{"gene":"CEP131","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2012,"finding":"CEP131/AZI1 localizes to centriolar satellites and its centrosomal localization is cell-cycle-regulated, requiring an intact microtubule network and a functional dynein-dynactin transport system. CEP131 is recruited to centriolar satellites by PCM1 and localized to the centriolar core region by both pericentrin and CEP290. Depletion of CEP131 results in reduced proliferation, centriole amplification, increased multipolar mitosis, chromosomal instability, and post-mitotic DNA damage.","method":"siRNA knockdown, immunofluorescence, co-localization studies in human cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, localization experiments with functional consequences, single lab, multiple orthogonal readouts","pmids":["22797915"],"is_preprint":false},{"year":2013,"finding":"Acute loss of AZI1/CEP131 by siRNA knockdown in mouse fibroblasts leads to a robust reduction in ciliogenesis, rescued by siRNA-resistant AZI1-GFP. AZI1 localizes to centriolar satellites, traffics along microtubules becoming enriched around the basal body, and also localizes to the transition zone. In AZI1 null mice, sperm flagella development is specifically impaired, causing microtubule-based trafficking defects in the manchette and flagella, resulting in male infertility, while cilia in other tissues are functionally normal.","method":"siRNA knockdown, rescue experiment with siRNA-resistant GFP fusion, Azi1 null mouse generation, live imaging, immunofluorescence, electron microscopy","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute vs. chronic loss comparison, genetic rescue, knockout mouse with tissue-specific phenotypic readouts, multiple orthogonal methods, replicated across zebrafish and Drosophila contexts","pmids":["24415959"],"is_preprint":false},{"year":2009,"finding":"In zebrafish embryos, depletion of Cep131 leads to shortened cilia in multiple tissues (kidney, ear) and randomized left-right asymmetry, phenocopying intraflagellar transport mutants, without eliminating centrosomes or basal bodies. Yeast two-hybrid assays failed to detect interaction with HDAC6 or IFT proteins tested.","method":"Morpholino knockdown in zebrafish, yeast two-hybrid (negative result for HDAC6/IFT interaction)","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with defined ciliary phenotype in vivo, negative yeast two-hybrid result, single lab","pmids":["19254375"],"is_preprint":false},{"year":2011,"finding":"Drosophila Dilatory (DILA), a homolog of vertebrate AZI1/CEP131, localizes to the ciliary base including the basal body and transition zone in sensory neurons. Loss of dila causes defects in ciliated sensory neurons and sperm consistent with intraflagellar transport defects. DILA interacts genetically with the ciliary coiled-coil protein Uncoordinated, implicating it in regulating intraflagellar transport at the ciliary base.","method":"Drosophila mutant analysis, immunofluorescence localization, genetic epistasis (double mutant with Uncoordinated)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog, genetic epistasis and localization, single lab","pmids":["21750193"],"is_preprint":false},{"year":2014,"finding":"AZI1/CEP131 interacts with BBS4 and, through this interaction, with the BBSome complex. AZI1 is not required for BBSome assembly, but its depletion enhances BBSome accumulation in cilia. In BBS3- or BBS5-depleted cells where BBSome cannot enter cilia, AZI1 siRNA knockdown restores BBSome ciliary trafficking. AZI1 knockdown in zebrafish causes BBS-like phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, zebrafish morpholino knockdown","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional epistasis in cell lines and zebrafish, single lab, multiple orthogonal methods","pmids":["24550735"],"is_preprint":false},{"year":2015,"finding":"CEP131 is a substrate of the p38-effector kinase MK2. Ser-47 and Ser-78 are critical MK2 phosphorylation sites in CEP131. UV-induced phosphorylation of these residues creates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm, blocking formation of new centriolar satellites and leading to rapid depletion of these structures. Mutating S47 and S78 in CEP131 abolishes stress-induced centriolar satellite reorganization, identifying CEP131 as the key regulatory target of MK2 and 14-3-3 in this process.","method":"In vitro kinase assay, phosphosite mutagenesis, co-immunoprecipitation, immunofluorescence, cell stress assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, direct binding sites