{"gene":"CCDC124","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2018,"finding":"Lso2 (yeast ortholog of CCDC124) is a ribosome-associated protein that crosslinks to 25S rRNA near the A site overlapping the GTPase activation center, and also crosslinks to most tRNAs. Deletion of LSO2 causes global translation defects during recovery from stationary phase, with ribosomes accumulating at start codons, depleted from stop codons, and showing codon-specific occupancy changes.","method":"Quantitative mass spectrometry (ribosome identification), genome-wide crosslinking and immunoprecipitation (CLIP), ribosome profiling of lso2Δ yeast","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CLIP, ribosome profiling, mass spectrometry), replicated with human CCDC124 ortholog crosslinking, single rigorous study","pmids":["30208026"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structures of translationally inactive yeast and human ribosomes show Lso2/CCDC124 accumulates on idle ribosomes in the non-rotated state and bridges the decoding site of the small subunit with the GTPase activating center (GAC) of the large subunit, in contrast to Stm1/SERBP1-bound ribosomes which are in the rotated state. Lso2-containing ribosomes are compatible with Dom34-dependent ribosome recycling (splitting), whereas Stm1-containing ribosomes are not.","method":"Cryo-electron microscopy (cryo-EM) structural determination of yeast and human hibernating ribosomes","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structures for both yeast and human ribosomes, functional comparison with Stm1/SERBP1 system, two organisms studied in one rigorous paper","pmids":["32687489"],"is_preprint":false},{"year":2020,"finding":"The microsporidian Lso2 homolog adopts a V-shaped conformation to bridge the mRNA decoding site and the large subunit tRNA binding sites in Paranosema locustae ribosomes, providing a conserved reversible ribosome inactivation mechanism consistent with the eukaryotic hibernation function of CCDC124/Lso2.","method":"Cryo-electron microscopy (cryo-EM) structural determination of P. locustae hibernating ribosomes","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional interpretation, independently replicates the bridging mechanism shown in yeast and human structures","pmids":["33125369"],"is_preprint":false},{"year":2013,"finding":"Human CCDC124 localizes to the centrosome and cytokinetic midbody. Knockdown of CCDC124 in HeLa cells leads to accumulation of enlarged and multinucleated cells without affecting centrosome maturation. CCDC124 interacts with Ras-guanine nucleotide exchange factor 1B (RasGEF1B), linking CCDC124 to Rap2 signaling at the midbody during cytokinetic abscission.","method":"Immunofluorescence/subcellular localization, siRNA knockdown with phenotypic readout (multinucleated cells), co-immunoprecipitation (interaction with RasGEF1B)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal localization, KD phenotype with specific readout, and Co-IP interaction, single lab but multiple orthogonal methods","pmids":["23894443"],"is_preprint":false},{"year":2021,"finding":"CCDC124 is an RNA-binding protein (RBP) that interacts with various mRNAs as demonstrated by RNA immunoprecipitation (RIP) and RNA-seq experiments.","method":"RNA immunoprecipitation (RIP) followed by RNA-seq","journal":"Cancer biomarkers : section A of Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — RIP-seq is a direct binding assay, but single lab and limited mechanistic follow-up on specific targets","pmids":["33896821"],"is_preprint":false},{"year":2021,"finding":"CCDC124 is a highly disordered protein with low-complexity regions at the N-terminus and an aggregation sequence (151-IAVLSV-156) in the middle region. CCDC124 forms dimers/oligomers predominantly in the cytoplasm, with residue V153 implicated in high-order oligomeric state formation by molecular docking and binding free energy analysis.","method":"In silico protein modeling, co-immunoprecipitation (Co-IP), immunostaining, bimolecular fluorescence complementation (BiFC) in live cells","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, BiFC, and immunostaining confirm dimerization, supported by computational structural analysis; single lab","pmids":["34369007"],"is_preprint":false},{"year":2023,"finding":"CCDC124 interacts with nucleophosmin-1 (Npm1/NPM1) and colocalizes with it in the nucleolus. Nucleolar localization of CCDC124 is impaired when Npm1 translocates from the nucleolus to the nucleoplasm in response to doxorubicin (a DNA-intercalator and Topo2 inhibitor), linking CCDC124 nucleolar localization to Npm1-dependent nucleolar stress-sensing.","method":"LC-MS/MS proteomics (unbiased interactome), co-immunoprecipitation, immunocytochemistry with GFP-tagged CCDC124 in HEK293 and U2OS cells, doxorubicin treatment to induce Npm1 translocation","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — LC-MS/MS interactome plus Co-IP and functional