{"gene":"CEP131","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2012,"finding":"CEP131/AZI1 is recruited to centriolar satellites by PCM1, and localised to the centriolar core region by both pericentrin and Cep290. Centrosomal localisation of Cep131 is cell-cycle-regulated and requires both an intact microtubule network and a functional dynein-dynactin transport system. Depletion of Cep131 results in reduced proliferation, centriole amplification, increased multipolar mitosis, chromosomal instability, and post-mitotic DNA damage.","method":"siRNA knockdown, immunofluorescence, co-localisation studies, cell-cycle analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, IF, functional readouts) in a single study with clear mechanistic pathway placement","pmids":["22797915"],"is_preprint":false},{"year":2013,"finding":"Azi1/Cep131 localises to centriolar satellites and traffics along microtubules to become enriched around the basal body; it also localises to the transition zone. Acute siRNA knockdown in mouse fibroblasts causes robust reduction in ciliogenesis, rescued by siRNA-resistant Azi1-GFP. In Azi1 null mice, spermatid manchette and flagella show microtubule-based trafficking defects leading to male infertility, demonstrating a conserved non-essential trafficking role in ciliogenesis and an essential role in flagellogenesis.","method":"siRNA knockdown, live imaging/localisation, gene-trap null mouse, rescue with siRNA-resistant GFP fusion","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic rescue, KO mouse phenotype, and live-imaging localisation across multiple labs/methods","pmids":["24415959"],"is_preprint":false},{"year":2009,"finding":"Cep131 depletion in zebrafish embryos results in shortened cilia in multiple tissues, kidney and ear developmental defects, and randomised left-right asymmetry, phenocopying intraflagellar transport mutants; centrosomes and basal bodies remain present, indicating Cep131 contributes to cilia length/axoneme formation.","method":"Morpholino knockdown in zebrafish embryos, ciliary imaging, phenotypic analysis","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — morpholino KD with specific ciliary phenotype readout in a vertebrate model, single study","pmids":["19254375"],"is_preprint":false},{"year":2011,"finding":"The Drosophila CEP131 ortholog Dilatory (DILA) localises to the ciliary base including basal body and transition zone, is required for ciliogenesis in sensory neurons and sperm, and genetically interacts with the ciliary coiled-coil protein Uncoordinated, implicating it in regulating intraflagellar transport at the ciliary base.","method":"Drosophila loss-of-function mutants, immunolocalisation, genetic epistasis with Uncoordinated","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function genetics, localization, and genetic interaction in ortholog model organism, replicated phenotype across tissues","pmids":["21750193"],"is_preprint":false},{"year":2014,"finding":"AZI1/CEP131 interacts with the BBSome through direct binding to BBS4. AZI1 is not required for BBSome assembly, but its depletion enhances BBSome accumulation in cilia. AZI1 knockdown restores BBSome trafficking to cilia in BBS3- or BBS5-depleted cells where the BBSome cannot normally enter cilia.","method":"Co-immunoprecipitation, siRNA knockdown, ciliary trafficking assays, zebrafish morpholino knockdown","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP identifying binding partner (BBS4), functional epistasis in mammalian cells and zebrafish","pmids":["24550735"],"is_preprint":false},{"year":2015,"finding":"CEP131 is a direct substrate of the p38 effector kinase MK2; MK2 phosphorylates CEP131 at S47 and S78. UV-induced phosphorylation of these residues creates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm, blocking new centriolar satellite formation and causing rapid depletion of centriolar satellites. Mutation of S47 and S78 abolishes stress-induced centriolar satellite reorganisation.","method":"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation with 14-3-3, immunofluorescence, UV stress experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay combined with mutagenesis and functional rescue in cells; multiple orthogonal approaches","pmids":["26616734"],"is_preprint":false},{"year":2019,"finding":"PLK4 directly phosphorylates CEP131 at Ser-78 in vitro and in cells. PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication but is essential for maintaining the integrity of centriolar satellites. PLK4 inhibition or non-phosphorylatable CEP131-S78A causes dispersed satellites; phosphomimetic S78D promotes satellite aggregation.","method":"Analog-sensitive PLK4 phosphoproteomic screen, in vitro kinase assay, phospho-site mutagenesis, immunofluorescence microscopy, RPE-1 cell engineering","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro