{"gene":"CEP19","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2017,"finding":"CEP19 is recruited to the ciliary base by the centriolar CEP350/FOP complex, where it specifically captures GTP-bound RABL2B (activated via its intrinsic nucleotide exchange). Activated RABL2B then captures and releases the IFT-B holocomplex from the pool of pre-docked IFT-B complexes to initiate ciliary entry of IFT trains.","method":"Affinity-purification mass spectrometry, Co-IP, rescue experiments, biochemical reconstitution of interactions","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — AP-MS plus functional reconstitution in one study, independently corroborated by a second lab (PMID:28428259) with orthogonal methods","pmids":["28625565"],"is_preprint":false},{"year":2017,"finding":"RABL2 is recruited to the mother centriole/basal body in a CEP19-dependent manner, and CEP19 itself is recruited to the centriole via its binding to FGFR1OP (FOP). RABL2 binds CEP19 and the IFT74-IFT81 heterodimer of the IFT-B complex in a mutually exclusive, GTP-dependent manner.","method":"Co-immunoprecipitation, siRNA knockdown, Chlamydomonas RABL2 gene disruption, localization by immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and genetic disruption in two organisms, independently consistent with PMID:28625565","pmids":["28428259"],"is_preprint":false},{"year":2013,"finding":"CEP19 localizes to the centrosome and primary cilia. Homozygous loss-of-function mutation (nonsense) in CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, establishing a functional role for CEP19 in energy balance via ciliary signaling.","method":"Homozygosity mapping, Sanger sequencing, Cep19 knockout mouse phenotyping (weight, food intake, glucose tolerance tests), immunofluorescence localization","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with multiple metabolic phenotypic readouts plus human genetics, replicated by subsequent clinical reports","pmids":["24268657"],"is_preprint":false},{"year":2018,"finding":"Talpid3, C2CD3, and OFD1 differentially regulate the assembly of the CEP350/FOP/CEP19 module at the distal centriole, placing CEP19 recruitment downstream of these distal centriolar hub proteins during organelle maturation.","method":"Genetic loss-of-function (siRNA/knockout) combined with immunofluorescence to measure CEP19 module assembly at the centriole","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by genetic depletion and localization, single lab, two orthogonal approaches","pmids":["30258116"],"is_preprint":false},{"year":2019,"finding":"Ablation of CEP19 causes mis-localization of ciliary GPCRs GPR161 and HTR6, placing CEP19 (via its interaction with RABL2 and IFT-B) in the pathway required for ciliary GPCR targeting.","method":"siRNA knockdown of CEP19 followed by immunofluorescence quantification of ciliary GPCR localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined ciliary GPCR phenotype, single lab, consistent with established RABL2-IFT-B-CEP19 axis","pmids":["30578315"],"is_preprint":false},{"year":2022,"finding":"GTP-locked RABL2 (Q80L) enters cilia in a manner dependent on the basal body protein CEP19, phenocopying IFT27 knockout by causing accumulation of BBSome components within cilia and suppressing export of ciliary GPCRs GPR161 and Smoothened, indicating that CEP19-dependent RABL2 recruitment at the ciliary base is required for BBSome-mediated GPCR export.","method":"Expression of GTP-locked RABL2(Q80L), IFT27 knockout, CEP19 knockout/depletion, immunofluorescence for ciliary cargo accumulation","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function combined with GTPase mutant analysis, single lab, consistent mechanistic pathway","pmids":["36074075"],"is_preprint":false},{"year":2023,"finding":"A reconstituted pentameric IFT complex containing IFT81/74 acts as an unconventional GAP (GTPase-activating protein) for RabL2 (RABL2), enhancing its GTP hydrolysis rate. CEP19 interacts with RabL2 at the basal body upstream of IFT engagement, and structural models validated in vitro and in cellulo show how RabL2 is incorporated into and then dissociates from the IFT complex after GTP hydrolysis.","method":"In vitro reconstitution and purification of RabL2 with CEP19 or IFT proteins, GTPase activity assay, structural modelling validated in vitro and in cellulo, mutagenesis of IFT81/74 coiled-coil","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with GTPase activity assay plus