identified, functional rescue with phosphosite mutants, multiple orthogonal methods","pmids":["26616734"],"is_preprint":false},{"year":2019,"finding":"PLK4 directly phosphorylates CEP131 at Ser-78, as confirmed by in vitro kinase assay using an analog-sensitive PLK4 system. PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication, but is essential for maintaining centriolar satellite integrity. PLK4 inhibition or a non-phosphorylatable CEP131-S78A variant causes dispersed centriolar satellites, while a phosphomimetic S78D variant promotes their aggregation.","method":"Analog-sensitive kinase system, multiplex phosphoproteomics, in vitro kinase assay, immunofluorescence, phosphomimetic and non-phosphorylatable mutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro kinase assay with analog-sensitive allele, phosphosite mutagenesis (S78A and S78D), unbiased phosphoproteomic identification, functional validation","pmids":["30804208"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, the Cep131-Cep162 module near the axoneme and the Cby-Fam92 module close to the ciliary membrane cooperatively maintain Cep290 at the basal body and are required for ciliogenesis initiation. Concurrent deletion of any protein from both modules leads to complete loss of Cep290 from the basal body and blocks ciliogenesis initiation.","method":"Drosophila genetic deletion, immunofluorescence, double-mutant epistasis analysis","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Drosophila ortholog, genetic epistasis with double mutants, defined cellular phenotype, single lab","pmids":["38442096"],"is_preprint":false},{"year":2022,"finding":"CEP131 interacts with the transcription factor ARID3A and co-occupies the KDM3A promoter to transcriptionally activate KDM3A, which in turn demethylates H3K9me2 to upregulate embryonic stem cell signature genes in liver cancer cells.","method":"Co-immunoprecipitation, ChIP assay, reporter assay, knockdown/overexpression in cancer cell lines and in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP identifying interaction and co-occupancy, functional downstream readout, single lab","pmids":["36008383"],"is_preprint":false},{"year":2020,"finding":"MDM2 associates with CEP131 protein and promotes its degradation. Overexpression of CEP131 accelerates neuroblastoma cell growth and confers resistance to CHK1 inhibitor-induced replication defects.","method":"Mass spectrometry (MDM2 interactome), co-immunoprecipitation, overexpression in neuroblastoma cell lines","journal":"Journal of oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification, limited mechanistic follow-up, single lab","pmids":["33014050"],"is_preprint":false},{"year":2024,"finding":"CEP131-positive centriolar satellites promote local translation at centrosomes. Unkempt (Unk) RNA binding protein localizes to centrosomes and Cep131-positive centriolar satellites, and both Unk and Cep131 promote localized translation at these structures, as part of a translational program required for centriole duplication.","method":"Immunofluorescence co-localization, translation reporter assays at centrosomes, knockdown of CEP131 in centriolar satellite translation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, localization co-localization and translation reporter, limited mechanistic dissection of CEP131 role specifically","pmids":["bio_10.1101_2024.07.29.605660"],"is_preprint":true}],"current_model":"CEP131/AZI1 is a centriolar satellite protein that localizes to centriolar satellites (via PCM1), the basal body, and the ciliary transition zone, where it plays a conserved but context-dependent role in ciliogenesis, flagellogenesis, and intraflagellar transport; it is phosphorylated by MK2 at S47/S78 (generating 14-3-3 binding sites that sequester CEP131 from satellites during stress) and by PLK4 at S78 (maintaining centriolar satellite integrity), interacts with BBS4 to regulate BBSome ciliary trafficking, and in non-ciliary contexts interacts with ARID3A to co-activate transcription and with MDM2 which targets it for degradation."