Affinage

CCDC50

Coiled-coil domain-containing protein 50 · UniProt Q8IVM0

Length
306 aa
Mass
35.8 kDa
Annotated
2026-04-28
22 papers in source corpus 17 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC50 (Ymer) is a selective autophagy receptor that uses dual MIU domains to recognize K63-linked polyubiquitinated substrates and an LIR motif that simultaneously engages both the LDS and UDS sites of LC3 on phagophore membranes, delivering diverse cargo—including innate immune sensors (RIG-I, MDA5, STING, NLRP3), damaged lysosomes, protein aggregates, and viral proteins—for lysosomal degradation (PMID:32612200, PMID:34453126, PMID:35343634, PMID:37672005, PMID:38869076, PMID:40554364). Through this autophagic cargo receptor activity, CCDC50 negatively regulates type I interferon signaling and NLRP3 inflammasome activation, as demonstrated by knockout mice that exhibit enhanced antiviral responses and increased susceptibility to colitis (PMID:32612200, PMID:35343634). CCDC50 additionally suppresses NF-κB signaling through A20-dependent binding of K63-ubiquitin chains on RIP1, with its activities regulated by Src-family kinase-mediated tyrosine phosphorylation and ZDHHC4-catalyzed palmitoylation (PMID:18029035, PMID:19059208, PMID:41566717). A frameshift mutation in CCDC50 causes autosomal dominant progressive hearing loss (DFNA44), with the aberrant protein tail driving dominant-negative aggregate formation rather than haploinsufficiency (PMID:17503326, PMID:37165931).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 Medium

    Identification of CCDC50 as an EGF-dependent, ubiquitin-binding protein that modulates EGFR trafficking established its molecular features—MIU domains, tyrosine phosphorylation, and ubiquitination—that would later prove central to its cargo receptor function.

    Evidence Co-immunoprecipitation, mutagenesis (Y145/146F, K129R), and subcellular fractionation in COS7 cells

    PMID:16803894

    Open questions at the time
    • Endogenous role in EGFR degradation not confirmed with loss-of-function
    • Physiological relevance of EGFR modulation unclear in vivo
  2. 2007 Medium

    Discovery that CCDC50 interacts with A20 and binds K63-ubiquitin chains on RIP1 to suppress NF-κB signaling revealed a second functional axis—immune regulation—beyond receptor trafficking, and linkage to DFNA44 connected the gene to human disease.

    Evidence Yeast two-hybrid and co-IP for A20/RIP1 interaction with NF-κB reporter; mutation analysis and inner ear immunostaining for DFNA44

    PMID:17503326 PMID:18029035

    Open questions at the time
    • Mechanism linking NF-κB regulation to hearing loss not established
    • Whether A20 interaction is direct or mediated through ubiquitin chains not fully resolved
  3. 2008 Medium

    Demonstration that Src-family kinase phosphorylation at Y217/Y279/Y304 is required for NF-κB suppression established that CCDC50 function is actively regulated by signal-dependent post-translational modification.

    Evidence Site-directed mutagenesis with NF-κB luciferase reporter and soft agar assay

    PMID:19059208

    Open questions at the time
    • No structural basis for how phosphorylation alters ubiquitin-chain recognition
    • Kinase specificity in immune cells not defined
  4. 2012 Medium

    Transgenic overexpression in mice confirmed that CCDC50 impairs NF-κB and MAPK activation in vivo, protecting against septic shock and autoimmune glomerulonephritis, while unexpectedly enhancing Fas-mediated apoptosis, revealing context-dependent regulatory roles.

    Evidence Ymer-transgenic mice with LPS sepsis model, lpr/lpr autoimmune model, and Fas-mediated hepatocyte death

    PMID:22331027

    Open questions at the time
    • Gain-of-function only; no loss-of-function in vivo at this stage
    • Mechanism of Fas-apoptosis enhancement not defined
  5. 2020 High

    Structural and functional characterization redefined CCDC50 as a selective autophagy receptor: the crystal structure of the CCDC50–LC3 complex revealed a unique dual-site LIR engagement (LDS + UDS), and knockout mice demonstrated that CCDC50 degrades K63-polyubiquitinated RIG-I/MDA5 to restrain type I interferon responses during RNA virus infection.

