{"gene":"LRRC45","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2018,"finding":"LRRC45 is recruited to the mother centriole distal appendages by the core appendage proteins Cep83 and SCLT1, and in turn recruits the keratin-binding protein FBF1.","method":"Localization studies and epistasis analysis in cultured cells (loss-of-function/recruitment hierarchy experiments)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal recruitment hierarchy established with multiple protein markers in a focused mechanistic study, single lab but multiple orthogonal methods","pmids":["30131441"],"is_preprint":false},{"year":2018,"finding":"LRRC45 promotes early ciliogenesis in CP110-uncapped centrioles by organising centriolar satellites, establishing the transition zone, and promoting docking of Rab8 GTPase-positive vesicles; it is not required for docking of early ciliary vesicles or for removal of CP110 (negative finding for those two steps).","method":"siRNA knockdown with functional readouts: transition zone assembly, centriolar satellite organisation, Rab8 vesicle docking, CP110 removal assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with multiple specific phenotypic readouts in a single focused study","pmids":["30131441"],"is_preprint":false},{"year":2018,"finding":"LRRC45 localizes to the basal body of primary and motile cilia in both differentiated and stem cells, indicating a broad role in ciliogenesis.","method":"Immunofluorescence localization in multiple cell types including stem cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization established across multiple cell contexts in single lab study","pmids":["30131441"],"is_preprint":false},{"year":2018,"finding":"CCDC102B interacts with the centrosome linker component LRRC45 and is required for centrosome cohesion; CCDC102B is recruited by C-Nap1 (CEP250) and facilitates rootletin filament formation.","method":"Co-immunoprecipitation, localization studies, siRNA knockdown with centrosome cohesion phenotype","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction with LRRC45 established, multiple methods in single lab study","pmids":["30404835"],"is_preprint":false},{"year":2020,"finding":"Cep44 does not impinge on the stability or centrosomal recruitment of LRRC45, and LRRC45 does not impinge on Cep44 — these proteins are independently recruited to the centrosome (negative finding establishing pathway independence).","method":"siRNA knockdown with immunofluorescence readout of centrosomal protein levels","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD/KO with defined protein-level readout, single lab single method","pmids":["31974111"],"is_preprint":false},{"year":2025,"finding":"Comprehensive CRISPR-Cas9 knockout analysis places LRRC45 within the distal appendage hierarchy; its precise position and requirement for each cilia-formation step (vesicle recruitment, IFT initiation, CP110 removal) was mapped relative to other distal appendage proteins including CEP83, SCLT1, CEP164, TTBK2, FBF1, CEP89.","method":"CRISPR-Cas9 knockout panel, localization, and functional assays for four ciliary steps","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive CRISPR KO panel with multiple functional assays, replicated from preprint in peer-reviewed journal","pmids":["39882846"],"is_preprint":false},{"year":2023,"finding":"CRISPR-Cas9 knockout analysis (preprint version) confirms LRRC45 as a distal appendage protein in a complex hierarchical assembly network; its localization depends on upstream components and it participates in multiple steps of cilia formation.","method":"CRISPR-Cas9 knockouts, localization, functional cilia-formation assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint, multiple KO experiments with functional assays, but superseded by published version","pmids":["36711481"],"is_preprint":true},{"year":2024,"finding":"Biallelic loss-of-function variants in LRRC45 impair ciliogenesis: patient fibroblasts with a splicing variant causing exon 14 skipping show drastically reduced LRRC45 mRNA and protein and a significant reduction in primary cilia frequency and length.","method":"Exome sequencing, RT-PCR splicing analysis, Western blot, immunofluorescence cilia frequency/length measurement in patient-derived fibroblasts","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional validation in patient-derived cells with multiple methods, single study","pmids":["39638757"],"is_preprint":false},{"year":2024,"finding":"LRRC45 competitively interacts with KEAP1, inhibiting ubiquitin-proteasome-mediated degradation of NRF2, thereby enhancing nuclear translocation of NRF2 and its anti-ferroptotic activity in bladder cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown, NRF2 protein stability/degradation assay, nuclear fractionation, ferroptosis assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — competitive binding and functional pathway established by Co-IP and KD with defined readouts, single lab study","pmids":["39522565"],"is_preprint":false},{"year":2024,"finding":"LRRC45 knockdown in lung adenocarcinoma cells reduces c-MYC, Slug, MMP2, and MMP9 expression; overexpression of c-MYC/Slug or MMP2/MMP9 in LRRC45-deficient cells partially or fully rescues proliferation and metastasis defects, placing these downstream of LRRC45.","method":"siRNA knockdown, western blot, colony formation, migration