},"narrative":{"mechanistic_narrative":"CEP131 (AZI1) is a centriolar satellite protein that supports ciliogenesis, flagellogenesis, and centriole homeostasis across vertebrate and invertebrate systems [PMID:22797915, PMID:24415959]. It is recruited to centriolar satellites by PCM1 and positioned at the centriolar core by pericentrin and CEP290, with its centrosomal localization regulated through the cell cycle and dependent on an intact microtubule network and dynein-dynactin transport [PMID:22797915]. CEP131 traffics along microtubules to become enriched at the basal body and transition zone, and its loss reduces ciliogenesis and produces intraflagellar-transport-like defects, including shortened cilia and randomized left-right asymmetry, with a flagellum-specific requirement in sperm that drives male infertility in null mice [PMID:24415959, PMID:19254375]. At the ciliary base it acts within a Cep131-Cep162 module that, cooperating with a Cby-Fam92 module, maintains CEP290 at the basal body to permit ciliogenesis initiation [PMID:38442096], and it interacts with BBS4 to restrain BBSome ciliary trafficking [PMID:24550735]. Centriolar satellite integrity and stress responsiveness are governed by phosphorylation: the p38 effector kinase MK2 phosphorylates CEP131 at Ser-47 and Ser-78 to create 14-3-3 binding sites that sequester it in the cytoplasm and trigger satellite disassembly during UV stress [PMID:26616734], while PLK4 directly phosphorylates Ser-78 to maintain satellite integrity independently of ciliogenesis and centriole duplication [PMID:30804208]. Beyond its centrosomal roles, CEP131 functions in a transcriptional context by interacting with ARID3A to co-activate KDM3A in liver cancer cells [PMID:36008383].","teleology":[{"year":2009,"claim":"Established that Cep131 is required for cilium formation in vivo, placing it functionally alongside intraflagellar transport machinery rather than core centrosome assembly.","evidence":"Morpholino knockdown in zebrafish with ciliary and laterality readouts; yeast two-hybrid screen against HDAC6/IFT proteins","pmids":["19254375"],"confidence":"Medium","gaps":["No direct molecular partner identified (negative two-hybrid)","Mechanism linking Cep131 to IFT not resolved","Morpholino specificity not controlled by genetic rescue"]},{"year":2011,"claim":"Showed the conserved ortholog acts at the ciliary base to regulate intraflagellar transport, generalizing CEP131's ciliary role beyond vertebrates.","evidence":"Drosophila dila mutant analysis, localization, and genetic epistasis with Uncoordinated","pmids":["21750193"],"confidence":"Medium","gaps":["Biochemical nature of the DILA-Uncoordinated link unknown","Direct IFT substrate engagement not demonstrated"]},{"year":2012,"claim":"Defined how CEP131 is delivered to and retained at centriolar satellites and the centriolar core, and linked its loss to genome instability.","evidence":"siRNA knockdown, co-localization, and functional phenotyping in human cells","pmids":["22797915"],"confidence":"Medium","gaps":["Mechanism connecting satellite loss to centriole amplification and DNA damage unresolved","PCM1/pericentrin/CEP290 recruitment hierarchy correlative"]},{"year":2013,"claim":"Distinguished acute from chronic loss and revealed a tissue-specific, flagellum-restricted requirement, demonstrating CEP131 is essential for sperm flagellogenesis but dispensable for cilia in other tissues.","evidence":"siRNA with siRNA-resistant rescue, Azi1 null mouse with EM and live imaging of basal body/transition zone trafficking","pmids":["24415959"],"confidence":"High","gaps":["Molecular basis of tissue-specific dependence unknown","Trafficking cargo of CEP131 in the manchette/flagellum not identified"]},{"year":2014,"claim":"Identified a direct BBS4 interaction through which CEP131 negatively regulates BBSome entry into cilia, providing a molecular handle on its IFT-related function.","evidence":"Co-IP, siRNA epistasis with BBS3/BBS5 depletion, and zebrafish morpholino phenotyping","pmids":["24550735"],"confidence":"Medium","gaps":["Structural basis of CEP131-BBS4 binding unknown","How CEP131 restrains BBSome trafficking mechanistically unresolved"]},{"year":2015,"claim":"Demonstrated that CEP131 is the key MK2/14-3-3 target controlling stress-induced centriolar satellite disassembly, defining a regulated mechanism for satellite plasticity.","evidence":"In vitro kinase assay, S47/S78 phosphosite mutagenesis, 14-3-3 co-IP, and UV stress assays","pmids":["26616734"],"confidence":"High","gaps":["Functional consequence of satellite disassembly for downstream signaling not fully defined","Whether other satellite proteins are co-regulated unknown"]},{"year":2019,"claim":"Resolved a second kinase input by showing PLK4 directly phosphorylates Ser-78 to maintain satellite integrity, separable from ciliogenesis and centriole duplication.","evidence":"Analog-sensitive PLK4 kinase assay, phosphoproteomics, and S78A/S78D mutant analysis","pmids":["30804208"],"confidence":"High","gaps":["How a shared S78 site integrates MK2 versus PLK4 signaling