CCDC50 (Coiled-coil domain-containing protein 50 / Ymer) — review notes

UniProt: Q8IVM0 (CCD50_HUMAN), 306 aa (isoform 1, major). HGNC:18111. Synonyms: C3orf6, Ymer.

Domain architecture (UniProt)

• Coiled-coil (63–130).
• Large disordered C-terminal region (215–306).
• N-terminal acetylated (Ala-2), phosphorylated on Ser-5 and on tyrosine residues (EGF-induced).
• A short crystallized peptide (170–178, PDB 6LAN).
  Note: Ymer harbors a "MIU"-type ubiquitin-interacting motif (reported in the literature) that binds K63-linked polyubiquitin; this is the molecular basis of its ubiquitin-binding behavior in NF-kB regulation and EGFR sorting.

EGFR signaling / Ymer

• PMID:15314609 — Ymer (CCDC50) identified as an EGF-induced tyrosine-phosphorylated protein involved in EGFR signaling. Basis of the UniProt FUNCTION "Involved in EGFR signaling" and the original "effector of EGF-mediated cell signaling" description. (Not cached; verified via UniProt reference list.)
• PMID:17503326 — DFNA44 progressive hearing-loss mutation; expression restricted to cochlear pillar cells, stria vascularis, vestibular sensory epithelia. Supports cytoplasm/cytosol localization and the sensory perception of sound (GO:0007605) phenotype annotation (IMP, deafness).

NF-kB / K63-polyubiquitin / innate immune signaling

• PMID:18029035 — Ymer interacts with A20 (TNFAIP3) and binds K63-linked polyubiquitin chains on RIP1/RIPK1; overexpression down-regulates NF-kB signaling, knockdown up-regulates it. Establishes K63-polyUb binding and a negative-regulator role in NF-kB signaling. Interactome (UniProt) includes OTUD7B, RIPK1, RNF8, ARRDC3, UBB — consistent with a ubiquitin-pathway scaffold.

EGFR endosomal sorting / ubiquitin ligase binding

• PMID:23418353 — CCDC50/Ymer interacts with RNF126 (source of the IPI ubiquitin protein ligase binding GO:0031625 annotation). RNF126 functions in EGFR endosomal sorting downstream of c-Cbl. Connects Ymer to ubiquitin-dependent receptor sorting.

Selective autophagy receptor (literature beyond cached set; context for review)

CCDC50/Ymer has been reported as a TBK1-binding selective autophagy receptor that recognizes K63-polyubiquitinated cargo and links it to LC3 — implicated in aggrephagy/reticulophagy and in negative regulation of antiviral innate immunity (RIG-I/MAVS) by delivering activated RIG-I/aggregated signaling components for autophagic degradation (e.g., Hou et al., Autophagy 2021). These roles are consistent with its K63-polyUb binding (PMID:18029035) and ubiquitin-ligase binding (PMID:23418353) but are not represented in the current GOA annotation set, so no existing annotation captures the autophagy-receptor MF directly. Recorded as a proposed gap / question.

Localization

Cytoplasm / cytosol (HPA IDA; PMID:17503326). Associated with microtubules of cytoskeleton and mitotic apparatus (by similarity / PMID:17503326). No nuclear core role.

Disease

DFNA44 autosomal dominant progressive hearing loss [MIM:607453] caused by CCDC50 variants PMID:17503326.

Annotation set (GOA): 8 annotations

1. GO:0005737 cytoplasm IBA (is_active_in) — localization OK; "is_active_in" qualifier unusual for a CC but reflects PAN-GO.
2. GO:0031625 ubiquitin protein ligase binding IBA — supported (RNF126 binding, PMID:23418353); enables.
3. GO:0005737 cytoplasm IEA (located_in) — OK.
4. GO:0005515 protein binding IPI (PMID:18029035) — A20/RIP1 K63-polyUb context; bare protein binding uninformative.
5. GO:0005515 protein binding IPI (PMID:32296183) — HuRI binary interactome.
6. GO:0005829 cytosol IDA (HPA, GO_REF:0000052) — OK core localization.
7. GO:0007605 sensory perception of sound IMP (PMID:17503326) — DFNA44 deafness phenotype; acts_upstream_of_or_within. Pleiotropic/tissue-specific.
8. GO:0031625 ubiquitin protein ligase binding IPI (PMID:23418353) — RNF126; supported.