perturbation (drug-induced translocation), single lab","pmids":["38029384"],"is_preprint":false},{"year":2024,"finding":"CCDC124 is present in G3BP1-overexpression-induced stress granules in living U2OS cells, identifying CCDC124 as a novel component of stress granules, membraneless organelles involved in translational shutdown during cellular stress.","method":"Live cell protein imaging using split-GFP (GFP11×4/GFP1-10) tagging and laser scanning confocal microscopy in U2OS cells with G3BP1 overexpression","journal":"The protein journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct live-cell imaging with functional context (stress granule induction), but single lab, single method for stress granule localization","pmids":["39009911"],"is_preprint":false},{"year":2025,"finding":"CCDC124 was identified as an essential regulator of m6A-modified R-loops within phase-separated viral replication compartments during HSV infection; disruption of CCDC124 selectively impairs viral late gene transcription.","method":"Proximity proteomics (split-APEX2 proximity labeling) and functional disruption assay in HSV-infected cells","journal":"Analytical chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling identifies CCDC124 in the interactome; disruption phenotype reported but limited mechanistic detail in abstract; single lab","pmids":["41335005"],"is_preprint":false}],"current_model":"CCDC124 (yeast ortholog Lso2) is a conserved eukaryotic ribosome-binding protein that bridges the mRNA decoding site of the small subunit with the GTPase activating center of the large subunit on translationally inactive (hibernating) ribosomes in the non-rotated state, facilitating Dom34-dependent ribosome recycling and translational recovery after stress; beyond its ribosomal role, CCDC124 is an RNA-binding protein that also localizes to the centrosome, cytokinetic midbody, nucleolus, and stress granules, interacts with RasGEF1B (linking it to Rap2 signaling during cytokinetic abscission) and with NPM1 (linking it to nucleolar stress-sensing), and forms cytoplasmic dimers/oligomers driven by a low-complexity disordered N-terminus."},"narrative":{"mechanistic_narrative":"CCDC124, with its yeast ortholog Lso2, is a conserved eukaryotic ribosome-binding protein that mediates reversible translational inactivation (ribosome hibernation) and recovery after stress [PMID:30208026, PMID:32687489]. On idle ribosomes in the non-rotated state it adopts a bridging conformation that connects the mRNA decoding site of the small subunit with the GTPase activating center of the large subunit, a configuration that — unlike Stm1/SERBP1-bound rotated ribosomes — remains compatible with Dom34-dependent ribosome splitting and recycling [PMID:32687489]. This bridging mode is structurally conserved from microsporidia to humans [PMID:33125369], and loss of the protein causes global translation defects during recovery from stationary phase, with ribosomes accumulating at start codons [PMID:30208026]. CCDC124 is itself an RNA-binding protein that associates with diverse mRNAs [PMID:33896821]. Beyond the ribosome, CCDC124 has discrete subcellular roles: it localizes to the centrosome and cytokinetic midbody, where its depletion produces enlarged multinucleated cells and where it interacts with RasGEF1B, linking it to Rap2 signaling during abscission [PMID:23894443]; it localizes to the nucleolus through interaction with NPM1, with its nucleolar residence depending on NPM1 and lost upon stress-induced NPM1 redistribution [PMID:38029384]; and it is a component of stress granules [PMID:39009911]. The protein is highly disordered, with an N-terminal low-complexity region and a central aggregation motif that drives cytoplasmic dimer/oligomer formation [PMID:34369007].","teleology":[{"year":2018,"claim":"Established that the Lso2/CCDC124 ortholog physically engages the translating ribosome and is functionally required for translational recovery, defining it as a ribosome-associated factor rather than an uncharacterized coiled-coil protein.","evidence":"CLIP, ribosome profiling, and mass spectrometry in lso2Δ yeast with human ortholog crosslinking","pmids":["30208026"],"confidence":"High","gaps":["Did not resolve the structural basis of ribosome binding","Direct mechanism linking start-codon accumulation to Lso2 loss not defined"]},{"year":2020,"claim":"Resolved how CCDC124/Lso2 inactivates ribosomes, showing it bridges the small-subunit decoding site to the large-subunit GTPase center on non-rotated ribosomes and distinguishing it functionally from the Stm1/SERBP1 hibernation mode by permitting Dom34-dependent recycling.","evidence":"Cryo-EM of yeast and human hibernating ribosomes with functional comparison to Stm1/SERBP1","pmids":["32687489"],"confidence":"High","gaps":["Trigger and kinetics of CCDC124 loading/release in vivo not defined","Relationship between hibernation role and non-ribosomal localizations unaddressed"]},{"year":2020,"claim":"Demonstrated