kinase assay plus mutagenesis with specific functional readout (satellite integrity)","pmids":["30804208"],"is_preprint":false},{"year":2024,"finding":"Cep131 forms a module with Cep162 near the axoneme at the basal body, and together with the Cby-Fam92 module cooperatively maintains Cep290 at the basal body and initiates ciliogenesis in Drosophila. Concurrent deletion of any protein in the Cep131-Cep162 module and the Cby-Fam92 module causes complete loss of Cep290 from the basal body and blocks ciliogenesis at its initiation stage.","method":"Drosophila genetics (double mutants), immunolocalisation, epistasis analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila ortholog model with clear localization and functional readouts; single study","pmids":["38442096"],"is_preprint":false},{"year":1997,"finding":"The mouse AZ1 protein (CEP131) is localised to the preacrosome region of spermatids; its gene is transcribed beginning in pachytene spermatocytes. The 5'-proximal region constitutes a CpG island and gene expression is induced by 5-azacytidine (DNA demethylation) in fibroblasts.","method":"Immunolocalisation, genomic cloning, RT-PCR, 5-azacytidine treatment","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 — localization with developmental context, single study, no further mechanistic follow-up","pmids":["9070930"],"is_preprint":false},{"year":2022,"finding":"CEP131 interacts with the transcription factor ARID3A in liver cancer cells and the ARID3A/CEP131 complex co-occupies the KDM3A promoter to transcriptionally activate KDM3A, which then demethylates H3K9me2 to upregulate embryonic stem cell-like signature genes, promoting cancer cell viability and metastasis.","method":"Co-immunoprecipitation, ChIP assay, loss-of-function/gain-of-function in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP identifying binding partner, ChIP demonstrating co-occupancy at promoter, functional rescue; single study","pmids":["36008383"],"is_preprint":false},{"year":2024,"finding":"CEP131-positive centriolar satellites promote local translation at centrosomes. The RNA binding protein Unkempt localises to Cep131-positive centriolar satellites and is required for Plk4-induced centriole overduplication in an RNA-binding-dependent manner, with Unk and Cep131 together promoting localised translation near centrosomes.","method":"Fluorescence microscopy, genetic knockdown, RNA binding domain mutagenesis, translation reporters at centrosomes","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, localisation and co-localisation data, KD phenotype; mechanistic link to CEP131 is indirect","pmids":["bio_10.1101_2024.07.29.605660"],"is_preprint":true},{"year":2020,"finding":"MDM2 interacts with CEP131 and promotes its protein degradation; overexpression of CEP131 accelerates neuroblastoma cell growth and confers resistance to CHK1 inhibitor-induced replication defects.","method":"Mass spectrometry (MDM2-binding proteins), overexpression studies, cell growth assays","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 — single pulldown/MS identification of MDM2-CEP131 interaction, overexpression phenotype without full mechanistic dissection","pmids":["33014050"],"is_preprint":false}],"current_model":"CEP131/AZI1 is a centriolar satellite protein that traffics along microtubules (via dynein-dynactin) to the basal body and transition zone, where it is recruited to satellites by PCM1 and anchored at the centriolar core by pericentrin and Cep290; it regulates BBSome ciliary trafficking through direct interaction with BBS4, supports ciliogenesis and flagellogenesis through a conserved microtubule-based trafficking role, cooperates with Cep162 to maintain Cep290 at the basal body for ciliogenesis initiation, and its centriolar satellite residency is dynamically controlled by two kinase cascades: MK2 phosphorylates S47/S78 under stress to recruit 14-3-3 proteins that sequester CEP131 in the cytoplasm (dispersing satellites), while PLK4 phosphorylates S78 to maintain satellite structural integrity under normal conditions."},"narrative":{"teleology":[{"year":1997,"claim":"Initial characterization placed CEP131 in the male germline, establishing its expression in spermatogenesis and localization to the preacrosome region of spermatids, but its molecular function was unknown.","evidence":"Immunolocalization and RT-PCR in mouse spermatids and fibroblasts","pmids":["9070930"],"confidence":"Medium","gaps":["No functional data beyond localization","Mechanism of preacrosomal targeting unknown","No connection to centrosomes or cilia yet recognized"]},{"year":2009,"claim":"Zebrafish knockdown revealed that CEP131 is required for proper cilia length and axoneme formation across multiple tissues, establishing it as a ciliary gene rather than merely a spermatogenesis factor.","evidence":"Morpholino knockdown