Desmoglein-4 is a desmosomal cadherin whose expression is concentrated in the hair follicle, where it is found in the inner root sheath and in all layers of the matrix and precortex, with lower expression in other stratified epithelia. Like the other desmogleins it is a single-pass type I membrane glycoprotein with calcium-binding extracellular cadherin domains that face the extracellular space, and a cytoplasmic tail that binds plakoglobin and couples the junction to the desmosomal plaque. Recessive loss-of-function mutations cause hypotrichosis and monilethrix, and a disease mutation that abolishes plakoglobin binding disrupts desmosomes in the hair shaft, placing DSG4 in the control of keratinocyte adhesion and differentiation during hair-shaft formation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001533 cornified envelope | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: No DSG4 localization experiment places the protein in the cornified envelope. Reason: The cornified envelope is the cross-linked scaffold of corneocytes. DSG4 protein is documented in the inner root sheath, matrix and precortex of the hair follicle and in other living epithelial layers, and the rule-based assignment follows desmoglein family membership rather than observation of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt In scalp follicles, present in the inner root sheath (IRS) and all layers of the matrix and precortex (at protein level) |
| GO:0001533 cornified envelope | TAS Reactome:R-HSA-6814764 | MARK AS OVER ANNOTATED | Summary: The compartment is inherited from membership in the cornification pathway. Reason: Reactome places desmogleins in keratinocyte cornification reactions, and the cornified-envelope compartment propagates from that pathway context rather than from DSG4-specific data. Same assessment as the rule-based row. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt In scalp follicles, present in the inner root sheath (IRS) and all layers of the matrix and precortex (at protein level) |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Calcium binding at the cadherin-domain interfaces is a conserved property of the desmoglein ectodomain. Reason: DSG4 retains the full cadherin ectodomain architecture, and UniProt records the canonical three-calcium interdomain sites. The ancestral assertion applies. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Cadherin and desmoglein signatures, plus the rat ortholog, support calcium binding. Reason: The combined automated evidence agrees with the structural expectation for the cadherin repeats present in DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections |
| GO:0005515 protein binding | IPI PMID:21495994 A case of monilethrix caused by novel compound heterozygous ... | MODIFY | Summary: The interactor is plakoglobin (JUP), also known as gamma-catenin, so an informative term is available. Reason: Co-immunoprecipitation shows DSG4 binds plakoglobin, and the disease mutation p.W823X severely reduces that affinity, which the authors link to desmosome disruption in the patient's hair shaft. Replace the uninformative generic term with gamma-catenin binding. Proposed replacements: gamma-catenin binding Supporting Evidence: PMID:21495994 we show that the mutant DSG4 protein with the mutation p.W823X severely affects the affinity to plakoglobin protein, which may contribute to disruption of desmosomes in the patient's hair shaft file:human/DSG4/DSG4-uniprot.txt Interacts with JUP. {ECO |
| GO:0005886 plasma membrane | EXP PMID:21495994 A case of monilethrix caused by novel compound heterozygous ... | ACCEPT | Summary: DSG4 is a cell-membrane protein, shown by immunofluorescence in this study. Reason: UniProt records the cell-membrane location with experimental evidence from this paper, and DSG4 colocalizes with plakoglobin at desmosomes. The plasma membrane is a core location, with the cadherin ectodomain facing the extracellular space. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Note=Colocalizes with JUP at desmosomes. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping agrees with the experimentally curated location. Reason: The cadherin cytoplasmic-region signature and the curated cell-membrane line both support plasma membrane. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6809393 | ACCEPT | Summary: DSG4 is modelled as a plasma-membrane desmosome component. Reason: Consistent with the curated and experimental plasma-membrane location. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6810357 | ACCEPT | Summary: Plasma-membrane assignment in a keratinocyte differentiation reaction. Reason: The compartment is correct for DSG4 even though the pathway context is cornification. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6810937 | ACCEPT | Summary: Plasma-membrane assignment in a cornified-envelope reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6811539 | ACCEPT | Summary: Plasma-membrane assignment in a cornified-envelope reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814298 | ACCEPT | Summary: Plasma-membrane assignment in a cornified-envelope reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814387 | ACCEPT | Summary: Plasma-membrane assignment in a keratinocyte differentiation reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814695 | ACCEPT | Summary: DSG4 is a plasma-membrane desmosome component in the PERP-binding reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814734 | ACCEPT | Summary: Plasma-membrane assignment in a cornified-envelope reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6814764 | ACCEPT | Summary: Plasma-membrane assignment in the plasma-membrane resorption reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8942224 | ACCEPT | Summary: DSG4 is a plasma-membrane desmosome component in the filaggrin-binding reaction. Reason: Consistent with the established location of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0005911 cell-cell junction | IEA GO_REF:0000117 | MODIFY | Summary: The cell-cell junction DSG4 occupies is specifically the desmosome. Reason: Desmosome is a descendant of cell-cell junction and is independently asserted for DSG4 by direct observation and by curated localization, so the specific term should be used. Proposed replacements: desmosome Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Note=Colocalizes with JUP at desmosomes. |