cross-kingdom conservation of the bridging mechanism, establishing the reversible ribosome inactivation function as a general eukaryotic property.","evidence":"Cryo-EM of Paranosema locustae (microsporidian) hibernating ribosomes","pmids":["33125369"],"confidence":"High","gaps":["Does not address human-specific regulation or non-ribosomal functions"]},{"year":2013,"claim":"Linked CCDC124 to cell division, showing it localizes to the centrosome and midbody and is required for cytokinetic abscission via interaction with RasGEF1B/Rap2 signaling.","evidence":"Immunofluorescence, siRNA knockdown with multinucleation readout, and Co-IP in HeLa cells","pmids":["23894443"],"confidence":"Medium","gaps":["RasGEF1B interaction from single-lab Co-IP without reciprocal validation","Mechanistic connection between ribosomal and cytokinetic roles unknown"]},{"year":2021,"claim":"Identified CCDC124 as an RNA-binding protein associating with cellular mRNAs, consistent with a broader role in RNA metabolism beyond the ribosome.","evidence":"RIP followed by RNA-seq","pmids":["33896821"],"confidence":"Medium","gaps":["No specific functional mRNA targets validated","Binding determinants and sequence specificity unknown"]},{"year":2021,"claim":"Characterized the biophysical basis of CCDC124 self-association, showing a disordered N-terminus and central aggregation motif drive cytoplasmic dimer/oligomer formation.","evidence":"In silico modeling, Co-IP, BiFC, and immunostaining in live cells","pmids":["34369007"],"confidence":"Medium","gaps":["Functional consequence of oligomerization not established","V153 role inferred from docking rather than mutagenesis in cells"]},{"year":2023,"claim":"Connected CCDC124 to nucleolar stress sensing by showing its nucleolar localization depends on NPM1 and is lost upon stress-induced NPM1 redistribution.","evidence":"LC-MS/MS interactome, Co-IP, and immunocytochemistry with doxorubicin-induced NPM1 translocation in HEK293/U2OS cells","pmids":["38029384"],"confidence":"Medium","gaps":["Functional role of CCDC124 in the nucleolus undefined","Single lab; NPM1 interaction not reciprocally validated"]},{"year":2024,"claim":"Placed CCDC124 within stress granules, the membraneless organelles of translational shutdown, consistent with its hibernation and RNA-binding roles.","evidence":"Split-GFP live-cell imaging in U2OS cells with G3BP1 overexpression","pmids":["39009911"],"confidence":"Medium","gaps":["Single method for stress-granule localization","Whether CCDC124 affects stress-granule assembly or dynamics untested"]},{"year":2025,"claim":"Implicated CCDC124 in viral late gene transcription via m6A-modified R-loops in phase-separated viral replication compartments.","evidence":"Split-APEX2 proximity labeling and functional disruption in HSV-infected cells","pmids":["41335005"],"confidence":"Low","gaps":["Proximity labeling does not establish direct interaction","Limited mechanistic detail; not independently confirmed"]},{"year":null,"claim":"How CCDC124's ribosome-hibernation role mechanistically integrates with its distinct localizations at the centrosome/midbody, nucleolus, and stress granules — and whether these reflect one coordinated stress-response program or independent functions — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism linking ribosomal and non-ribosomal pools","Regulatory signals controlling CCDC124 partitioning unknown","No structural data on non-ribosomal complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["RASGEF1B","NPM1","G3BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CT7","full_name":"Coiled-coil domain-containing protein 124","aliases":[],"length_aa":223,"mass_kda":25.8,"function":"Ribosome-binding protein involved in ribosome hibernation: associates with translationally inactive ribosomes and stabilizes the nonrotated conformation of the 80S ribosome, thereby promoting ribosome preservation and storage (PubMed:32687489). Also required for proper progression of late cytokinetic stages (PubMed:23894443)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Midbody","url":"https://www.uniprot.org/uniprotkb/Q96CT7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC124","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RPL19","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0},{"gene":"PSPC1","stoichiometry":4.0},{"gene":"RPL11","stoichiometry":4.0},{"gene":"RPL4","stoichiometry":4.0},{"gene":"SRP68","stoichiometry":4.0},{"gene":"SRP9","stoichiometry":4.0},{"gene":"ABCE1","stoichiometry":0.2},{"gene":"ATG13","stoichiometry":0.2},{"gene":"ATG4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CCDC124","total_profiled":1310},"omim":[{"mim_id":"621286","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 124; CCDC124","url":"https://www.omim.org/entry/621286"},{"mim_id":"614532","title":"RASGEF DOMAIN FAMILY, MEMBER 1B; RASGEF1B","url":"https://www.omim.org/entry/614532"},{"mim_id":"164040","title":"NUCLEOPHOSMIN/NUCLEOPLASMIN FAMILY, MEMBER 1; NPM1","url":"https://www.omim.org/entry/164040"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC124"},"hgnc":{"alias_symbol":["Lso2","oxs1"],"prev_symbol":[]},"alphafold":{"accession":"Q96CT7","domains":[{"cath_id":"-","chopping":"164-212","consensus_level":"high","plddt":86.4833,"start":164,"end":212}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CT7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CT7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CT7-F1-predicted_aligned_error_v6.png","plddt_mean":79.