in zebrafish embryos with ciliary imaging and laterality phenotyping","pmids":["19254375"],"confidence":"Medium","gaps":["Morpholino-only approach without genetic confirmation","Molecular mechanism of cilia shortening not defined","Whether CEP131 acts cell-autonomously was untested"]},{"year":2011,"claim":"The Drosophila ortholog Dilatory was shown to localize to the basal body and transition zone and to be required for ciliogenesis and sperm motility, establishing an evolutionarily conserved role at the ciliary base and a genetic link to intraflagellar transport.","evidence":"Drosophila loss-of-function mutants with immunolocalization and genetic epistasis with Uncoordinated","pmids":["21750193"],"confidence":"High","gaps":["Direct biochemical partners at the ciliary base not identified","Mechanism of IFT regulation unresolved"]},{"year":2012,"claim":"CEP131 was placed within the centriolar satellite protein network: PCM1 recruits it to satellites, pericentrin and Cep290 anchor it at the centriolar core, and its transport requires microtubules and dynein-dynactin, establishing a mechanistic framework for its satellite-dependent functions.","evidence":"siRNA knockdown, immunofluorescence, co-localization, and cell-cycle analysis in human cells","pmids":["22797915"],"confidence":"High","gaps":["Direct physical interactions among PCM1/pericentrin/Cep290 and CEP131 not biochemically demonstrated","Precise cell-cycle signals regulating CEP131 localization unknown"]},{"year":2013,"claim":"Live imaging and a null mouse demonstrated that CEP131 traffics along microtubules to the basal body, is required for efficient ciliogenesis (rescued by siRNA-resistant construct), and is essential for spermatid manchette and flagella formation, unifying its roles in cilia and male fertility.","evidence":"siRNA knockdown with genetic rescue in mouse fibroblasts; gene-trap null mouse phenotyping","pmids":["24415959"],"confidence":"High","gaps":["Cargo carried by CEP131 during microtubule-based trafficking not identified","Whether ciliogenesis defect is indirect via satellite disruption versus direct at the basal body undetermined"]},{"year":2014,"claim":"CEP131 was identified as a BBSome regulator through direct binding to BBS4, revealing it restrains BBSome ciliary entry and acts as a negative regulator of BBS-dependent ciliary trafficking.","evidence":"Reciprocal co-immunoprecipitation, siRNA epistasis in mammalian cells, zebrafish morpholino knockdown","pmids":["24550735"],"confidence":"High","gaps":["Structural basis of CEP131-BBS4 interaction undefined","Whether CEP131 regulates other ciliary trafficking complexes beyond the BBSome untested"]},{"year":2015,"claim":"The p38-MK2 stress kinase pathway was shown to directly phosphorylate CEP131 at S47 and S78, creating 14-3-3 binding sites that sequester CEP131 in the cytoplasm and disperse centriolar satellites, establishing the first signaling mechanism controlling satellite dynamics through CEP131.","evidence":"In vitro kinase assay, phospho-site mutagenesis, co-IP with 14-3-3, UV stress in human cells","pmids":["26616734"],"confidence":"High","gaps":["Whether 14-3-3 sequestration affects ciliogenesis under stress not tested","Additional phosphorylation sites and kinases potentially involved"]},{"year":2019,"claim":"PLK4 was identified as a second kinase phosphorylating CEP131 at Ser-78 under basal conditions, with this modification being essential for centriolar satellite structural integrity but dispensable for ciliogenesis and centriole duplication, revealing that the same phosphosite is read differently depending on kinase context.","evidence":"Analog-sensitive PLK4 phosphoproteomics, in vitro kinase assay, phospho-site mutagenesis in RPE-1 cells","pmids":["30804208"],"confidence":"High","gaps":["How cells distinguish MK2-mediated vs PLK4-mediated phosphorylation at the same site is unresolved","Downstream effectors of satellite integrity maintenance unknown"]},{"year":2022,"claim":"A non-centrosomal function was reported: CEP131 interacts with ARID3A to co-occupy the KDM3A promoter and transcriptionally activate a histone demethylase cascade in liver cancer cells, suggesting CEP131 has nuclear roles beyond its satellite function.","evidence":"Co-immunoprecipitation, ChIP assay, gain/loss-of-function in hepatocellular carcinoma cells and xenografts","pmids":["36008383"],"confidence":"Medium","gaps":["Nuclear localization of endogenous CEP131 not independently confirmed","Whether transcriptional role is widespread or cancer-specific is unknown","Single study without replication"]},{"year":2024,"claim":"Drosophila genetics revealed that CEP131 forms a cooperative module with Cep162 that, together with the Cby-Fam92 module, maintains Cep290 at the basal body to initiate ciliogenesis, placing CEP131 in a defined epistatic hierarchy for ciliogenesis initiation.","evidence":"Drosophila double-mutant genetics, immunolocalization, epistasis analysis","pmids":["38442096"],"confidence":"Medium","gaps":["Direct physical interaction between CEP131 and Cep162 not biochemically demonstrated","Whether this modular architecture is conserved in mammals untested","Single study in Drosophila"]},{"year":null,"claim":"Key unresolved questions include the identity of cargoes transported by CEP131 along microtubules to the basal body, the structural basis of its interactions with BBS4 and satellite components, and whether its reported nuclear/transcriptional functions represent a bona fide second role or an overexpression artifact.