    Evidence Crystal structure of CCDC50–LC3 complex, CCDC50 KO mice with viral infection, autophagic flux assays

    PMID:32612200

    Open questions at the time
    • Whether the dual-site LIR interaction is required for all cargo types not tested
    • Redundancy with other autophagy receptors for RIG-I/MDA5 not assessed
  6. 2021 High

    Extension to the DNA-sensing pathway showed that CCDC50 also targets K63-polyubiquitinated STING for autophagic degradation, establishing it as a pan-innate-immune autophagy receptor bridging both RNA and DNA sensing pathways.

    Evidence Co-IP, CCDC50 KO mice with HSV-1 infection, SLE patient sample correlation

    PMID:34453126

    Open questions at the time
    • Causal role of reduced CCDC50 in SLE pathogenesis not proven
    • STING ubiquitination writer that tags STING for CCDC50 recognition not identified
  7. 2022 High

    Demonstration that CCDC50 recognizes K63-polyubiquitinated NLRP3 and prevents inflammasome assembly broadened its substrate repertoire to include inflammasome components, with in vivo validation in a colitis model.

    Evidence Co-IP, autophagic flux assays, CCDC50 KO mice with DSS-colitis

    PMID:35343634

    Open questions at the time
    • Whether CCDC50 targets assembled or monomeric NLRP3 not resolved
    • Selectivity determinants beyond K63-polyubiquitin not defined
  8. 2023 High

    Discovery that CCDC50 acts as a lysophagy receptor recognizing galectin-3 and K63-polyubiquitin on damaged lysosomes, and as an aggrephagy receptor clearing neurodegenerative protein aggregates, demonstrated that its cargo receptor function extends well beyond immune signaling molecules.

    Evidence Lysosomal damage assays and melanoma tumor models; neuronal aggregate co-localization and KO mouse brain histology

    PMID:37672005 PMID:38869076

    Open questions at the time
    • Galectin-3 binding interface on CCDC50 not structurally resolved
    • Relative contribution of CCDC50 versus p62/OPTN in aggrephagy not defined
  9. 2023 Medium

    Characterization of DFNA44 frameshift mutations established a dominant-negative/gain-of-function mechanism driven by a six-amino-acid motif (CLENGL) in the aberrant protein tail that causes perinuclear aggregate formation, ruling out haploinsufficiency.

    Evidence In vitro mutagenesis with aggregate imaging, heterozygous Ccdc50 mouse ABR testing

    PMID:37165931

    Open questions at the time
    • Aggregate toxicity mechanism in cochlear cells not defined
    • Whether aggregates sequester wild-type CCDC50 not tested
  10. 2026 High

    Identification of ZDHHC4-mediated palmitoylation as required for CCDC50's autophagic targeting of MAP2K4, and of coronavirus NSP5-mediated cleavage at Q171 as a viral evasion strategy, defined two new regulatory layers—lipid modification and pathogen antagonism—that control CCDC50 cargo receptor activity.

    Evidence Acyl-biotin exchange palmitoylation assay with OA mouse model; NSP5 cleavage assays with mutagenesis across four coronaviruses

    PMID:40554364 PMID:41566717 PMID:41964373

    Open questions at the time
    • Whether palmitoylation regulates membrane association for all cargo types not tested
    • Whether other viral proteases also target CCDC50 remains unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for K63-polyubiquitin selectivity over other chain types, the physiological hierarchy among CCDC50's diverse substrates, and whether its autophagy receptor and NF-κB–suppressive functions are mechanistically separable.
  • No structure of MIU domain bound to K63-linked chains
  • Substrate hierarchy and tissue-specific cargo preference unknown
  • Relationship between A20-dependent NF-κB suppression and autophagy-dependent immune regulation not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0038024 cargo receptor activity 6
Localization
GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 7 R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4
Partners
DDX58IFIH1LGALS3MAP1LC3BNLRP3RIPK1STING1TNFAIP3