mutagenesis and structural validation in a single rigorous study","pmids":["37606072"],"is_preprint":false}],"current_model":"CEP19 is a centrosomal/ciliary-base scaffold protein recruited by the CEP350/FOP module that captures GTP-bound RABL2; RABL2 in turn binds and releases the IFT-B holocomplex (via IFT74/IFT81) to initiate intraflagellar transport entry into the cilium, with IFT81/74 subsequently acting as a GAP to promote RABL2 GTP hydrolysis and dissociation from anterograde IFT trains, and this CEP19-RABL2-IFT-B axis is also required for BBSome-mediated ciliary GPCR export; loss of CEP19 in humans and mice causes morbid obesity, hyperphagia, and metabolic syndrome."},"narrative":{"mechanistic_narrative":"CEP19 is a centrosomal and ciliary-base scaffold protein that initiates intraflagellar transport (IFT) by coupling the distal centriole to the small GTPase RABL2 [PMID:28625565, PMID:28428259]. Recruited to the mother centriole through binding FGFR1OP (FOP) within the CEP350/FOP module, CEP19 captures GTP-bound RABL2, which in turn engages and releases the IFT-B holocomplex via the IFT74-IFT81 heterodimer in a mutually exclusive, GTP-dependent manner, thereby licensing entry of IFT trains into the cilium [PMID:28625565, PMID:28428259]. The IFT81/74 coiled-coil acts as an unconventional GAP that accelerates RABL2 GTP hydrolysis, driving RABL2 dissociation from anterograde IFT trains after engagement [PMID:37606072]. Assembly of the CEP350/FOP/CEP19 module at the distal centriole is positioned downstream of the distal centriolar hub proteins Talpid3, C2CD3, and OFD1 during organelle maturation [PMID:30258116]. Through this RABL2-IFT-B axis, CEP19 is required for proper ciliary trafficking of G-protein-coupled receptors: its loss mislocalizes GPR161 and HTR6 [PMID:30578315], and CEP19-dependent RABL2 recruitment is needed for BBSome-mediated export of ciliary GPCRs including GPR161 and Smoothened [PMID:36074075]. Homozygous loss-of-function mutation of CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, linking this ciliary signaling function to energy balance [PMID:24268657].","teleology":[{"year":2013,"claim":"Established that CEP19 is a centrosomal/ciliary protein with a physiological role, by tying its loss to a defined metabolic disease phenotype.","evidence":"Homozygosity mapping and Sanger sequencing in humans plus Cep19 knockout mouse phenotyping and immunofluorescence localization","pmids":["24268657"],"confidence":"High","gaps":["Did not define the molecular partners or biochemical activity of CEP19","Mechanism linking ciliary function to energy balance unresolved"]},{"year":2017,"claim":"Defined the core molecular axis, showing CEP19 is recruited by the CEP350/FOP module and captures GTP-bound RABL2 to license IFT-B train entry into the cilium.","evidence":"Affinity-purification mass spectrometry, reciprocal Co-IP, siRNA knockdown, Chlamydomonas RABL2 disruption, rescue and biochemical reconstitution across two independent labs","pmids":["28625565","28428259"],"confidence":"High","gaps":["Did not resolve how RABL2 is subsequently released from IFT trains","Structural basis of the mutually exclusive CEP19/IFT74-IFT81 binding not determined"]},{"year":2018,"claim":"Placed CEP19 module assembly within centriole maturation, ordering its recruitment downstream of distal centriolar hub proteins.","evidence":"Genetic loss-of-function (siRNA/knockout) of Talpid3, C2CD3, OFD1 with immunofluorescence readout of CEP19 module assembly","pmids":["30258116"],"confidence":"Medium","gaps":["Single lab","Direct versus indirect regulation of CEP19 recruitment not distinguished"]},{"year":2019,"claim":"Connected the CEP19 axis to ciliary GPCR targeting by showing its loss mislocalizes specific receptors.","evidence":"siRNA knockdown of CEP19 with immunofluorescence quantification of GPR161 and HTR6 ciliary localization","pmids":["30578315"],"confidence":"Medium","gaps":["Single lall single-method phenotype","Whether the defect reflects import, retention, or export not distinguished here"]},{"year":2022,"claim":"Extended the role to BBSome-mediated export, showing CEP19-dependent RABL2 entry is required for ciliary GPCR removal.","evidence":"GTP-locked RABL2(Q80L) expression, IFT27 knockout, CEP19 depletion, immunofluorescence for ciliary cargo accumulation","pmids":["36074075"],"confidence":"Medium","gaps":["Single lab","Direct biochemical link between CEP19/RABL2 and the BBSome not