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cargo identified for CEP131 microtubule-based trafficking","No structural model of CEP131 or its complexes","Nuclear role lacks independent replication"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,3,6]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2,3,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]}],"complexes":["centriolar satellites"],"partners":["PCM1","CEP290","BBS4","CEP162","ARID3A","YWHAB"],"other_free_text":[]},"mechanistic_narrative":"CEP131 (AZI1) is a centriolar satellite protein that functions as a microtubule-dependent trafficking factor essential for ciliogenesis, flagellogenesis, and centriolar satellite integrity. CEP131 is recruited to centriolar satellites by PCM1 and anchored at the centriolar core by pericentrin and Cep290; it traffics along microtubules via dynein-dynactin to the basal body and transition zone, where it cooperates with Cep162 to maintain Cep290 and initiate ciliogenesis [PMID:22797915, PMID:24415959, PMID:38442096]. CEP131 regulates BBSome ciliary entry through direct interaction with BBS4, acting as a gatekeeper that restrains BBSome accumulation in cilia [PMID:24550735]. Its satellite residency is dynamically controlled by phosphorylation at Ser-78 by both MK2 (stress-induced, creating 14-3-3 binding sites that sequester CEP131 cytoplasmically and disperse satellites) and PLK4 (maintaining satellite structural integrity under basal conditions) [PMID:26616734, PMID:30804208]."},"prefetch_data":{"uniprot":{"accession":"Q9UPN4","full_name":"Centrosomal protein of 131 kDa","aliases":["5-azacytidine-induced protein 1","Pre-acrosome localization protein 1"],"length_aa":1083,"mass_kda":122.1,"function":"Component of centriolar satellites contributing to the building of a complex and dynamic network required to regulate cilia/flagellum formation (PubMed:17954613, PubMed:24185901). In proliferating cells, MIB1-mediated ubiquitination induces its sequestration within centriolar satellites, precluding untimely cilia formation initiation (PubMed:24121310). In contrast, during normal and ultraviolet or heat shock cellular stress-induced ciliogenesis, its non-ubiquitinated form is rapidly displaced from centriolar satellites and recruited to centrosome/basal bodies in a microtubule- and p38 MAPK-dependent manner (PubMed:24121310, PubMed:26616734). Also acts as a negative regulator of BBSome ciliary trafficking (PubMed:24550735). Plays a role in sperm flagellar formation; may be involved in the regulation of intraflagellar transport (IFT) and/or intramanchette (IMT) trafficking, which are important for axoneme extension and/or cargo delivery to the nascent sperm tail (By similarity). Required for optimal cell proliferation and cell cycle progression; may play a role in the regulation of genome stability in non-ciliogenic cells (PubMed:22797915, PubMed:26297806). Involved in centriole duplication (By similarity). Required for CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:26297806). Essential for maintaining proper centriolar satellite integrity (PubMed:30804208)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasmic vesicle, secretory vesicle, acrosome","url":"https://www.uniprot.org/uniprotkb/Q9UPN4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP131","classification":"Common Essential","n_dependent_lines":692,"n_total_lines":1208,"dependency_fraction":0.5728476821192053},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141577","cell_line_id":"CID000196","localizations":[{"compartment":"centrosome","grade":3}],"interactors":[{"gene":"CALM3","stoichiometry":0.2},{"gene":"PCM1","stoichiometry":0.2},{"gene":"MAP4","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000196","total_profiled":1310},"omim":[{"mim_id":"620676","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 61; CCDC61","url":"https://www.omim.org/entry/620676"},{"mim_id":"618631","title":"NRDE2, NECESSARY FOR RNA INTERFERENCE, DOMAIN CONTAINING; NRDE2","url":"https://www.omim.org/entry/618631"},{"mim_id":"613479","title":"CENTROSOMAL PROTEIN 131; CEP131","url":"https://www.omim.org/entry/613479"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centriolar