unclear","Downstream effectors of satellite aggregation/dispersal unknown"]},{"year":2022,"claim":"Uncovered a non-centrosomal transcriptional role, with CEP131 partnering ARID3A to activate KDM3A and an embryonic stem-cell gene program in liver cancer.","evidence":"Co-IP, ChIP co-occupancy, reporter assays, and knockdown/xenograft in cancer cells","pmids":["36008383"],"confidence":"Medium","gaps":["How a satellite protein accesses chromatin not explained","Direct DNA binding versus adaptor role for CEP131 undetermined"]},{"year":2024,"claim":"Extended the basal body model by showing the Cep131-Cep162 module cooperates with the Cby-Fam92 module to retain Cep290 and license ciliogenesis initiation.","evidence":"Drosophila genetic deletion and double-mutant epistasis with immunofluorescence","pmids":["38442096"],"confidence":"Medium","gaps":["Direct physical interactions within the module not biochemically mapped","Conservation of module architecture in vertebrates untested here"]},{"year":2024,"claim":"Proposed that CEP131-positive satellites support localized translation at centrosomes coupled to centriole duplication.","evidence":"Immunofluorescence co-localization with Unkempt and centrosomal translation reporter assays with CEP131 knockdown (preprint)","pmids":["bio_10.1101_2024.07.29.605660"],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Specific role of CEP131 in translation versus scaffolding not dissected","Direct RNA or ribosome association of CEP131 not shown"]},{"year":null,"claim":"How CEP131's distinct activities—satellite scaffolding, basal body CEP290 retention, BBSome trafficking control, and stress-regulated kinase inputs—are coordinated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CEP131 or its interaction interfaces","Molecular link between satellite integrity and centriole/genome stability unknown","Reconciliation of ciliary and transcriptional roles not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8]}],"complexes":["centriolar satellites","Cep131-Cep162 basal body module"],"partners":["PCM1","CEP290","PCNT","BBS4","MK2","PLK4","ARID3A","MDM2"],"other_free_text":[]}},"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 feedback regulatory loop between G3P and lipid transfer proteins DIR1 and AZI1 mediates azelaic-acid-induced systemic immunity.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23602565","citation_count":149,"is_preprint":false},{"pmid":"24415959","id":"PMC_24415959","title":"Acute versus chronic loss of mammalian Azi1/Cep131 results in distinct ciliary phenotypes.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24415959","citation_count":102,"is_preprint":false},{"pmid":"22797915","id":"PMC_22797915","title":"The centriolar satellite protein Cep131 is important for genome stability.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22797915","citation_count":92,"is_preprint":false},{"pmid":"19254375","id":"PMC_19254375","title":"Cep70 and Cep131 contribute to ciliogenesis in zebrafish embryos.","date":"2009","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19254375","citation_count":66,"is_preprint":false},{"pmid":"21750193","id":"PMC_21750193","title":"Dilatory is a Drosophila protein related to AZI1 (CEP131) that is located at the ciliary base and required for cilium formation.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21750193","citation_count":60,"is_preprint":false},{"pmid":"26616734","id":"PMC_26616734","title":"p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/26616734","citation_count":46,"is_preprint":false},{"pmid":"24550735","id":"PMC_24550735","title":"The centriolar satellite protein AZI1 interacts with BBS4 and regulates ciliary trafficking of the BBSome.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24550735","citation_count":35,"is_preprint":false},{"pmid":"29608565","id":"PMC_29608565","title":"Natural allelic variation of the AZI1 gene controls root growth under zinc-limiting condition.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29608565","citation_count":34,"is_preprint":false},{"pmid":"18062773","id":"PMC_18062773","title":"ODCp, a brain- and testis-specific ornithine decarboxylase paralogue, functions as an antizyme inhibitor, although less efficiently than AzI1.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18062773","citation_count":27,"is_preprint":false},{"pmid":"30804208","id":"PMC_30804208","title":"Polo-like kinase 4 maintains centriolar satellite integrity by phosphorylation of centrosomal protein 131 (CEP131).","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30804208","citation_count":23,"is_preprint":false},{"pmid":"36008383","id":"PMC_36008383","title":"Hepatic ARID3A facilitates liver cancer malignancy by cooperating with CEP131 to regulate an embryonic stem cell-like gene signature.