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC124","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC124"},"sequence":{"accession":"Q96CT7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CT7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CT7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CT7"}},"corpus_meta":[{"pmid":"32687489","id":"PMC_32687489","title":"Structure and function of yeast 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Deletion of LSO2 causes global translation defects during recovery from stationary phase, with ribosomes accumulating at start codons, depleted from stop codons, and showing codon-specific occupancy changes.\",\n      \"method\": \"Quantitative mass spectrometry (ribosome identification), genome-wide crosslinking and immunoprecipitation (CLIP), ribosome profiling of lso2Δ yeast\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CLIP, ribosome profiling, mass spectrometry), replicated with human CCDC124 ortholog crosslinking, single rigorous study\",\n      \"pmids\": [\"30208026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structures of translationally inactive yeast and human ribosomes show Lso2/CCDC124 accumulates on idle ribosomes in the non-rotated state and bridges the decoding site of the small subunit with the GTPase activating center (GAC) of the large subunit, in contrast to Stm1/SERBP1-bound ribosomes which are in the rotated state. Lso2-containing ribosomes are compatible with Dom34-dependent ribosome recycling (splitting), whereas Stm1-containing ribosomes are not.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structural determination of yeast and human hibernating ribosomes\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structures for both yeast and human ribosomes, functional comparison with Stm1/SERBP1 system, two organisms studied in one rigorous paper\",\n      \"pmids\": [\"32687489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The microsporidian Lso2 homolog adopts a V-shaped conformation to bridge the mRNA decoding site and the large subunit tRNA binding sites in Paranosema locustae ribosomes, providing a conserved reversible ribosome inactivation mechanism consistent with the eukaryotic hibernation function of CCDC124/Lso2.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structural determination of P. locustae hibernating ribosomes\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional interpretation, independently replicates the bridging mechanism shown in yeast and human structures\",\n      \"pmids\": [\"33125369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human CCDC124 localizes to the centrosome and cytokinetic midbody. Knockdown of CCDC124 in HeLa cells leads to accumulation of enlarged and multinucleated cells without affecting centrosome maturation. CCDC124 interacts with Ras-guanine nucleotide exchange factor 1B (RasGEF1B), linking CCDC124 to Rap2 signaling at the midbody during cytokinetic abscission.\",\n      \"method\": \"Immunofluorescence/subcellular localization, siRNA knockdown with phenotypic readout (multinucleated cells), co-immunoprecipitation (interaction with RasGEF1B)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal localization, KD phenotype with specific readout, and Co-IP interaction, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23894443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCDC124 is an RNA-binding protein (RBP) that interacts with various mRNAs as demonstrated by RNA immunoprecipitation (RIP) and RNA-seq experiments.\",\n      \"method\": \"RNA immunoprecipitation (RIP) followed by RNA-seq\",\n      \"journal\": \"Cancer biomarkers : section A of Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — RIP-seq is a direct binding assay, but single lab and limited mechanistic follow-up on specific targets\",\n      \"pmids\": [\"33896821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CCDC124 is a highly disordered protein with low-complexity regions at the N-terminus and an aggregation sequence (151-IAVLSV-156) in the middle region. CCDC124 forms dimers/oligomers predominantly in the cytoplasm, with residue V153 implicated in high-order oligomeric state formation by molecular docking and binding free energy analysis.