established"]},{"year":2023,"claim":"Resolved the cycle's termination step by identifying IFT81/74 as the GAP that drives RABL2 GTP hydrolysis and release from IFT trains.","evidence":"In vitro reconstitution of RabL2 with CEP19 or IFT proteins, GTPase activity assays, IFT81/74 coiled-coil mutagenesis, and structural modelling validated in vitro and in cellulo","pmids":["37606072"],"confidence":"High","gaps":["High-resolution structure of the CEP19-RABL2 complex not reported","Nucleotide exchange factor activity for RABL2 loading not fully defined"]},{"year":null,"claim":"How the molecular CEP19-RABL2-IFT-B trafficking cycle mechanistically produces the organismal hyperphagia and obesity phenotype remains unresolved.","evidence":"No timeline study bridges the ciliary GPCR trafficking defect to the neuroendocrine circuits controlling energy balance","pmids":[],"confidence":"Medium","gaps":["No in vivo link between specific mislocalized GPCRs and the metabolic phenotype","Tissue-specific requirements for CEP19 not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,4,5]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3]}],"complexes":["CEP350/FOP/CEP19 module"],"partners":["RABL2","RABL2B","FGFR1OP","IFT74","IFT81","CEP350"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96LK0","full_name":"Centrosomal protein of 19 kDa","aliases":[],"length_aa":163,"mass_kda":19.2,"function":"Required for ciliation (PubMed:28428259, PubMed:28625565, PubMed:28659385). Recruits the RABL2B GTPase to the ciliary base to initiate ciliation. After specifically capturing the activated GTP-bound RABL2B, the CEP19-RABL2B complex binds intraflagellar transport (IFT) complex B from the large pool pre-docked at the base of the cilium and thus triggers its entry into the cilia (PubMed:28428259, PubMed:28625565). Involved in the early steps in cilia formation by recruiting the ciliary vesicles (CVs) to the distal end of the mother centriole where they fuse to initiate cilium assembly. Involved in microtubule (MT) anchoring to the centrosomes (PubMed:28659385)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, spindle pole; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q96LK0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP19","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEP19","total_profiled":1310},"omim":[{"mim_id":"617870","title":"CENTROSOMAL PROTEIN 350; CEP350","url":"https://www.omim.org/entry/617870"},{"mim_id":"615703","title":"MORBID OBESITY AND SPERMATOGENIC FAILURE; MOSPGF","url":"https://www.omim.org/entry/615703"},{"mim_id":"615586","title":"CENTROSOMAL PROTEIN, 19-KD; CEP19","url":"https://www.omim.org/entry/615586"},{"mim_id":"605413","title":"RAB, MEMBER OF RAS ONCOGENE FAMILY-LIKE 2B; RABL2B","url":"https://www.omim.org/entry/605413"},{"mim_id":"605412","title":"RAB, MEMBER OF RAS ONCOGENE FAMILY-LIKE 2A; RABL2A","url":"https://www.omim.org/entry/605412"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP19"},"hgnc":{"alias_symbol":["MGC14126"],"prev_symbol":["C3orf34"]},"alphafold":{"accession":"Q96LK0","domains":[{"cath_id":"-","chopping":"4-99","consensus_level":"high","plddt":89.4672,"start":4,"end":99},{"cath_id":"1.20.5","chopping":"106-131","consensus_level":"medium","plddt":82.7669,"start":106,"end":131}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LK0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LK0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LK0-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP19","jax_strain_url":"https://www.jax.org/strain/search?query=CEP19"},"sequence":{"accession":"Q96LK0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96LK0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96LK0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LK0"}},"corpus_meta":[{"pmid":"28625565","id":"PMC_28625565","title":"The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/28625565","citation_count":94,"is_preprint":false},{"pmid":"28428259","id":"PMC_28428259","title":"RABL2 interacts with the intraflagellar transport-B complex and CEP19 and participates in ciliary assembly.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28428259","citation_count":76,"is_preprint":false},{"pmid":"24268657","id":"PMC_24268657","title":"Morbid obesity resulting from inactivation of the ciliary protein CEP19 in humans and mice.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24268657","citation_count":55,"is_preprint":false},{"pmid":"30258116","id":"PMC_30258116","title":"A distal centriolar protein network controls organelle maturation and asymmetry.