Key GO terms verified via QuickGO API

• GO:0031625 ubiquitin protein ligase binding (existing label correct).
• GO:0035973 aggrephagy; GO:0061709 reticulophagy; GO:0160247 autophagy cargo adaptor activity; GO:0032480 negative regulation of type I interferon production (candidate proposed terms / questions).

CCDC50 PN Consistency Notes

• Generated: 2026-06-18
• Project: PROTEOSTASIS
• Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
• UniProt: Q8IVM0
• AIGR review status: COMPLETE
• Review batch: proteostasis-batch-2026-06-14
• Batch change status: added

Source Files Checked

• AIGR review YAML: present - genes/human/CCDC50/CCDC50-ai-review.yaml
• AIGR review HTML: missing - genes/human/CCDC50/CCDC50-ai-review.html
• Gene notes: present - genes/human/CCDC50/CCDC50-notes.md
• GOA TSV: present - genes/human/CCDC50/CCDC50-goa.tsv
• UniProt record: present - genes/human/CCDC50/CCDC50-uniprot.txt
• PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/CCDC50.md
• PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/CCDC50.md
• PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
• PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

• No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

• 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).
• Existing/core annotation action counts: ACCEPT: 3; KEEP_AS_NON_CORE: 5

PN Consistency Summary

• Consistency: Consistent at the conclusion level but with an evidence-source divergence. PN row 1 rests on ONE paper — "CCDC50 suppresses NLRP3 inflammasome... autophagic degradation of NLRP3" (EMBO reports) — delivering ubiquitinated NLRP3 to autophagosomes. The review/notes do NOT cite that EMBO paper; instead the autophagy-receptor role is built from K63-polyUb binding (PMID:18029035), RNF126/EGFR sorting (PMID:23418353), and a literature-level "TBK1-binding SLR in aggrephagy/reticulophagy / RIG-I-MAVS turnover" framing (Hou et al. Autophagy 2021, not cached). Both routes converge on the same MF.
• PN story / NEW pressure: PN and review AGREE on the new MF: GO:0160247 autophagy cargo adaptor activity (verified real) is new_to_goa in PN and proposed_new_terms in the review (proposed child "K63-linked polyubiquitin selective autophagy receptor activity" under GO:0160247, supported_by PMID:18029035). Clear ADD, well-justified — current GOA has only ubiquitin-ligase binding (GO:0031625) and bare protein binding.
• Evidence alignment: DIVERGENT references — PN cites the EMBO NLRP3 paper; review cites NF-kB/EGFR/K63 papers. Same destination, different supporting literature; the EMBO NLRP3 paper would strengthen the review's NEW-term justification.
• Verdict: CONSISTENT conclusion (GO:0160247 ADD agreed by both); evidence sources diverge. Recommended edits: [REF] add the CCDC50/NLRP3 autophagic-degradation EMBO reports paper to the review references and as supporting_text for the proposed GO:0160247 receptor MF.