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 CCDC50 (Ymer) is a tyrosine-phosphorylated and ubiquitinated protein that suppresses ligand-mediated down-regulation of the EGF receptor. It is phosphorylated at tyrosine 145 and 146 upon EGF stimulation, ubiquitinated at lysine 129, and contains two MIU (motif interacting with ubiquitin) domains that bind the ubiquitinated EGF receptor. Ymer associates with EGF receptor in an EGF-dependent manner requiring both MIU domains and tyrosine phosphorylation, localizes to the plasma membrane with EGFR, and overexpression inhibits EGF-mediated secondary modifications and degradation of activated EGFR. Co-immunoprecipitation, site-directed mutagenesis (Y145/146F, K129R), subcellular fractionation/immunofluorescence, overexpression in COS7 cells The Journal of biological chemistry Medium 16803894
2007 CCDC50 (Ymer) interacts with A20 and binds K63-linked polyubiquitin chains on RIP1, negatively regulating NF-κB signaling. Overexpression of Ymer down-regulates NF-κB signaling while knockdown up-regulates it even without stimulation. Yeast two-hybrid, co-immunoprecipitation, luciferase reporter (NF-κB), siRNA knockdown Biochimica et biophysica acta Medium 18029035
2007 A frameshift mutation in CCDC50 causes autosomal dominant progressive hearing loss (DFNA44). Ymer is a soluble cytoplasmic protein expressed in cochlear pillar cells, stria vascularis, and vestibular sensory epithelia, where it colocalizes with the microtubule-based cytoskeleton; in dividing cells it colocalizes with mitotic microtubules. Western blotting, cell transfection, immunostaining in mouse inner ear, mutation analysis American journal of human genetics Medium 17503326
2008 Tyrosine phosphorylation of Ymer (at Y217, Y279, Y304) by Src-family kinases (including Lck) is required for its inhibitory activity on NF-κB signaling. Mutation of these tyrosines (YmerY217/279/304F) abolishes NF-κB inhibition and eliminates the ability of SrcY527F+Ymer to promote anchorage-independent growth. Site-directed mutagenesis, luciferase NF-κB reporter assay, soft agar colony formation assay Biochemical and biophysical research communications Medium 19059208
2009 CCDC50 knockdown reduces cell viability in primary CLL cells and MCL cell lines and is required for NF-κB signaling in these malignancies, as demonstrated by an NF-κB reporter gene assay. RNA interference screening, NF-κB luciferase reporter assay, cell viability assay in primary CLL and MCL cell lines Leukemia Medium 19641524
2012 Ymer transgenic mice exhibit impaired NF-κB and MAPK activation, reduced cell proliferation and cytokine production in response to TNF-α, polyI:C, or LPS, and are more resistant to LPS-induced septic shock. Ymer transgene also inhibits glomerulonephritis onset in lpr/lpr autoimmune mice but enhances Fas-mediated cell death in liver, demonstrating that Ymer is a positive or negative regulator depending on the signaling pathway context. Transgenic mouse model, cytokine measurement, LPS-induced septic shock model, autoimmune disease model (lpr/lpr), Fas-mediated apoptosis assay Molecular medicine (Cambridge, Mass.) Medium 22331027
2020 CCDC50 functions as a selective autophagy receptor that specifically recognizes K63-polyubiquitinated RIG-I and MDA5 and delivers them to autophagosomes for lysosomal degradation, thereby negatively regulating type I IFN signaling during RNA virus infection. Crystal structure analysis confirms CCDC50 association with phagophore membrane protein LC3 via both the LIR-docking site (LDS) and UIM-docking site (UDS), a dual interaction mode not previously described for cargo receptors. CCDC50 deficiency in mice reduces autophagic degradation of RIG-I/MDA5, enhances type I IFN responses, and improves survival upon RNA virus infection. High-throughput screening, co-immunoprecipitation, crystal structure of CCDC50-LC3 complex, CCDC50 knockout mice, viral infection models, autophagic flux assays Cell research High 32612200
2020 HnRNP A1 promotes skipping of exon 6 in CCDC50 pre-mRNA, generating a truncated oncogenic isoform (CCDC50-S) in clear cell renal cell carcinoma. CCDC50-S promotes proliferation, migration, invasion, and tumorigenesis, while full-length CCDC50-FL exerts tumor-suppressive functions. CCDC50-S exerts its oncogenic effects through the downstream protein ZNF395. RNA splicing analysis (semi-quantitative RT-PCR), Western blot, shRNA knockdown, overexpression plasmids, in vitro and in vivo functional assays, RNAseq downstream analysis Journal of experimental & clinical cancer research : CR Medium 32560659