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36008383","citation_count":21,"is_preprint":false},{"pmid":"33342031","id":"PMC_33342031","title":"Kinases and protein motifs required for AZI1 plastid localization and trafficking during plant defense induction.","date":"2021","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33342031","citation_count":10,"is_preprint":false},{"pmid":"38442096","id":"PMC_38442096","title":"Cep131-Cep162 and Cby-Fam92 complexes cooperatively maintain Cep290 at the basal body and contribute to ciliogenesis initiation.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/38442096","citation_count":7,"is_preprint":false},{"pmid":"32218865","id":"PMC_32218865","title":"CEP131 knockdown inhibits cell proliferation by inhibiting the ERK and AKT signaling pathways in non-small cell lung cancer.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32218865","citation_count":7,"is_preprint":false},{"pmid":"24518841","id":"PMC_24518841","title":"Mitogen-activated protein kinase-regulated AZI1 - an attractive candidate for genetic engineering.","date":"2014","source":"Plant signaling & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/24518841","citation_count":6,"is_preprint":false},{"pmid":"33014050","id":"PMC_33014050","title":"CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma.","date":"2020","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33014050","citation_count":6,"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9170,"output_tokens":3004,"usd":0.036285,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10351,"output_tokens":3461,"usd":0.06914,"stage2_stop_reason":"end_turn"},"total_usd":0.105425,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"CEP131/AZI1 localizes to centriolar satellites and its centrosomal localization is cell-cycle-regulated, requiring an intact microtubule network and a functional dynein-dynactin transport system. CEP131 is recruited to centriolar satellites by PCM1 and localized to the centriolar core region by both pericentrin and CEP290. 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-localization studies in human cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, localization experiments with functional consequences, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"22797915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Acute loss of AZI1/CEP131 by siRNA knockdown in mouse fibroblasts leads to a robust reduction in ciliogenesis, rescued by siRNA-resistant AZI1-GFP. AZI1 localizes to centriolar satellites, traffics along microtubules becoming enriched around the basal body, and also localizes to the transition zone. In AZI1 null mice, sperm flagella development is specifically impaired, causing microtubule-based trafficking defects in the manchette and flagella, resulting in male infertility, while cilia in other tissues are functionally normal.\",\n      \"method\": \"siRNA knockdown, rescue experiment with siRNA-resistant GFP fusion, Azi1 null mouse generation, live imaging, immunofluorescence, electron microscopy\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute vs. chronic loss comparison, genetic rescue, knockout mouse with tissue-specific phenotypic readouts, multiple orthogonal methods, replicated across zebrafish and Drosophila contexts\",\n      \"pmids\": [\"24415959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish embryos, depletion of Cep131 leads to shortened cilia in multiple tissues (kidney, ear) and randomized left-right asymmetry, phenocopying intraflagellar transport mutants, without eliminating centrosomes or basal bodies. Yeast two-hybrid assays failed to detect interaction with HDAC6 or IFT proteins tested.\",\n      \"method\": \"Morpholino knockdown in zebrafish, yeast two-hybrid (negative result for HDAC6/IFT interaction)\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with defined ciliary phenotype in vivo, negative yeast two-hybrid result, single lab\",\n      \"pmids\": [\"19254375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Dilatory (DILA), a homolog of vertebrate AZI1/CEP131, localizes to the ciliary base including the basal body and transition zone in sensory neurons. Loss of dila causes defects in ciliated sensory neurons and sperm consistent with intraflagellar transport defects. DILA interacts genetically with the ciliary coiled-coil protein Uncoordinated, implicating it in regulating intraflagellar transport at the ciliary base.