satellite","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Flagellar centriole","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP131"},"hgnc":{"alias_symbol":["AZ1","KIAA1118"],"prev_symbol":["AZI1"]},"alphafold":{"accession":"Q9UPN4","domains":[{"cath_id":"-","chopping":"720-922","consensus_level":"medium","plddt":96.1746,"start":720,"end":922},{"cath_id":"1.20.5","chopping":"957-1005","consensus_level":"medium","plddt":83.7894,"start":957,"end":1005}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPN4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPN4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPN4-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP131","jax_strain_url":"https://www.jax.org/strain/search?query=CEP131"},"sequence":{"accession":"Q9UPN4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPN4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPN4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPN4"}},"corpus_meta":[{"pmid":"23602565","id":"PMC_23602565","title":"A 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gene.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/22310384","citation_count":2,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.29.605660","title":"The Unkempt RNA binding protein reveals a local translation program in centriole overduplication","date":"2024-07-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.29.605660","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.05.658137","title":"Drought stress modulates the molecular response of Arabidopsis plants to root-knot nematode infection","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.05.658137","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13209,"output_tokens":3069,"usd":0.042831},"stage2":{"model":"claude-opus-4-6","input_tokens":6411,"output_tokens":2611,"usd":0.145995},"total_usd":0.188826,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"CEP131/AZI1 is recruited to centriolar satellites by PCM1, and localised to the centriolar core region by both pericentrin and Cep290. Centrosomal localisation of Cep131 is cell-cycle-regulated and requires both an intact microtubule network and a functional dynein-dynactin transport system. Depletion of Cep131 results in reduced proliferation, centriole amplification, increased multipolar mitosis, chromosomal instability, and post-mitotic DNA damage.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, co-localisation studies, cell-cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, IF, functional readouts) in a single study with clear mechanistic pathway placement\",\n      \"pmids\": [\"22797915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Azi1/Cep131 localises to centriolar satellites and traffics along microtubules to become enriched around the basal body; it also localises to the transition zone. Acute siRNA knockdown in mouse fibroblasts causes robust reduction in ciliogenesis, rescued by siRNA-resistant Azi1-GFP. In Azi1 null mice, spermatid manchette and flagella show microtubule-based trafficking defects leading to male infertility, demonstrating a conserved non-essential trafficking role in ciliogenesis and an essential role in flagellogenesis.\",\n      \"method\": \"siRNA knockdown, live imaging/localisation, gene-trap null mouse, rescue with siRNA-resistant GFP fusion\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic rescue, KO mouse phenotype, and live-imaging localisation across multiple labs/methods\",\n      \"pmids\": [\"24415959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Cep131 depletion in zebrafish embryos results in shortened cilia in multiple tissues, kidney and ear developmental defects, and randomised left-right asymmetry, phenocopying intraflagellar transport mutants; centrosomes and basal bodies remain present, indicating Cep131 contributes to cilia length/axoneme formation.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos, ciliary imaging, phenotypic analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — morpholino KD with specific ciliary phenotype readout in a vertebrate model, single study\",\n      \"pmids\": [\"19254375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Drosophila CEP131 ortholog Dilatory (DILA) localises to the ciliary base including basal body and transition zone, is required for ciliogenesis in sensory neurons and sperm, and genetically interacts with the ciliary coiled-coil protein Uncoordinated, implicating it in regulating intraflagellar transport at the ciliary base.