\",\n      \"method\": \"In silico protein modeling, co-immunoprecipitation (Co-IP), immunostaining, bimolecular fluorescence complementation (BiFC) in live cells\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, BiFC, and immunostaining confirm dimerization, supported by computational structural analysis; single lab\",\n      \"pmids\": [\"34369007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC124 interacts with nucleophosmin-1 (Npm1/NPM1) and colocalizes with it in the nucleolus. Nucleolar localization of CCDC124 is impaired when Npm1 translocates from the nucleolus to the nucleoplasm in response to doxorubicin (a DNA-intercalator and Topo2 inhibitor), linking CCDC124 nucleolar localization to Npm1-dependent nucleolar stress-sensing.\",\n      \"method\": \"LC-MS/MS proteomics (unbiased interactome), co-immunoprecipitation, immunocytochemistry with GFP-tagged CCDC124 in HEK293 and U2OS cells, doxorubicin treatment to induce Npm1 translocation\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — LC-MS/MS interactome plus Co-IP and functional perturbation (drug-induced translocation), single lab\",\n      \"pmids\": [\"38029384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC124 is present in G3BP1-overexpression-induced stress granules in living U2OS cells, identifying CCDC124 as a novel component of stress granules, membraneless organelles involved in translational shutdown during cellular stress.\",\n      \"method\": \"Live cell protein imaging using split-GFP (GFP11×4/GFP1-10) tagging and laser scanning confocal microscopy in U2OS cells with G3BP1 overexpression\",\n      \"journal\": \"The protein journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct live-cell imaging with functional context (stress granule induction), but single lab, single method for stress granule localization\",\n      \"pmids\": [\"39009911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC124 was identified as an essential regulator of m6A-modified R-loops within phase-separated viral replication compartments during HSV infection; disruption of CCDC124 selectively impairs viral late gene transcription.\",\n      \"method\": \"Proximity proteomics (split-APEX2 proximity labeling) and functional disruption assay in HSV-infected cells\",\n      \"journal\": \"Analytical chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling identifies CCDC124 in the interactome; disruption phenotype reported but limited mechanistic detail in abstract; single lab\",\n      \"pmids\": [\"41335005\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC124 (yeast ortholog Lso2) is a conserved eukaryotic ribosome-binding protein that bridges the mRNA decoding site of the small subunit with the GTPase activating center of the large subunit on translationally inactive (hibernating) ribosomes in the non-rotated state, facilitating Dom34-dependent ribosome recycling and translational recovery after stress; beyond its ribosomal role, CCDC124 is an RNA-binding protein that also localizes to the centrosome, cytokinetic midbody, nucleolus, and stress granules, interacts with RasGEF1B (linking it to Rap2 signaling during cytokinetic abscission) and with NPM1 (linking it to nucleolar stress-sensing), and forms cytoplasmic dimers/oligomers driven by a low-complexity disordered N-terminus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC124, with its yeast ortholog Lso2, is a conserved eukaryotic ribosome-binding protein that mediates reversible translational inactivation (ribosome hibernation) and recovery after stress [#0, #1]. On idle ribosomes in the non-rotated state it adopts a bridging conformation that connects the mRNA decoding site of the small subunit with the GTPase activating center of the large subunit, a configuration that — unlike Stm1/SERBP1-bound rotated ribosomes — remains compatible with Dom34-dependent ribosome splitting and recycling [#1]. This bridging mode is structurally conserved from microsporidia to humans [#2], and loss of the protein causes global translation defects during recovery from stationary phase, with ribosomes accumulating at start codons [#0]. CCDC124 is itself an RNA-binding protein that associates with diverse mRNAs [#4]. Beyond the ribosome, CCDC124 has discrete subcellular roles: it localizes to the centrosome and cytokinetic midbody, where its depletion produces enlarged multinucleated cells and where it interacts with RasGEF1B, linking it to Rap2 signaling during abscission [#3]; it localizes to the nucleolus through interaction with NPM1, with its nucleolar residence depending on NPM1 and lost upon stress-induced NPM1 redistribution [#6]; and it is a component of stress granules [#7]. The protein is highly disordered, with an N-terminal low-complexity region and a central aggregation motif that drives cytoplasmic dimer/oligomer formation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established that the Lso2/CCDC124 ortholog physically engages the translating ribosome and is functionally required for translational recovery, defining it as a ribosome-associated factor rather than an uncharacterized coiled-coil protein.