\",\n      \"method\": \"Drosophila mutant analysis, immunofluorescence localization, genetic epistasis (double mutant with Uncoordinated)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog, genetic epistasis and localization, single lab\",\n      \"pmids\": [\"21750193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AZI1/CEP131 interacts with BBS4 and, through this interaction, with the BBSome complex. AZI1 is not required for BBSome assembly, but its depletion enhances BBSome accumulation in cilia. In BBS3- or BBS5-depleted cells where BBSome cannot enter cilia, AZI1 siRNA knockdown restores BBSome ciliary trafficking. AZI1 knockdown in zebrafish causes BBS-like phenotypes including Kupffer's vesicle abnormalities and melanosome transport delay.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence, zebrafish morpholino knockdown\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional epistasis in cell lines and zebrafish, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24550735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEP131 is a substrate of the p38-effector kinase MK2. Ser-47 and Ser-78 are critical MK2 phosphorylation sites in CEP131. UV-induced phosphorylation of these residues creates direct binding sites for 14-3-3 proteins, which sequester CEP131 in the cytoplasm, blocking formation of new centriolar satellites and leading to rapid depletion of these structures. Mutating S47 and S78 in CEP131 abolishes stress-induced centriolar satellite reorganization, identifying CEP131 as the key regulatory target of MK2 and 14-3-3 in this process.\",\n      \"method\": \"In vitro kinase assay, phosphosite mutagenesis, co-immunoprecipitation, immunofluorescence, cell stress assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, direct binding sites identified, functional rescue with phosphosite mutants, multiple orthogonal methods\",\n      \"pmids\": [\"26616734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PLK4 directly phosphorylates CEP131 at Ser-78, as confirmed by in vitro kinase assay using an analog-sensitive PLK4 system. PLK4-mediated phosphorylation of Ser-78 is dispensable for CEP131 localization, ciliogenesis, and centriole duplication, but is essential for maintaining centriolar satellite integrity. PLK4 inhibition or a non-phosphorylatable CEP131-S78A variant causes dispersed centriolar satellites, while a phosphomimetic S78D variant promotes their aggregation.\",\n      \"method\": \"Analog-sensitive kinase system, multiplex phosphoproteomics, in vitro kinase assay, immunofluorescence, phosphomimetic and non-phosphorylatable mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro kinase assay with analog-sensitive allele, phosphosite mutagenesis (S78A and S78D), unbiased phosphoproteomic identification, functional validation\",\n      \"pmids\": [\"30804208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, the Cep131-Cep162 module near the axoneme and the Cby-Fam92 module close to the ciliary membrane cooperatively maintain Cep290 at the basal body and are required for ciliogenesis initiation. Concurrent deletion of any protein from both modules leads to complete loss of Cep290 from the basal body and blocks ciliogenesis initiation.\",\n      \"method\": \"Drosophila genetic deletion, immunofluorescence, double-mutant epistasis analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Drosophila ortholog, genetic epistasis with double mutants, defined cellular phenotype, single lab\",\n      \"pmids\": [\"38442096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP131 interacts with the transcription factor ARID3A and co-occupies the KDM3A promoter to transcriptionally activate KDM3A, which in turn demethylates H3K9me2 to upregulate embryonic stem cell signature genes in liver cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, reporter assay, knockdown/overexpression in cancer cell lines and in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP identifying interaction and co-occupancy, functional downstream readout, single lab\",\n      \"pmids\": [\"36008383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MDM2 associates with CEP131 protein and promotes its degradation. Overexpression of CEP131 accelerates neuroblastoma cell growth and confers resistance to CHK1 inhibitor-induced replication defects.