\",\n      \"method\": \"Drosophila loss-of-function mutants, immunolocalisation, genetic epistasis with Uncoordinated\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function genetics, localization, and genetic interaction in ortholog model organism, replicated phenotype across tissues\",\n      \"pmids\": [\"21750193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AZI1/CEP131 interacts with the BBSome through direct binding to BBS4. AZI1 is not required for BBSome assembly, but its depletion enhances BBSome accumulation in cilia. AZI1 knockdown restores BBSome trafficking to cilia in BBS3- or BBS5-depleted cells where the BBSome cannot normally enter cilia.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ciliary trafficking assays, zebrafish morpholino knockdown\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP identifying binding partner (BBS4), functional epistasis in mammalian cells and zebrafish\",\n      \"pmids\": [\"24550735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEP131 is a direct substrate of the p38 effector kinase MK2; MK2 phosphorylates CEP131 at S47 and S78. UV-induced phosphorylation of these residues creates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm, blocking new centriolar satellite formation and causing rapid depletion of centriolar satellites. Mutation of S47 and S78 abolishes stress-induced centriolar satellite reorganisation.\",\n      \"method\": \"In vitro kinase assay, phospho-site mutagenesis, co-immunoprecipitation with 14-3-3, immunofluorescence, UV stress experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay combined with mutagenesis and functional rescue in cells; multiple orthogonal approaches\",\n      \"pmids\": [\"26616734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLK4 directly phosphorylates CEP131 at Ser-78 in vitro and in cells. PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication but is essential for maintaining the integrity of centriolar satellites. PLK4 inhibition or non-phosphorylatable CEP131-S78A causes dispersed satellites; phosphomimetic S78D promotes satellite aggregation.\",\n      \"method\": \"Analog-sensitive PLK4 phosphoproteomic screen, in vitro kinase assay, phospho-site mutagenesis, immunofluorescence microscopy, RPE-1 cell engineering\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro kinase assay plus mutagenesis with specific functional readout (satellite integrity)\",\n      \"pmids\": [\"30804208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cep131 forms a module with Cep162 near the axoneme at the basal body, and together with the Cby-Fam92 module cooperatively maintains Cep290 at the basal body and initiates ciliogenesis in Drosophila. Concurrent deletion of any protein in the Cep131-Cep162 module and the Cby-Fam92 module causes complete loss of Cep290 from the basal body and blocks ciliogenesis at its initiation stage.\",\n      \"method\": \"Drosophila genetics (double mutants), immunolocalisation, epistasis analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila ortholog model with clear localization and functional readouts; single study\",\n      \"pmids\": [\"38442096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The mouse AZ1 protein (CEP131) is localised to the preacrosome region of spermatids; its gene is transcribed beginning in pachytene spermatocytes. The 5'-proximal region constitutes a CpG island and gene expression is induced by 5-azacytidine (DNA demethylation) in fibroblasts.\",\n      \"method\": \"Immunolocalisation, genomic cloning, RT-PCR, 5-azacytidine treatment\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization with developmental context, single study, no further mechanistic follow-up\",\n      \"pmids\": [\"9070930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP131 interacts with the transcription factor ARID3A in liver cancer cells and the ARID3A/CEP131 complex co-occupies the KDM3A promoter to transcriptionally activate KDM3A, which then demethylates H3K9me2 to upregulate embryonic stem cell-like signature genes, promoting cancer cell viability and metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, loss-of-function/gain-of-function in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifying binding partner, ChIP demonstrating co-occupancy at promoter, functional rescue; single study\",\n      \"pmids\": [\"36008383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEP131-positive centriolar satellites promote local translation at centrosomes. The RNA binding protein Unkempt localises to Cep131-positive centriolar satellites and is required for Plk4-induced centriole overduplication in an RNA-binding-dependent manner, with Unk and Cep131 together promoting localised translation near centrosomes.\",\n      \"method\": \"Fluorescence microscopy, genetic knockdown, RNA binding domain mutagenesis, translation reporters at centrosomes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, localisation and co-localisation data, KD phenotype; mechanistic link to CEP131 is indirect\",\n      \"pmids\": [\"bio_10.1101_2024.07.29.605660\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MDM2 interacts with CEP131 and promotes its protein degradation; overexpression of CEP131 accelerates neuroblastoma cell growth and confers resistance to CHK1 inhibitor-induced replication defects.