Full Consistency Review

• UniProt: Q8IVM0 (Ymer) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (~239 lines, small)
• PN placement: ALP Autophagy substrate selection|Selective autophagy receptor|Individual substrates + UPS Ubiquitin and UBL binding|trafficking|macroautophagy|MIU ; PN-node mapping: Individual substrates→GO:0160247 cargo adaptor (new_to_goa); UPS macroautophagy type→GO:0016236 context_only; ancestors no_mapping/context_only.
• Consistency: Consistent at the conclusion level but with an evidence-source divergence. PN row 1 rests on ONE paper — "CCDC50 suppresses NLRP3 inflammasome... autophagic degradation of NLRP3" (EMBO reports) — delivering ubiquitinated NLRP3 to autophagosomes. The review/notes do NOT cite that EMBO paper; instead the autophagy-receptor role is built from K63-polyUb binding (PMID:18029035), RNF126/EGFR sorting (PMID:23418353), and a literature-level "TBK1-binding SLR in aggrephagy/reticulophagy / RIG-I-MAVS turnover" framing (Hou et al. Autophagy 2021, not cached). Both routes converge on the same MF.
• PN story / NEW pressure: PN and review AGREE on the new MF: GO:0160247 autophagy cargo adaptor activity (verified real) is new_to_goa in PN and proposed_new_terms in the review (proposed child "K63-linked polyubiquitin selective autophagy receptor activity" under GO:0160247, supported_by PMID:18029035). Clear ADD, well-justified — current GOA has only ubiquitin-ligase binding (GO:0031625) and bare protein binding.
• Mapping strategy: Mapping is correct (KEY PATTERN: elevate cargo-adaptor MF over bare protein binding, ~2 IPI kept non-core). PN GO:0160247 = review proposed parent. Sound, not an over-reach.
• Evidence alignment: DIVERGENT references — PN cites the EMBO NLRP3 paper; review cites NF-kB/EGFR/K63 papers. Same destination, different supporting literature; the EMBO NLRP3 paper would strengthen the review's NEW-term justification.
• Verdict: CONSISTENT conclusion (GO:0160247 ADD agreed by both); evidence sources diverge. Recommended edits: [REF] add the CCDC50/NLRP3 autophagic-degradation EMBO reports paper to the review references and as supporting_text for the proposed GO:0160247 receptor MF.

PN Dossier Context

• review_batch: proteostasis-batch-2026-06-14
• review_yaml: genes/human/CCDC50/CCDC50-ai-review.yaml
• PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Individual substrates

• UniProt: Q8IVM0
• In branches: ALP, UPS
• Notes: Delivers ubiquitinated NLRP3 inflammasome to autophagosome for degradation
• PN references (titles):
  • CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3 | EMBO reports (embopress.org)
• PN-node mapping records (path + ancestors):
  • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Individual substrates
    status=mapped scope=ok_for_propagation_to_go GO=[GO:0160247 autophagy cargo adaptor activity]
    rationale: This PN category groups receptors such as TRIM-family factors that bind specific substrates and recruit autophagy components for their turnover. That aligns best with autophagy cargo adaptor activity rather than with a single selective-autophagy process term.
  • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
    status=no_mapping scope= GO=[]
    rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
  • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
    status=no_mapping scope= GO=[]
    rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
  • [branch] Autophagy-Lysosome Pathway
    status=no_mapping scope= GO=[]
    rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | macroautophagy | MIU

• UniProt: Q8IVM0
• In branches: ALP, UPS
• Signature domains: PMID: 16499958
• Auxiliary domains: (none)
• PN references (titles):
  • 16499958
• PN-node mapping records (path + ancestors):
  • [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|macroautophagy|MIU
    status=no_mapping scope= GO=[]
    rationale: Reviewed as a selective-autophagy or trafficking subdivision under a UPS binding context. The autophagy context is real, but this node is too indirect for automatic GO propagation.
  • [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|macroautophagy
    status=context_only scope=too_broad_to_propagate GO=[GO:0016236 macroautophagy]
    rationale: This PN type is an autophagy-related trafficking context, but the earlier TRAPP review showed that generic autophagy propagation from component or binding-context buckets can be too strong. Keep as context unless gene-level evidence supports macroautophagy.
  • [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking
    status=no_mapping scope= GO=[]
    rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
  • [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
    status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
    rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
  • [branch] Ubiquitin Proteasome System
    status=no_mapping scope= GO=[]
    rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

• GO:0160247 autophagy cargo adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Individual substrates

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.