\",\n      \"evidence\": \"CLIP, ribosome profiling, and mass spectrometry in lso2\\u0394 yeast with human ortholog crosslinking\",\n      \"pmids\": [\"30208026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of ribosome binding\", \"Direct mechanism linking start-codon accumulation to Lso2 loss not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved how CCDC124/Lso2 inactivates ribosomes, showing it bridges the small-subunit decoding site to the large-subunit GTPase center on non-rotated ribosomes and distinguishing it functionally from the Stm1/SERBP1 hibernation mode by permitting Dom34-dependent recycling.\",\n      \"evidence\": \"Cryo-EM of yeast and human hibernating ribosomes with functional comparison to Stm1/SERBP1\",\n      \"pmids\": [\"32687489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and kinetics of CCDC124 loading/release in vivo not defined\", \"Relationship between hibernation role and non-ribosomal localizations unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated cross-kingdom conservation of the bridging mechanism, establishing the reversible ribosome inactivation function as a general eukaryotic property.\",\n      \"evidence\": \"Cryo-EM of Paranosema locustae (microsporidian) hibernating ribosomes\",\n      \"pmids\": [\"33125369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address human-specific regulation or non-ribosomal functions\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CCDC124 to cell division, showing it localizes to the centrosome and midbody and is required for cytokinetic abscission via interaction with RasGEF1B/Rap2 signaling.\",\n      \"evidence\": \"Immunofluorescence, siRNA knockdown with multinucleation readout, and Co-IP in HeLa cells\",\n      \"pmids\": [\"23894443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RasGEF1B interaction from single-lab Co-IP without reciprocal validation\", \"Mechanistic connection between ribosomal and cytokinetic roles unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CCDC124 as an RNA-binding protein associating with cellular mRNAs, consistent with a broader role in RNA metabolism beyond the ribosome.\",\n      \"evidence\": \"RIP followed by RNA-seq\",\n      \"pmids\": [\"33896821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No specific functional mRNA targets validated\", \"Binding determinants and sequence specificity unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterized the biophysical basis of CCDC124 self-association, showing a disordered N-terminus and central aggregation motif drive cytoplasmic dimer/oligomer formation.\",\n      \"evidence\": \"In silico modeling, Co-IP, BiFC, and immunostaining in live cells\",\n      \"pmids\": [\"34369007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of oligomerization not established\", \"V153 role inferred from docking rather than mutagenesis in cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected CCDC124 to nucleolar stress sensing by showing its nucleolar localization depends on NPM1 and is lost upon stress-induced NPM1 redistribution.\",\n      \"evidence\": \"LC-MS/MS interactome, Co-IP, and immunocytochemistry with doxorubicin-induced NPM1 translocation in HEK293/U2OS cells\",\n      \"pmids\": [\"38029384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of CCDC124 in the nucleolus undefined\", \"Single lab; NPM1 interaction not reciprocally validated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed CCDC124 within stress granules, the membraneless organelles of translational shutdown, consistent with its hibernation and RNA-binding roles.\",\n      \"evidence\": \"Split-GFP live-cell imaging in U2OS cells with G3BP1 overexpression\",\n      \"pmids\": [\"39009911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method for stress-granule localization\", \"Whether CCDC124 affects stress-granule assembly or dynamics untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated CCDC124 in viral late gene transcription via m6A-modified R-loops in phase-separated viral replication compartments.\",\n      \"evidence\": \"Split-APEX2 proximity labeling and functional disruption in HSV-infected cells\",\n      \"pmids\": [\"41335005\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Proximity labeling does not establish direct interaction\", \"Limited mechanistic detail; not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCDC124's ribosome-hibernation role mechanistically integrates with its distinct localizations at the centrosome/midbody, nucleolus, and stress granules — and whether these reflect one coordinated stress-response program or independent functions — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism linking ribosomal and non-ribosomal pools\", \"Regulatory signals controlling CCDC124 partitioning unknown\", \"No structural data on non-ribosomal complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RasGEF1B\", \"NPM1\", \"G3BP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}