\",\n      \"method\": \"Mass spectrometry (MDM2 interactome), co-immunoprecipitation, overexpression in neuroblastoma cell lines\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"33014050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEP131-positive centriolar satellites promote local translation at centrosomes. Unkempt (Unk) RNA binding protein localizes to centrosomes and Cep131-positive centriolar satellites, and both Unk and Cep131 promote localized translation at these structures, as part of a translational program required for centriole duplication.\",\n      \"method\": \"Immunofluorescence co-localization, translation reporter assays at centrosomes, knockdown of CEP131 in centriolar satellite translation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, localization co-localization and translation reporter, limited mechanistic dissection of CEP131 role specifically\",\n      \"pmids\": [\"bio_10.1101_2024.07.29.605660\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CEP131/AZI1 is a centriolar satellite protein that localizes to centriolar satellites (via PCM1), the basal body, and the ciliary transition zone, where it plays a conserved but context-dependent role in ciliogenesis, flagellogenesis, and intraflagellar transport; it is phosphorylated by MK2 at S47/S78 (generating 14-3-3 binding sites that sequester CEP131 from satellites during stress) and by PLK4 at S78 (maintaining centriolar satellite integrity), interacts with BBS4 to regulate BBSome ciliary trafficking, and in non-ciliary contexts interacts with ARID3A to co-activate transcription and with MDM2 which targets it for degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP131 (AZI1) is a centriolar satellite protein that supports ciliogenesis, flagellogenesis, and centriole homeostasis across vertebrate and invertebrate systems [#0, #1]. It is recruited to centriolar satellites by PCM1 and positioned at the centriolar core by pericentrin and CEP290, with its centrosomal localization regulated through the cell cycle and dependent on an intact microtubule network and dynein-dynactin transport [#0]. CEP131 traffics along microtubules to become enriched at the basal body and transition zone, and its loss reduces ciliogenesis and produces intraflagellar-transport-like defects, including shortened cilia and randomized left-right asymmetry, with a flagellum-specific requirement in sperm that drives male infertility in null mice [#1, #2]. At the ciliary base it acts within a Cep131-Cep162 module that, cooperating with a Cby-Fam92 module, maintains CEP290 at the basal body to permit ciliogenesis initiation [#7], and it interacts with BBS4 to restrain BBSome ciliary trafficking [#4]. Centriolar satellite integrity and stress responsiveness are governed by phosphorylation: the p38 effector kinase MK2 phosphorylates CEP131 at Ser-47 and Ser-78 to create 14-3-3 binding sites that sequester it in the cytoplasm and trigger satellite disassembly during UV stress [#5], while PLK4 directly phosphorylates Ser-78 to maintain satellite integrity independently of ciliogenesis and centriole duplication [#6]. Beyond its centrosomal roles, CEP131 functions in a transcriptional context by interacting with ARID3A to co-activate KDM3A in liver cancer cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that Cep131 is required for cilium formation in vivo, placing it functionally alongside intraflagellar transport machinery rather than core centrosome assembly.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with ciliary and laterality readouts; yeast two-hybrid screen against HDAC6/IFT proteins\",\n      \"pmids\": [\"19254375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct molecular partner identified (negative two-hybrid)\", \"Mechanism linking Cep131 to IFT not resolved\", \"Morpholino specificity not controlled by genetic rescue\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed the conserved ortholog acts at the ciliary base to regulate intraflagellar transport, generalizing CEP131's ciliary role beyond vertebrates.\",\n      \"evidence\": \"Drosophila dila mutant analysis, localization, and genetic epistasis with Uncoordinated\",\n      \"pmids\": [\"21750193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical nature of the DILA-Uncoordinated link unknown\", \"Direct IFT substrate engagement not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined how CEP131 is delivered to and retained at centriolar satellites and the centriolar core, and linked its loss to genome instability.