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30258116","citation_count":41,"is_preprint":false},{"pmid":"29127258","id":"PMC_29127258","title":"Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29127258","citation_count":25,"is_preprint":false},{"pmid":"30578315","id":"PMC_30578315","title":"RABL2 positively controls localization of GPCRs in mammalian primary cilia.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30578315","citation_count":25,"is_preprint":false},{"pmid":"32681070","id":"PMC_32681070","title":"Analysis of the \"centrosome-ome\" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32681070","citation_count":14,"is_preprint":false},{"pmid":"36474803","id":"PMC_36474803","title":"Genetic and epigenetic interplay allows rapid transgenerational adaptation to metal pollution in zebrafish.","date":"2022","source":"Environmental epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/36474803","citation_count":11,"is_preprint":false},{"pmid":"36074075","id":"PMC_36074075","title":"CEP19-RABL2-IFT-B axis controls BBSome-mediated ciliary GPCR export.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/36074075","citation_count":9,"is_preprint":false},{"pmid":"37606072","id":"PMC_37606072","title":"The IFT81-IFT74 complex acts as an unconventional RabL2 GTPase-activating protein during intraflagellar transport.","date":"2023","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/37606072","citation_count":9,"is_preprint":false},{"pmid":"34646484","id":"PMC_34646484","title":"Comparative transcriptome provides insights into the selection adaptation between wild and farmed foxes.","date":"2021","source":"Ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/34646484","citation_count":7,"is_preprint":false},{"pmid":"37540954","id":"PMC_37540954","title":"Comparison of symmetrical and asymmetrical cleavage 2-cell embryos of porcine by Smart-seq2.","date":"2023","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/37540954","citation_count":4,"is_preprint":false},{"pmid":"38585545","id":"PMC_38585545","title":"Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C>T p.Arg57* Variant in CEP19 Gene.","date":"2023","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/38585545","citation_count":1,"is_preprint":false},{"pmid":"28697332","id":"PMC_28697332","title":"Gating Ciliary Transport.","date":"2017","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/28697332","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8661,"output_tokens":1903,"usd":0.027264,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8722,"output_tokens":2570,"usd":0.05393,"stage2_stop_reason":"end_turn"},"total_usd":0.081194,"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\": 2017,\n      \"finding\": \"CEP19 is recruited to the ciliary base by the centriolar CEP350/FOP complex, where it specifically captures GTP-bound RABL2B (activated via its intrinsic nucleotide exchange). Activated RABL2B then captures and releases the IFT-B holocomplex from the pool of pre-docked IFT-B complexes to initiate ciliary entry of IFT trains.\",\n      \"method\": \"Affinity-purification mass spectrometry, Co-IP, rescue experiments, biochemical reconstitution of interactions\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — AP-MS plus functional reconstitution in one study, independently corroborated by a second lab (PMID:28428259) with orthogonal methods\",\n      \"pmids\": [\"28625565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RABL2 is recruited to the mother centriole/basal body in a CEP19-dependent manner, and CEP19 itself is recruited to the centriole via its binding to FGFR1OP (FOP). RABL2 binds CEP19 and the IFT74-IFT81 heterodimer of the IFT-B complex in a mutually exclusive, GTP-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Chlamydomonas RABL2 gene disruption, localization by immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and genetic disruption in two organisms, independently consistent with PMID:28625565\",\n      \"pmids\": [\"28428259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEP19 localizes to the centrosome and primary cilia. Homozygous loss-of-function mutation (nonsense) in CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, establishing a functional role for CEP19 in energy balance via ciliary signaling.