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). |
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Download this section (compressed HTML)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
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