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. |
Loading supporting content…
Download this section (compressed HTML)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
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)