\",\n      \"method\": \"Homozygosity mapping, Sanger sequencing, Cep19 knockout mouse phenotyping (weight, food intake, glucose tolerance tests), immunofluorescence localization\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with multiple metabolic phenotypic readouts plus human genetics, replicated by subsequent clinical reports\",\n      \"pmids\": [\"24268657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Talpid3, C2CD3, and OFD1 differentially regulate the assembly of the CEP350/FOP/CEP19 module at the distal centriole, placing CEP19 recruitment downstream of these distal centriolar hub proteins during organelle maturation.\",\n      \"method\": \"Genetic loss-of-function (siRNA/knockout) combined with immunofluorescence to measure CEP19 module assembly at the centriole\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by genetic depletion and localization, single lab, two orthogonal approaches\",\n      \"pmids\": [\"30258116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ablation of CEP19 causes mis-localization of ciliary GPCRs GPR161 and HTR6, placing CEP19 (via its interaction with RABL2 and IFT-B) in the pathway required for ciliary GPCR targeting.\",\n      \"method\": \"siRNA knockdown of CEP19 followed by immunofluorescence quantification of ciliary GPCR localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined ciliary GPCR phenotype, single lab, consistent with established RABL2-IFT-B-CEP19 axis\",\n      \"pmids\": [\"30578315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GTP-locked RABL2 (Q80L) enters cilia in a manner dependent on the basal body protein CEP19, phenocopying IFT27 knockout by causing accumulation of BBSome components within cilia and suppressing export of ciliary GPCRs GPR161 and Smoothened, indicating that CEP19-dependent RABL2 recruitment at the ciliary base is required for BBSome-mediated GPCR export.\",\n      \"method\": \"Expression of GTP-locked RABL2(Q80L), IFT27 knockout, CEP19 knockout/depletion, immunofluorescence for ciliary cargo accumulation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function combined with GTPase mutant analysis, single lab, consistent mechanistic pathway\",\n      \"pmids\": [\"36074075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A reconstituted pentameric IFT complex containing IFT81/74 acts as an unconventional GAP (GTPase-activating protein) for RabL2 (RABL2), enhancing its GTP hydrolysis rate. CEP19 interacts with RabL2 at the basal body upstream of IFT engagement, and structural models validated in vitro and in cellulo show how RabL2 is incorporated into and then dissociates from the IFT complex after GTP hydrolysis.\",\n      \"method\": \"In vitro reconstitution and purification of RabL2 with CEP19 or IFT proteins, GTPase activity assay, structural modelling validated in vitro and in cellulo, mutagenesis of IFT81/74 coiled-coil\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with GTPase activity assay plus mutagenesis and structural validation in a single rigorous study\",\n      \"pmids\": [\"37606072\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP19 is a centrosomal/ciliary-base scaffold protein recruited by the CEP350/FOP module that captures GTP-bound RABL2; RABL2 in turn binds and releases the IFT-B holocomplex (via IFT74/IFT81) to initiate intraflagellar transport entry into the cilium, with IFT81/74 subsequently acting as a GAP to promote RABL2 GTP hydrolysis and dissociation from anterograde IFT trains, and this CEP19-RABL2-IFT-B axis is also required for BBSome-mediated ciliary GPCR export; loss of CEP19 in humans and mice causes morbid obesity, hyperphagia, and metabolic syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP19 is a centrosomal and ciliary-base scaffold protein that initiates intraflagellar transport (IFT) by coupling the distal centriole to the small GTPase RABL2 [#0, #1]. Recruited to the mother centriole through binding FGFR1OP (FOP) within the CEP350/FOP module, CEP19 captures GTP-bound RABL2, which in turn engages and releases the IFT-B holocomplex via the IFT74-IFT81 heterodimer in a mutually exclusive, GTP-dependent manner, thereby licensing entry of IFT trains into the cilium [#0, #1]. The IFT81/74 coiled-coil acts as an unconventional GAP that accelerates RABL2 GTP hydrolysis, driving RABL2 dissociation from anterograde IFT trains after engagement [#6]. Assembly of the CEP350/FOP/CEP19 module at the distal centriole is positioned downstream of the distal centriolar hub proteins Talpid3, C2CD3, and