\",\n      \"method\": \"Mass spectrometry (MDM2-binding proteins), overexpression studies, cell growth assays\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/MS identification of MDM2-CEP131 interaction, overexpression phenotype without full mechanistic dissection\",\n      \"pmids\": [\"33014050\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP131/AZI1 is a centriolar satellite protein that traffics along microtubules (via dynein-dynactin) to the basal body and transition zone, where it is recruited to satellites by PCM1 and anchored at the centriolar core by pericentrin and Cep290; it regulates BBSome ciliary trafficking through direct interaction with BBS4, supports ciliogenesis and flagellogenesis through a conserved microtubule-based trafficking role, cooperates with Cep162 to maintain Cep290 at the basal body for ciliogenesis initiation, and its centriolar satellite residency is dynamically controlled by two kinase cascades: MK2 phosphorylates S47/S78 under stress to recruit 14-3-3 proteins that sequester CEP131 in the cytoplasm (dispersing satellites), while PLK4 phosphorylates S78 to maintain satellite structural integrity under normal conditions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CEP131 (AZI1) is a centriolar satellite protein that functions as a microtubule-dependent trafficking factor essential for ciliogenesis, flagellogenesis, and centriolar satellite integrity. CEP131 is recruited to centriolar satellites by PCM1 and anchored at the centriolar core by pericentrin and Cep290; it traffics along microtubules via dynein-dynactin to the basal body and transition zone, where it cooperates with Cep162 to maintain Cep290 and initiate ciliogenesis [PMID:22797915, PMID:24415959, PMID:38442096]. CEP131 regulates BBSome ciliary entry through direct interaction with BBS4, acting as a gatekeeper that restrains BBSome accumulation in cilia [PMID:24550735]. Its satellite residency is dynamically controlled by phosphorylation at Ser-78 by both MK2 (stress-induced, creating 14-3-3 binding sites that sequester CEP131 cytoplasmically and disperse satellites) and PLK4 (maintaining satellite structural integrity under basal conditions) [PMID:26616734, PMID:30804208].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Initial characterization placed CEP131 in the male germline, establishing its expression in spermatogenesis and localization to the preacrosome region of spermatids, but its molecular function was unknown.\",\n      \"evidence\": \"Immunolocalization and RT-PCR in mouse spermatids and fibroblasts\",\n      \"pmids\": [\"9070930\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional data beyond localization\", \"Mechanism of preacrosomal targeting unknown\", \"No connection to centrosomes or cilia yet recognized\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Zebrafish knockdown revealed that CEP131 is required for proper cilia length and axoneme formation across multiple tissues, establishing it as a ciliary gene rather than merely a spermatogenesis factor.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish embryos with ciliary imaging and laterality phenotyping\",\n      \"pmids\": [\"19254375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-only approach without genetic confirmation\", \"Molecular mechanism of cilia shortening not defined\", \"Whether CEP131 acts cell-autonomously was untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The Drosophila ortholog Dilatory was shown to localize to the basal body and transition zone and to be required for ciliogenesis and sperm motility, establishing an evolutionarily conserved role at the ciliary base and a genetic link to intraflagellar transport.\",\n      \"evidence\": \"Drosophila loss-of-function mutants with immunolocalization and genetic epistasis with Uncoordinated\",\n      \"pmids\": [\"21750193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical partners at the ciliary base not identified\", \"Mechanism of IFT regulation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"CEP131 was placed within the centriolar satellite protein network: PCM1 recruits it to satellites, pericentrin and Cep290 anchor it at the centriolar core, and its transport requires microtubules and dynein-dynactin, establishing a mechanistic framework for its satellite-dependent functions.\",\n      \"evidence\": \"siRNA knockdown, immunofluorescence, co-localization, and cell-cycle analysis in human cells\",\n      \"pmids\": [\"22797915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interactions among PCM1/pericentrin/Cep290 and CEP131 not biochemically demonstrated\", \"Precise cell-cycle signals regulating CEP131 localization unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Live imaging and a null mouse demonstrated that CEP131 traffics along microtubules to the basal body, is required for efficient ciliogenesis (rescued by siRNA-resistant construct), and is essential for spermatid manchette and flagella formation, unifying its roles in cilia and male fertility.