CCDC50 (Coiled-coil domain-containing protein 50), also known as Ymer, is a soluble, predominantly cytoplasmic/cytosolic protein with an N-terminal coiled-coil region and a large disordered, basic C-terminal region. It is a ubiquitin-binding adapter that recognizes lysine-63-linked polyubiquitin chains and functions in ubiquitin-dependent signaling and receptor trafficking. CCDC50/Ymer is rapidly tyrosine-phosphorylated upon epidermal growth factor (EGF) stimulation and modulates EGF receptor (EGFR) signaling; it associates with the RING E3 ubiquitin ligase RNF126 and participates in ubiquitin-dependent endosomal sorting of activated EGFR. Through its interaction with the deubiquitinase/ubiquitin-editing enzyme A20 (TNFAIP3) and binding to K63-linked polyubiquitin on RIPK1, CCDC50/Ymer negatively regulates NF-kB signaling. It has additionally been reported (in literature beyond the current annotation set) to act as a TBK1-binding selective autophagy receptor that links K63-polyubiquitinated cargo to LC3 in aggrephagy/reticulophagy and in restraint of antiviral innate immunity. CCDC50 is associated with microtubules of the cytoskeleton and mitotic apparatus. It is broadly expressed, with isoform 1 (the major isoform) detected in most tissues; in the adult inner ear its expression is restricted to cochlear pillar cells, the stria vascularis, and the vestibular sensory epithelia. Mutations in CCDC50 cause autosomal dominant progressive non-syndromic hearing loss (DFNA44).
Definition: An autophagy cargo adaptor activity in which the adaptor recognizes K63-linked-polyubiquitinated cargo and bridges it to a phagophore-conjugated ATG8-family protein, targeting the cargo for selective autophagic degradation.
Justification: CCDC50/Ymer has been reported in the literature (beyond the current GOA annotation set) to act as a TBK1-binding selective autophagy receptor that links K63-polyubiquitinated cargo to LC3 in aggrephagy/reticulophagy. Its experimentally demonstrated K63-polyubiquitin binding (PMID:18029035) is consistent with this role, which is not represented by any current annotation.
Parent term: autophagy cargo adaptor activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (PAN-GO) inference that CCDC50 is active in the cytoplasm, its established compartment as a soluble ubiquitin-binding adapter. Reason: Correct localization; CCDC50/Ymer is a soluble cytoplasmic protein, but this generic cytoplasm term is subsumed by the more specific cytosol (IDA) annotation. Supporting Evidence: PMID:17503326 Ymer is a soluble, cytoplasmic protein |
| GO:0031625 ubiquitin protein ligase binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of ubiquitin-protein-ligase binding, consistent with CCDC50/Ymer's experimentally demonstrated interaction with the E3 ligase RNF126. Reason: Supported molecular function; CCDC50 binds the RING E3 ligase RNF126 and functions in ubiquitin-dependent EGFR sorting, redundant with the IPI annotation. Supporting Evidence: file:human/CCDC50/CCDC50-uniprot.txt Interacts with RNF126 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location. Reason: Correct but generic; the specific cytosol annotation better captures the localization, and this is redundant with the IBA cytoplasm annotation. Supporting Evidence: file:human/CCDC50/CCDC50-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005515 protein binding | IPI PMID:18029035 Involvement of Ymer in suppression of NF-kappaB activation b... | KEEP AS NON CORE | Summary: Interactions with A20/TNFAIP3 and K63-linked polyubiquitin on RIPK1 in the NF-kB-regulation study. Bare protein binding is uninformative. Reason: Records functionally important interactions (A20, K63-polyubiquitin/RIPK1) underlying CCDC50's role as a negative regulator of NF-kB signaling, but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:18029035 bound to lysine (K)-63-linked |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput binary (HuRI) interactome interaction. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-curated (HPA) cytosolic localization, the core compartment of CCDC50. Reason: Correct core localization directly supported by imaging data. Supporting Evidence: PMID:17503326 Ymer is a soluble, cytoplasmic protein |
| GO:0007605 sensory perception of sound | IMP PMID:17503326 A mutation in CCDC50, a gene encoding an effector of epiderm... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that CCDC50 mutation causes autosomal dominant progressive hearing loss (DFNA44); CCDC50/Ymer is expressed in cochlear pillar cells, stria vascularis and vestibular sensory epithelia. Reason: Genuine, experimentally supported disease/phenotype association (DFNA44), but a tissue-specific physiological outcome rather than the molecular core function of the ubiquitin-binding adapter; appropriately retained as non-core. Supporting Evidence: PMID:17503326 causes progressive hearing loss |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:23418353 The E3 ubiquitin ligases RNF126 and Rabring7 regulate endoso... | ACCEPT | Summary: Direct interaction with the RING E3 ubiquitin ligase RNF126, which functions in ubiquitin-dependent endosomal sorting of EGFR. Reason: Informative molecular function directly supported by experiment; CCDC50/Ymer binds the E3 ligase RNF126, linking it to ubiquitin-dependent receptor sorting. This is the core molecular-function annotation (preferred over bare protein binding). Supporting Evidence: file:human/CCDC50/CCDC50-uniprot.txt Interacts with RNF126 |
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Download this section (compressed HTML)Q: Is CCDC50/Ymer's reported selective-autophagy-receptor function (TBK1-binding, K63-polyubiquitin to LC3) mediated by the same K63-polyubiquitin-binding module used in NF-kB and EGFR regulation, and which cargo classes (aggregates, ER, RIG-I/innate-immune signaling components) does it serve?
Q: How does the DFNA44 hearing-loss mutation mechanistically perturb CCDC50 function (ubiquitin binding, EGFR sorting, microtubule/cytoskeletal association) in cochlear pillar cells and stria vascularis?
Experiment: Define the CCDC50 ubiquitin-binding determinant (e.g. the reported MIU-type motif) by mutagenesis and test, in CCDC50-knockout cells reconstituted with wild-type versus ubiquitin-binding-dead CCDC50, its requirement for K63-polyubiquitin binding, NF-kB suppression, EGFR endosomal sorting, and any LC3/autophagy-flux readouts.
Experiment: Use quantitative interactome/proximity profiling (AP-MS, BioID with TBK1, A20, RNF126, RIG-I, LC3 baits) under resting versus EGF-, TNF-, and virus-stimulated conditions to determine whether the NF-kB, EGFR-sorting, and reported autophagy-receptor activities reflect distinct complexes.
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