OFD1 during organelle maturation [#3]. Through this RABL2-IFT-B axis, CEP19 is required for proper ciliary trafficking of G-protein-coupled receptors: its loss mislocalizes GPR161 and HTR6 [#4], and CEP19-dependent RABL2 recruitment is needed for BBSome-mediated export of ciliary GPCRs including GPR161 and Smoothened [#5]. Homozygous loss-of-function mutation of CEP19 causes morbid obesity, hyperphagia, glucose intolerance, and insulin resistance in humans and mice, linking this ciliary signaling function to energy balance [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that CEP19 is a centrosomal/ciliary protein with a physiological role, by tying its loss to a defined metabolic disease phenotype.\",\n      \"evidence\": \"Homozygosity mapping and Sanger sequencing in humans plus Cep19 knockout mouse phenotyping and immunofluorescence localization\",\n      \"pmids\": [\"24268657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular partners or biochemical activity of CEP19\", \"Mechanism linking ciliary function to energy balance unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core molecular axis, showing CEP19 is recruited by the CEP350/FOP module and captures GTP-bound RABL2 to license IFT-B train entry into the cilium.\",\n      \"evidence\": \"Affinity-purification mass spectrometry, reciprocal Co-IP, siRNA knockdown, Chlamydomonas RABL2 disruption, rescue and biochemical reconstitution across two independent labs\",\n      \"pmids\": [\"28625565\", \"28428259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how RABL2 is subsequently released from IFT trains\", \"Structural basis of the mutually exclusive CEP19/IFT74-IFT81 binding not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CEP19 module assembly within centriole maturation, ordering its recruitment downstream of distal centriolar hub proteins.\",\n      \"evidence\": \"Genetic loss-of-function (siRNA/knockout) of Talpid3, C2CD3, OFD1 with immunofluorescence readout of CEP19 module assembly\",\n      \"pmids\": [\"30258116\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct versus indirect regulation of CEP19 recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected the CEP19 axis to ciliary GPCR targeting by showing its loss mislocalizes specific receptors.\",\n      \"evidence\": \"siRNA knockdown of CEP19 with immunofluorescence quantification of GPR161 and HTR6 ciliary localization\",\n      \"pmids\": [\"30578315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lall single-method phenotype\", \"Whether the defect reflects import, retention, or export not distinguished here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the role to BBSome-mediated export, showing CEP19-dependent RABL2 entry is required for ciliary GPCR removal.\",\n      \"evidence\": \"GTP-locked RABL2(Q80L) expression, IFT27 knockout, CEP19 depletion, immunofluorescence for ciliary cargo accumulation\",\n      \"pmids\": [\"36074075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct biochemical link between CEP19/RABL2 and the BBSome not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the cycle's termination step by identifying IFT81/74 as the GAP that drives RABL2 GTP hydrolysis and release from IFT trains.\",\n      \"evidence\": \"In vitro reconstitution of RabL2 with CEP19 or IFT proteins, GTPase activity assays, IFT81/74 coiled-coil mutagenesis, and structural modelling validated in vitro and in cellulo\",\n      \"pmids\": [\"37606072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the CEP19-RABL2 complex not reported\", \"Nucleotide exchange factor activity for RABL2 loading not fully defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the molecular CEP19-RABL2-IFT-B trafficking cycle mechanistically produces the organismal hyperphagia and obesity phenotype remains unresolved.\",\n      \"evidence\": \"No timeline study bridges the ciliary GPCR trafficking defect to the neuroendocrine circuits controlling energy balance\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo link between specific mislocalized GPCRs and the metabolic phenotype\", \"Tissue-specific requirements for CEP19 not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 4, 5]},\n      {\"term_id\": \"GO:0005813\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"CEP350/FOP/CEP19 module\"],\n    \"partners\": [\"RABL2\", \"RABL2B\", \"FGFR1OP\", \"IFT74\", \"IFT81\", \"CEP350\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}