| GO:0007155 cell adhesion | IEA GO_REF:0000002 | TOO GENERAL | Summary: A parent of the specific adhesion terms already asserted for DSG4. Reason: Cell-cell adhesion and homophilic cell-cell adhesion are accepted in this review and entail this term, which therefore adds nothing. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion |
| GO:0007156 homophilic cell-cell adhesion | IEA GO_REF:0000002 | ACCEPT | Summary: Desmoglein-type adhesion between opposing keratinocytes. Reason: DSG4 carries the desmoglein and cadherin signatures that define the calcium- dependent homophilic adhesion mechanism of this family, and UniProt describes it as a desmosomal component required for positive regulation of cellular adhesion. No DSG4-specific binding assay was found, so the family-level inference is retained rather than strengthened. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Correct but less specific than the evidence allows. Reason: DSG4 is a single-pass type I protein of the plasma membrane, a term it already carries with experimental evidence. Use the specific descendant. Proposed replacements: plasma membrane Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Single-pass type I membrane protein |
| GO:0030057 desmosome | IBA GO_REF:0000033 | ACCEPT | Summary: The desmosome is where DSG4 acts. Reason: The PAINT node covers the desmosomal cadherin clade, and human DSG4 appears among the descendant evidences because it has its own experimental desmosome localization. Core location. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Note=Colocalizes with JUP at desmosomes. |
| GO:0030057 desmosome | IDA PMID:21495994 A case of monilethrix caused by novel compound heterozygous ... | ACCEPT | Summary: DSG4 colocalizes with plakoglobin at desmosomes. Reason: Immunofluorescence in this study places DSG4 at desmosomes, and the W823X mutant that cannot bind plakoglobin is associated with desmosome disruption in the patient's hair shaft. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Note=Colocalizes with JUP at desmosomes. PMID:21495994 which may contribute to disruption of desmosomes in the patient's hair shaft |
| GO:0030057 desmosome | IEA GO_REF:0000120 | ACCEPT | Summary: Automated mapping of the curated desmosome location, corroborated by the mouse ortholog. Reason: Agrees with the direct human evidence, so the inference introduces no error. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Note=Colocalizes with JUP at desmosomes. |
| GO:0098609 cell-cell adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: Cell-cell adhesion is the core process of DSG4. Reason: The inherited cadherin-family assertion fits DSG4, whose loss-of-function mutations disrupt desmosomes in the hair shaft and produce monilethrix and hypotrichosis. Supporting Evidence: PMID:21495994 which may contribute to disruption of desmosomes in the patient's hair shaft file:human/DSG4/DSG4-uniprot.txt A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion |
| GO:2000401 regulation of lymphocyte migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: A rodent-derived role in moderating lymphocyte traffic to inflamed skin. Reason: UniProt records this role only by similarity to the rat and mouse orthologs, with no human data. It is plausible as a consequence of epidermal barrier and adhesion defects, but it is remote from the adhesive core function, so it is retained as non-core rather than accepted. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Plays a role in moderating lymphocyte migration to inflamed skin and maintaining homeostasis of the epidermal inflammatory response (By similarity) |
| GO:2000401 regulation of lymphocyte migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator-judged transfer of the same rat phenotype. Reason: Same assessment as the Compara row. The claim rests entirely on the rodent ortholog and describes an inflammatory consequence rather than the adhesive function of DSG4. Supporting Evidence: file:human/DSG4/DSG4-uniprot.txt Plays a role in moderating lymphocyte migration to inflamed skin and maintaining homeostasis of the epidermal inflammatory response (By similarity) |
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Download this section (compressed HTML)Q: Does DSG4 form homophilic trans-interactions of its own, or does it function mainly by heterophilic pairing with DSG1, DSG3 or desmocollins in follicular desmosomes?
Q: Is the reported effect of DSG4 on lymphocyte migration to inflamed skin a direct function, or a secondary consequence of impaired follicular and epidermal barrier integrity?
Q: How does DSG4 coordinate the transition from proliferation to differentiation in hair follicle keratinocytes, and is that role separable from its adhesive function?
Experiment: Single-molecule atomic force spectroscopy with recombinant DSG4 ectodomains against DSG1, DSG3 and DSC1-3 ectodomains and against DSG4-expressing keratinocytes, with and without calcium.
Hypothesis: DSG4 mediates calcium-dependent trans-adhesion with measurable binding forces comparable to other desmogleins.
Experiment: Express DSG4 variants that separate the plakoglobin-binding tail from the adhesive ectodomain in DSG4-null follicular keratinocytes, then assay desmosome ultrastructure, plaque composition and adhesion strength for each variant.
Hypothesis: The hair-shaft phenotype of DSG4 loss is caused specifically by failure of plakoglobin recruitment rather than by loss of extracellular adhesion.
Experiment: Immunogold electron microscopy and sequential extraction of human scalp skin and hair follicles, comparing DSG4 with DSG1 and corneodesmosin across follicular and interfollicular compartments.
Hypothesis: DSG4 is absent from the cornified envelope.
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