2021 CCDC50 tunes STING-mediated type I IFN signaling by recognizing K63-polyubiquitinated STING and delivering it to autolysosomes for degradation. CCDC50 knockout increases HSV-1- or DNA ligand-induced type I IFN and proinflammatory cytokine production, reduces viral replication, and improves survival in mice. CCDC50 expression is reduced in SLE patients and negatively correlates with IFN signaling activation and disease severity. Co-immunoprecipitation, CCDC50 knockout mice, HSV-1 infection model, autophagic flux assays, cytokine measurement, SLE patient samples Cellular & molecular immunology High 34453126
2022 CCDC50 functions as an autophagy cargo receptor that recognizes K63-polyubiquitinated NLRP3 and delivers it for autophagic degradation, thereby inhibiting NLRP3 polymerization, ASC recruitment, inflammasome assembly, pro-caspase-1 cleavage, and IL-1β release. Ccdc50-deficient mice are more susceptible to DSS-induced colitis with elevated NLRP3 inflammasome activity. Co-immunoprecipitation, autophagic flux assays, CCDC50 knockout mice, DSS-colitis model, transcriptome analysis, cytokine measurement EMBO reports High 35343634
2023 CCDC50 serves as a lysophagy receptor that monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and targets them for autophagy-dependent degradation. CCDC50 deficiency causes accumulation of ruptured lysosomes, impaired autophagic flux, excess reactive oxygen species, and cell death. CCDC50 promotes tumor growth and metastasis in melanoma by maintaining lysosomal integrity. Co-immunoprecipitation (galectin-3, ubiquitin), lysosomal damage assays, CCDC50 KO cell lines and mouse tumor models, autophagic flux assays, ROS measurement, melanoma lung metastasis models EMBO reports High 37672005
2023 DFNA44-associated frameshift mutations in CCDC50 (e.g., p.Asp276Glufs*40) cause dominant-negative or gain-of-function effects rather than haploinsufficiency. The aberrant protein tail containing the six-amino-acid sequence CLENGL is necessary and sufficient to form perinuclear protein aggregates, as shown by in vitro studies with artificial mutants and patient-derived mutations. Heterozygous Ccdc50 mouse mutants show normal hearing up to 6 months, ruling out haploinsufficiency. In vitro mutagenesis, cell transfection with mutant constructs, immunofluorescence (protein aggregate distribution), mouse auditory threshold testing (ABR) Disease models & mechanisms Medium 37165931
2023 CCDC50 promotes ABC-DLBCL cell proliferation in vitro and in vivo by inhibiting ubiquitination-mediated c-Myc degradation through stimulation of the PI3K/AKT/GSK-3β pathway. Cell line knockdown/overexpression, mouse xenograft model, ubiquitination assay, PI3K/AKT/GSK-3β pathway analysis, protein co-expression analysis Annals of hematology Medium 37684379
2024 CCDC50 functions as an aggrephagy receptor in neuronal cells, being recruited to polyubiquitinated protein aggregates induced by proteotoxic stress and to aggregation-prone proteins (e.g., mutant HTT, FUS, SOD1, MAPT/tau). CCDC50 clears these cytotoxic aggregates through autophagy, and its deficiency causes accumulation of lipid deposits and polyubiquitinated protein conjugates in the brains of one-year-old mice. Fluorescence imaging (co-localization with aggregates), CCDC50 overexpression/KO in neuronal cells, autophagic flux assays, brain histology of KO mice Autophagy Medium 38869076
2026 ZDHHC4-catalyzed palmitoylation of CCDC50 is required for its ability to mediate selective autophagic degradation of MAP2K4/MKK4, thereby suppressing MAPK/JNK signaling and chondrocyte senescence. Lactucopicrin (LCP) binds His72 of ZDHHC4 to boost its enzymatic activity, enhancing CCDC50 palmitoylation and MAP2K4 degradation. Acyl-biotin exchange (palmitoylation assay), co-immunoprecipitation, structural analysis (ligand binding), mouse OA model (DMM), autophagic flux assays Autophagy Medium 41566717
2026 Coronavirus NSP5 protease cleaves CCDC50 at glutamine 171 (Q171), a conserved site targeted by NSP5 from PDCoV, PEDV, TGEV, and SARS-CoV-2. This cleavage disrupts CCDC50's interaction with LC3 and ubiquitin, impairing its ability to recognize K63-linked polyubiquitinated viral envelope (E) protein (at K72) and route it for autophagic degradation, thereby promoting viral replication. Co-immunoprecipitation, site-directed mutagenesis (Q171 cleavage site, E protein K72), autophagic degradation assays, viral replication assays in KO/overexpression cells, protease cleavage assays mBio High 40554364 41964373

