MUP-4 is a large single-pass transmembrane receptor of the C. elegans epidermis (hypodermis). Its extracellular region has 28 EGF-like repeats (many of the calcium-binding type), a von Willebrand factor A domain and two SEA modules. Its intracellular domain resembles the intermediate filament-associated protein filaggrin. MUP-4 localizes to the apical hemidesmosomes (fibrous organelles) that overlie body wall muscles, and to other sites where cells attach mechanically to cuticle. There it anchors the apical epidermal membrane and its intermediate filament network to the cuticle, forming part of the mechanical link that transmits muscle force across the epidermis. mup-4 mutants detach the epidermis from the cuticle, fail epidermal enclosure or elongation, and displace body wall muscles. MUP-4 also binds the STAT-like transcription factor STA-2 at hemidesmosomes. When hemidesmosomes or specific cuticle collagens are damaged, STA-2 is released and drives antimicrobial peptide gene expression. This makes the MUP-4/STA-2 complex a sensor of structural damage in the epidermis. The cuticle collagen BLI-1 is a proposed extracellular ligand.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005201 extracellular matrix structural constituent | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA transfer of extracellular matrix structural constituent from fibrillin (FBN1) and C. elegans FBN-1. Reason: The PANTHER family (PTHR24039, fibrillin-related) groups proteins by their arrays of calcium-binding EGF repeats. Fibrillins are secreted microfibril components, but MUP-4 is a single-pass transmembrane receptor. It mediates attachment between the apical membrane and the cuticle and is not itself an ECM structural constituent. MUP-4 sits in its own subfamily (PTHR24039:SF40). The comparable apical hemidesmosome receptor MUA-3 carries the same IBA, which reflects family scope rather than evidence for either protein. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION Sources checked: PANTHER:PTN000620536 SUPPORTS SOURCE BUT NOT TARGET Grounded by secreted fibrillins (FBN1, FBN-1); MUP-4 is a transmembrane cell-matrix receptor, not a secreted matrix constituent. Supporting Evidence: PMID:11470827 Here, we report that mup-4 encodes a novel transmembrane protein that is required for attachments between the apical epithelial surface and the cuticular matrix. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro calcium-binding EGF-like domain assignment. Reason: About half of the 28 MUP-4 EGF-like repeats have the consensus residues of the calcium-binding EGF subclass, so calcium binding is very likely structural, as in other cbEGF arrays. It has not been tested directly and is not the functional output of the protein. Supporting Evidence: PMID:11470827 Based on conserved residues, the 28 EGF-like repeats fall into different subclasses including 27 unusual repeats, 14 with residues that mediate Ca2+ binding |
| GO:0005515 protein binding | IPI PMID:25692704 Structural damage in the C. elegans epidermis causes release... | MODIFY | Summary: IPI with STA-2 (UniProtKB:Q20977); MUP-4 binds STA-2 at hemidesmosomes. Reason: The interaction is supported: STA-2 is held at hemidesmosomes and is detached when they are disrupted, and a later study describes MUP-4 as binding and sequestering STA-2. "protein binding" is uninformative. STA-2 is a STAT-like protein, so GO:0097677 STAT family protein binding names the partner class. The functional consequence (holding STA-2 away from the nucleus) is captured in core_functions as protein sequestering activity. Proposed replacements: STAT family protein binding Supporting Evidence: PMID:25692704 The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. PMID:37759445 MUP-4 exerts immune surveillance function through binding and sequestering STA-2 under normal conditions and releasing STA-2 to induce AMPs upon apical structural damage |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping to cytoskeleton (intermediate filaments). Reason: The MUP-4 cytoplasmic domain resembles filaggrin, and MUP-4 is proposed to tether intermediate filaments at hemidesmosomes. Association with the cytoskeleton is reasonable, but MUP-4 is a transmembrane junctional protein. Hemidesmosome is the more accurate location. Supporting Evidence: PMID:11470827 Its intracellular domain is homologous to filaggrin, an intermediate filament (IF)-associated protein that regulates IF compaction and that has not previously been reported as part of a junctional complex. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to plasma membrane (single-pass membrane protein). Reason: MUP-4 has a single transmembrane segment and acts at the apical plasma membrane of the epidermis, where hemidesmosomes attach it to the cuticle. Supporting Evidence: PMID:11470827 Here, we report that mup-4 encodes a novel transmembrane protein that is required for attachments between the apical epithelial surface and the cuticular matrix. |
| GO:0030056 hemidesmosome | IDA PMID:11470827 MUP-4 is a novel transmembrane protein with functions in epi... | ACCEPT | Summary: MUP-4::GFP and anti-MUP-4 antibodies colocalize with epidermal hemidesmosomes overlying body wall muscles. Reason: Direct localization by GFP fusion and antibody staining. This is the defining location of MUP-4. Supporting Evidence: PMID:11470827 MUP-4 colocalizes with epithelial hemidesmosomes overlying body wall muscles, beginning at the time of embryonic cuticle maturation, as well as with other sites of mechanical coupling. |
| GO:0030056 hemidesmosome | IDA PMID:25692704 Structural damage in the C. elegans epidermis causes release... | ACCEPT | Summary: MUP-4 is found at hemidesmosomes together with STA-2. Reason: Independent experimental confirmation (abstract-only in our cache; the curator read the full text). Consistent with the 2001 localization. Supporting Evidence: PMID:25692704 The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. |
