls TREM2 partitioning and shedding by organizing
raft-localized membrane complexes.
description: Perturb MS4A4A in primary human macrophages or iPSC-derived
microglia and measure TREM2 surface abundance, raft partitioning,
ADAM10/ADAM17 access, and sTREM2 release.
experiment_type: membrane trafficking and shedding assay
- hypothesis: High-throughput MS4A4A interactors include a smaller set of
myeloid-cell-relevant membrane partners.
description: Validate candidate MS4A4A protein partners in macrophages or
microglia using endogenous co-immunoprecipitation, proximity labeling, and
reciprocal perturbation of sTREM2 output.
experiment_type: interaction validation