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection. Cell research 91 32612200
2021 Autophagy receptor CCDC50 tunes the STING-mediated interferon response in viral infections and autoimmune diseases. Cellular & molecular immunology 49 34453126
2007 A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss. American journal of human genetics 44 17503326
2009 Gene knockdown studies revealed CCDC50 as a candidate gene in mantle cell lymphoma and chronic lymphocytic leukemia. Leukemia 39 19641524
2007 Involvement of Ymer in suppression of NF-kappaB activation by regulated interaction with lysine-63-linked polyubiquitin chain. Biochimica et biophysica acta 34 18029035
2006 Suppression of the ligand-mediated down-regulation of epidermal growth factor receptor by Ymer, a novel tyrosine-phosphorylated and ubiquitinated protein. The Journal of biological chemistry 32 16803894
2022 CCDC50 suppresses NLRP3 inflammasome activity by mediating autophagic degradation of NLRP3. EMBO reports 24 35343634
2002 A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28-29. Human genetics 19 12483295
2020 HnRNP A1 - mediated alternative splicing of CCDC50 contributes to cancer progression of clear cell renal cell carcinoma via ZNF395. Journal of experimental & clinical cancer research : CR 17 32560659
2022 The regulation of NLRP3 inflammasome activation by CCDC50-mediated autophagy. Autophagy 16 35620989
2023 CCDC50 promotes tumor growth through regulation of lysosome homeostasis. EMBO reports 14 37672005
2003 Identification and characterization of C3orf6, a new conserved human gene mapping to chromosome 3q28. Gene 14 14527723
2012 Ymer acts as a multifunctional regulator in nuclear factor-κB and Fas signaling pathways. Molecular medicine (Cambridge, Mass.) 12 22331027
2008 Inhibition of NF-kappaB signaling via tyrosine phosphorylation of Ymer. Biochemical and biophysical research communications 10 19059208
2024 CCDC50 mediates the clearance of protein aggregates to prevent cellular proteotoxicity. Autophagy 6 38869076
2023 Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants. Disease models & mechanisms 3 37165931
2023 CCDC50, an essential driver involved in tumorigenesis, is a potential severity marker of diffuse large B cell lymphoma. Annals of hematology 2 37684379
2026 Lactucopicrin promotes the autophagic degradation of MAP2K4/MKK4 by mediating CCDC50 palmitoylation to alleviate osteoarthritis progression. Autophagy 0 41566717
2026 PDCoV NSP5 cleaves the selective autophagy receptor CCDC50 to disrupt autophagic degradation of the viral envelope protein. mBio 0 41817175
2026 Coronavirus NSP5 protease cleaves CCDC50 to evade antiviral autophagy. Autophagy 0 41964373
2025 BVDV antagonizes the antiviral activity of MDA5 by promoting its degradation via CCDC50-dependent selective autophagy. Veterinary microbiology 0 40554364
2025 Y-mer: a k-mer based method for determining human Y chromosome haplogroups from ultra-low sequencing depth data. Genome biology 0 40797266