| GO:0030056 hemidesmosome | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA (ARBA rule and UniProt subcellular location) for hemidesmosome. Reason: Matches experimental localization. Supporting Evidence: PMID:11470827 MUP-4 colocalizes with epithelial hemidesmosomes overlying body wall muscles, beginning at the time of embryonic cuticle maturation, as well as with other sites of mechanical coupling. |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA transfer of extracellular matrix localization from fibrillins. Reason: Fibrillins are secreted ECM components. MUP-4 is a transmembrane protein whose ectodomain contacts the apical cuticle (ECM) at hemidesmosomes, but it is anchored in the plasma membrane and is not an ECM component. Hemidesmosome and plasma membrane describe its location more accurately. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000620536 SUPPORTS SOURCE BUT NOT TARGET ECM localization is correct for the secreted fibrillin seeds but not for the transmembrane receptor MUP-4. Supporting Evidence: PMID:11470827 Here, we report that mup-4 encodes a novel transmembrane protein that is required for attachments between the apical epithelial surface and the cuticular matrix. |
| GO:0098733 hemidesmosome associated protein complex | IDA PMID:25692704 Structural damage in the C. elegans epidermis causes release... | ACCEPT | Summary: MUP-4 is part of the hemidesmosome-associated protein complex that holds STA-2. Reason: Experimental annotation from the paper showing that STA-2 is held in a hemidesmosome-associated complex and released on damage. MUP-4 is the transmembrane receptor of the apical hemidesmosome. Supporting Evidence: PMID:25692704 The epidermis recognized structural damage through hemidesmosomes associated with a STAT-like protein, whose disruption led to detachment of STA-2 molecules from hemidesmosomes and transcription of AMPs. PMID:37759445 Apical CeHDs connect the cuticle through the transmembrane receptor MUP-4, while basal CeHDs link the basement ECM and body wall muscles through the receptor LET-805 |
| GO:0007160 cell-matrix adhesion | IMP PMID:11470827 MUP-4 is a novel transmembrane protein with functions in epi... | NEW | Summary: In all mup-4 mutants examined by electron microscopy, the apical epidermal membrane separates from the cuticle. MUP-4 is the transmembrane receptor of the apical hemidesmosome. Reason: MUP-4 is a structural participant here, not just a required factor: it is the transmembrane protein that physically links the apical membrane to the cuticular matrix, and its loss causes a lesion exactly at that interface. Comparator check: MUA-3, the other apical hemidesmosome transmembrane receptor (characterized in PMID:11470828), is annotated to GO:0007160 cell-matrix adhesion by IMP. MUP-4 lacks any adhesion process term. Supporting Evidence: PMID:11470827 In contrast, all mup-4 mutants (n = 14) showed a lesion between the apical hypodermal membrane and the cuticle. PMID:11470827 Analyses of the localization of MUP-4 and the ultrastructural lesions in mutants support the hypothesis that MUP-4 functions to tether IFs and to adhere the hypodermis to the apical ECM, thus providing a mechanical link that transmits muscle forces to the cuticle. |
| GO:0140311 protein sequestering activity | IDA PMID:37759445 C. elegans Hemidesmosomes Sense Collagen Damage to Trigger I... | NEW | Summary: MUP-4 binds STA-2 and holds it at apical hemidesmosomes under normal conditions; STA-2 is released to induce AMPs on structural damage, and deleting the MUP-4 ectodomain detaches STA-2. Reason: Sequestering describes what MUP-4 does to STA-2 better than "protein binding": it keeps STA-2 at hemidesmosomes, away from its transcriptional targets, until damage releases it. The binding is supported by the WormBase IPI (PMID:25692704) and by localization studies in which loss of MUP-4 integrity (ectodomain deletion, collagen damage) detaches STA-2. Supporting Evidence: PMID:37759445 MUP-4 exerts immune surveillance function through binding and sequestering STA-2 under normal conditions and releasing STA-2 to induce AMPs upon apical structural damage PMID:37759445 Moreover, the deletion of the extracellular portion of MUP-4 containing the collagen-binding domain caused STA-2 detachment from CeHDs, suggesting that the interaction between MUP-4 and STA-2 responds to signals from ECM collagens |
| GO:0098631 cell adhesion mediator activity | IMP PMID:11470827 MUP-4 is a novel transmembrane protein with functions in epi... | NEW | Summary: MUP-4 is the transmembrane protein that adheres the apical epidermal membrane to the cuticular matrix at hemidesmosomes. Reason: Adhesion of the cell to an external substrate (the cuticle) is the molecular role MUP-4 plays at the apical hemidesmosome: it is transmembrane, sits at the junction, and its loss causes a lesion exactly between the apical membrane and the cuticle. The ligand is not established; BLI-1 is a candidate. Supporting Evidence: PMID:11470827 In contrast, all mup-4 mutants (n = 14) showed a lesion between the apical hypodermal membrane and the cuticle. PMID:11470827 Here, we report that mup-4 encodes a novel transmembrane protein that is required for attachments between the apical epithelial surface and the cuticular matrix. |
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Download this section (compressed HTML)Q: Does BLI-1 bind the MUP-4 ectodomain directly? If so, which MUP-4 domain (vWFA, SEA or EGF repeats) mediates collagen binding?
Q: Does the MUP-4 cytoplasmic (filaggrin-like) domain bind STA-2 directly, and what conformational or proteolytic change in MUP-4 releases STA-2 after damage? Do the SEA modules undergo autoproteolysis, as in other SEA-domain receptors?
Experiment: Run in vitro binding assays (pull-down or SPR) between recombinant MUP-4 ectodomain fragments and BLI-1, and between the MUP-4 cytoplasmic domain and STA-2, to test the proposed direct collagen-receptor-STAT links.
Experiment: Use CRISPR to make domain-specific MUP-4 deletions (vWFA, SEA, cytoplasmic tail) and measure both cuticle attachment and nlp-29 AMP reporter induction, to separate the adhesion and damage-sensing functions.
The mup-4 gene encodes a novel transmembrane protein required for junctional attachments between hypodermis and muscle, and between the apical epithelial surface and the cuticular matrix.
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