\",\n      \"evidence\": \"siRNA knockdown with genetic rescue in mouse fibroblasts; gene-trap null mouse phenotyping\",\n      \"pmids\": [\"24415959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo carried by CEP131 during microtubule-based trafficking not identified\", \"Whether ciliogenesis defect is indirect via satellite disruption versus direct at the basal body undetermined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"CEP131 was identified as a BBSome regulator through direct binding to BBS4, revealing it restrains BBSome ciliary entry and acts as a negative regulator of BBS-dependent ciliary trafficking.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA epistasis in mammalian cells, zebrafish morpholino knockdown\",\n      \"pmids\": [\"24550735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CEP131-BBS4 interaction undefined\", \"Whether CEP131 regulates other ciliary trafficking complexes beyond the BBSome untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The p38-MK2 stress kinase pathway was shown to directly phosphorylate CEP131 at S47 and S78, creating 14-3-3 binding sites that sequester CEP131 in the cytoplasm and disperse centriolar satellites, establishing the first signaling mechanism controlling satellite dynamics through CEP131.\",\n      \"evidence\": \"In vitro kinase assay, phospho-site mutagenesis, co-IP with 14-3-3, UV stress in human cells\",\n      \"pmids\": [\"26616734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether 14-3-3 sequestration affects ciliogenesis under stress not tested\", \"Additional phosphorylation sites and kinases potentially involved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"PLK4 was identified as a second kinase phosphorylating CEP131 at Ser-78 under basal conditions, with this modification being essential for centriolar satellite structural integrity but dispensable for ciliogenesis and centriole duplication, revealing that the same phosphosite is read differently depending on kinase context.\",\n      \"evidence\": \"Analog-sensitive PLK4 phosphoproteomics, in vitro kinase assay, phospho-site mutagenesis in RPE-1 cells\",\n      \"pmids\": [\"30804208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cells distinguish MK2-mediated vs PLK4-mediated phosphorylation at the same site is unresolved\", \"Downstream effectors of satellite integrity maintenance unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A non-centrosomal function was reported: CEP131 interacts with ARID3A to co-occupy the KDM3A promoter and transcriptionally activate a histone demethylase cascade in liver cancer cells, suggesting CEP131 has nuclear roles beyond its satellite function.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP assay, gain/loss-of-function in hepatocellular carcinoma cells and xenografts\",\n      \"pmids\": [\"36008383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear localization of endogenous CEP131 not independently confirmed\", \"Whether transcriptional role is widespread or cancer-specific is unknown\", \"Single study without replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Drosophila genetics revealed that CEP131 forms a cooperative module with Cep162 that, together with the Cby-Fam92 module, maintains Cep290 at the basal body to initiate ciliogenesis, placing CEP131 in a defined epistatic hierarchy for ciliogenesis initiation.\",\n      \"evidence\": \"Drosophila double-mutant genetics, immunolocalization, epistasis analysis\",\n      \"pmids\": [\"38442096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between CEP131 and Cep162 not biochemically demonstrated\", \"Whether this modular architecture is conserved in mammals untested\", \"Single study in Drosophila\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of cargoes transported by CEP131 along microtubules to the basal body, the structural basis of its interactions with BBS4 and satellite components, and whether its reported nuclear/transcriptional functions represent a bona fide second role or an overexpression artifact.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No cargo identified for CEP131 microtubule-based trafficking\", \"No structural model of CEP131 or its complexes\", \"Nuclear role lacks independent replication\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"centriolar satellites\"\n    ],\n    \"partners\": [\n      \"PCM1\",\n      \"CEP290\",\n      \"BBS4\",\n      \"CEP162\",\n      \"ARID3A\",\n      \"YWHAB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}