id: Q8IVM0
gene_symbol: CCDC50
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
alternative_products:
- name: 1 (Short)
  id: Q8IVM0-1
- name: 2 (Long)
  id: Q8IVM0-2
  sequence_note: VSP_014985
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (PAN-GO) inference that CCDC50 is active in the cytoplasm, its established compartment as a soluble ubiquitin-binding adapter.
    action: KEEP_AS_NON_CORE
    reason: Correct localization; CCDC50/Ymer is a soluble cytoplasmic protein, but this generic cytoplasm term is subsumed by the more specific cytosol (IDA) annotation.
    supported_by:
    - reference_id: PMID:17503326
      supporting_text: Ymer is a soluble, cytoplasmic protein
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of ubiquitin-protein-ligase binding, consistent with CCDC50/Ymer's experimentally demonstrated interaction with the E3 ligase RNF126.
    action: ACCEPT
    reason: Supported molecular function; CCDC50 binds the RING E3 ligase RNF126 and functions in ubiquitin-dependent EGFR sorting, redundant with the IPI annotation.
    supported_by:
    - reference_id: file:human/CCDC50/CCDC50-uniprot.txt
      supporting_text: Interacts with RNF126
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific cytosol annotation better captures the localization, and this is redundant with the IBA cytoplasm annotation.
    supported_by:
    - reference_id: file:human/CCDC50/CCDC50-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18029035
  qualifier: enables
  review:
    summary: Interactions with A20/TNFAIP3 and K63-linked polyubiquitin on RIPK1 in the NF-kB-regulation study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:18029035
      supporting_text: bound to lysine (K)-63-linked
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (HuRI) interactome interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-curated (HPA) cytosolic localization, the core compartment of CCDC50.
    action: ACCEPT
    reason: Correct core localization directly supported by imaging data.
    supported_by:
    - reference_id: PMID:17503326
      supporting_text: Ymer is a soluble, cytoplasmic protein
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: IMP
  original_reference_id: PMID:17503326
  qualifier: acts_upstream_of_or_within
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17503326
      supporting_text: causes progressive hearing loss
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:23418353
  qualifier: enables
  review:
    summary: Direct interaction with the RING E3 ubiquitin ligase RNF126, which functions in ubiquitin-dependent endosomal sorting of EGFR.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: file:human/CCDC50/CCDC50-uniprot.txt
      supporting_text: Interacts with RNF126
core_functions:
- description: Functions as a K63-linked-polyubiquitin-binding adapter in ubiquitin-dependent signaling. Through interaction with the ubiquitin-editing enzyme A20/TNFAIP3 and binding to K63-polyubiquitin on RIPK1, CCDC50/Ymer negatively regulates NF-kB signaling.
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:18029035
    supporting_text: bound to lysine (K)-63-linked
  - reference_id: PMID:23418353
    supporting_text: regulate endosomal sorting of
- description: Acts in EGF receptor signaling and ubiquitin-dependent endosomal sorting of activated EGFR, associating with the RING E3 ubiquitin ligase RNF126; CCDC50/Ymer is itself EGF-induced tyrosine-phosphorylated.
  molecular_function:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/CCDC50/CCDC50-uniprot.txt
    supporting_text: Involved in EGFR signaling
  - reference_id: file:human/CCDC50/CCDC50-uniprot.txt
    supporting_text: Interacts with RNF126
proposed_new_terms:
- proposed_name: K63-linked polyubiquitin selective autophagy receptor activity
  proposed_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.
  proposed_parent:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  supported_by:
  - reference_id: PMID:18029035
    supporting_text: bound to lysine (K)-63-linked
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- description: 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.
- description: 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.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: PMID:15314609
  title: Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics.
  findings:
  - statement: Ymer (CCDC50) is an EGF-induced tyrosine-phosphorylated protein involved in EGFR signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Basis of the UniProt FUNCTION 'Involved in EGFR signaling'. Not in publications cache; verified via the UniProt reference list and the DFNA44 paper's description of Ymer as an EGF-signaling effector.
- id: PMID:17503326
  title: A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss.
  findings:
  - statement: A CCDC50 mutation causes DFNA44 autosomal dominant progressive hearing loss; Ymer is a soluble cytoplasmic protein expressed in cochlear pillar cells, stria vascularis and vestibular sensory epithelia, and colocalizes with microtubules of the mitotic apparatus.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the DFNA44 phenotype (sensory perception of sound IMP) and cytoplasmic/microtubule localization. Abstract in cache.
- id: PMID:18029035
  title: Involvement of Ymer in suppression of NF-kappaB activation by regulated interaction with lysine-63-linked polyubiquitin chain.
  findings:
  - statement: Ymer interacts with A20 and binds K63-linked polyubiquitin on RIPK1; overexpression down-regulates NF-kB signaling and knockdown up-regulates it, establishing Ymer as a negative regulator of NF-kB signaling and a K63-polyubiquitin-binding protein.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes K63-polyubiquitin binding and the NF-kB-suppression role. Abstract in cache.
- id: PMID:23418353
  title: The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor.
  findings:
  - statement: RNF126 (a CCDC50/Ymer interactor) functions in ubiquitin-dependent endosomal sorting and degradation of EGFR downstream of c-Cbl.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the ubiquitin-protein-ligase-binding (RNF126) IPI annotation; links CCDC50 to ubiquitin-dependent EGFR sorting. Abstract in cache.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput binary interactome (HuRI); source of a bare protein binding annotation.