\",\n      \"evidence\": \"siRNA knockdown, co-localization, and functional phenotyping in human cells\",\n      \"pmids\": [\"22797915\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting satellite loss to centriole amplification and DNA damage unresolved\", \"PCM1/pericentrin/CEP290 recruitment hierarchy correlative\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Distinguished acute from chronic loss and revealed a tissue-specific, flagellum-restricted requirement, demonstrating CEP131 is essential for sperm flagellogenesis but dispensable for cilia in other tissues.\",\n      \"evidence\": \"siRNA with siRNA-resistant rescue, Azi1 null mouse with EM and live imaging of basal body/transition zone trafficking\",\n      \"pmids\": [\"24415959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of tissue-specific dependence unknown\", \"Trafficking cargo of CEP131 in the manchette/flagellum not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a direct BBS4 interaction through which CEP131 negatively regulates BBSome entry into cilia, providing a molecular handle on its IFT-related function.\",\n      \"evidence\": \"Co-IP, siRNA epistasis with BBS3/BBS5 depletion, and zebrafish morpholino phenotyping\",\n      \"pmids\": [\"24550735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CEP131-BBS4 binding unknown\", \"How CEP131 restrains BBSome trafficking mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that CEP131 is the key MK2/14-3-3 target controlling stress-induced centriolar satellite disassembly, defining a regulated mechanism for satellite plasticity.\",\n      \"evidence\": \"In vitro kinase assay, S47/S78 phosphosite mutagenesis, 14-3-3 co-IP, and UV stress assays\",\n      \"pmids\": [\"26616734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of satellite disassembly for downstream signaling not fully defined\", \"Whether other satellite proteins are co-regulated unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved a second kinase input by showing PLK4 directly phosphorylates Ser-78 to maintain satellite integrity, separable from ciliogenesis and centriole duplication.\",\n      \"evidence\": \"Analog-sensitive PLK4 kinase assay, phosphoproteomics, and S78A/S78D mutant analysis\",\n      \"pmids\": [\"30804208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a shared S78 site integrates MK2 versus PLK4 signaling unclear\", \"Downstream effectors of satellite aggregation/dispersal unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a non-centrosomal transcriptional role, with CEP131 partnering ARID3A to activate KDM3A and an embryonic stem-cell gene program in liver cancer.\",\n      \"evidence\": \"Co-IP, ChIP co-occupancy, reporter assays, and knockdown/xenograft in cancer cells\",\n      \"pmids\": [\"36008383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a satellite protein accesses chromatin not explained\", \"Direct DNA binding versus adaptor role for CEP131 undetermined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the basal body model by showing the Cep131-Cep162 module cooperates with the Cby-Fam92 module to retain Cep290 and license ciliogenesis initiation.\",\n      \"evidence\": \"Drosophila genetic deletion and double-mutant epistasis with immunofluorescence\",\n      \"pmids\": [\"38442096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interactions within the module not biochemically mapped\", \"Conservation of module architecture in vertebrates untested here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed that CEP131-positive satellites support localized translation at centrosomes coupled to centriole duplication.\",\n      \"evidence\": \"Immunofluorescence co-localization with Unkempt and centrosomal translation reporter assays with CEP131 knockdown (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.29.605660\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Specific role of CEP131 in translation versus scaffolding not dissected\", \"Direct RNA or ribosome association of CEP131 not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEP131's distinct activities—satellite scaffolding, basal body CEP290 retention, BBSome trafficking control, and stress-regulated kinase inputs—are coordinated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CEP131 or its interaction interfaces\", \"Molecular link between satellite integrity and centriole/genome stability unknown\", \"Reconciliation of ciliary and transcriptional roles not addressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"centriolar satellites\", \"Cep131-Cep162 basal body module\"],\n    \"partners\": [\"PCM1\", \"CEP290\", \"PCNT\", \"BBS4\", \"MK2\", \"PLK4\", \"ARID3A\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}