assay, rescue overexpression, xenograft mouse model","journal":"Advances in medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiments with multiple readouts, single lab","pmids":["39326735"],"is_preprint":false}],"current_model":"LRRC45 is a centrosomal protein with dual roles: at the proximal centriole it forms part of the proteinaceous centrosome linker (interacting with rootletin, CCDC102B, and C-Nap1/CEP250) to maintain centrosome cohesion, and at the distal appendages of the mother centriole it is recruited by Cep83-SCLT1 to recruit FBF1, organize centriolar satellites, establish the transition zone, and promote Rab8-vesicle docking during early axoneme extension—but is dispensable for CP110 removal or early ciliary vesicle docking; additionally, LRRC45 can interact with KEAP1 to stabilize NRF2 against proteasomal degradation and promote downstream oncogenic transcriptional programs in cancer contexts."},"narrative":{"mechanistic_narrative":"LRRC45 is a centriolar protein that functions in centrosome architecture and ciliogenesis [PMID:30131441, PMID:39882846]. At the distal appendages of the mother centriole it is recruited by the core appendage proteins Cep83 and SCLT1 and in turn recruits the keratin-binding protein FBF1, placing it within the hierarchical distal-appendage assembly network [PMID:30131441, PMID:39882846]. Functionally, LRRC45 promotes early ciliogenesis in CP110-uncapped centrioles by organizing centriolar satellites, establishing the transition zone, and promoting docking of Rab8-positive vesicles, while being dispensable for CP110 removal and for docking of early ciliary vesicles [PMID:30131441]. It also acts as a centrosome linker component, interacting with CCDC102B downstream of C-Nap1/CEP250 to support rootletin filament formation and centrosome cohesion [PMID:30404835], and localizes to the basal body of both primary and motile cilia across differentiated and stem cell types [PMID:30131441]. Biallelic loss-of-function variants in LRRC45 impair ciliogenesis, with patient fibroblasts showing reduced LRRC45 mRNA/protein and reduced cilia frequency and length, establishing a ciliopathy-associated role [PMID:39638757]. Independently of its centriolar function, LRRC45 competitively binds KEAP1 to inhibit ubiquitin-proteasome degradation of NRF2, enhancing NRF2 nuclear translocation and anti-ferroptotic activity in bladder cancer [PMID:39522565], and drives proliferation and metastasis through c-MYC/Slug and MMP2/MMP9 in lung adenocarcinoma [PMID:39326735].","teleology":[{"year":2018,"claim":"Established where LRRC45 sits in the distal-appendage recruitment hierarchy, answering how it is targeted to the mother centriole and what it recruits in turn.","evidence":"Localization and epistasis/recruitment-hierarchy experiments in cultured cells","pmids":["30131441"],"confidence":"High","gaps":["Molecular nature of the Cep83-SCLT1 binding interface not defined","Direct versus indirect recruitment of FBF1 not resolved"]},{"year":2018,"claim":"Defined which specific ciliogenesis steps require LRRC45, distinguishing its role in transition zone and satellite organization and Rab8 vesicle docking from steps it does not control.","evidence":"siRNA knockdown with functional readouts for transition zone assembly, centriolar satellite organization, Rab8 vesicle docking, and CP110 removal","pmids":["30131441"],"confidence":"High","gaps":["Mechanism by which LRRC45 organizes satellites unknown","Direct effectors linking LRRC45 to Rab8 vesicle docking not identified"]},{"year":2018,"claim":"Showed LRRC45 broadly localizes to the basal body across primary and motile cilia and multiple cell types, indicating a general rather than cell-type-restricted ciliary function.","evidence":"Immunofluorescence across differentiated and stem cells","pmids":["30131441"],"confidence":"Medium","gaps":["Functional contribution in motile cilia not tested","Quantitative localization dynamics across the cell cycle not addressed"]},{"year":2018,"claim":"Connected LRRC45 to the centrosome cohesion machinery, showing it interacts with CCDC102B within the C-Nap1/rootletin linker, expanding its role beyond ciliogenesis.","evidence":"Co-immunoprecipitation, localization, and siRNA knockdown with centrosome cohesion phenotype","pmids":["30404835"],"confidence":"Medium","gaps":["Direct binding between LRRC45 and CCDC102B not biochemically reconstituted","Whether LRRC45 is required for rootletin filament formation independent of CCDC102B unclear"]},{"year":2020,"claim":"Defined pathway independence between LRRC45 and Cep44, ruling out mutual dependence in centrosomal recruitment and clarifying the modularity of the appendage network.","evidence":"siRNA knockdown with immunofluorescence readout of centrosomal protein levels","pmids":["31974111"],"confidence":"Medium","gaps":["Functional interplay during ciliogenesis not tested","Single-method negative finding"]},{"year":2023,"claim":"Systematic CRISPR knockout mapping (preprint) positioned LRRC45 within the multi-step distal-appendage assembly network and its dependence on upstream components.","evidence":"CRISPR-Cas9 knockouts, localization, and functional cilia-formation assays (preprint)","pmids":["36711481"],"confidence":"Medium","gaps":["Superseded by peer-reviewed version","Precise step-by-step requirements still being resolved at this stage"]},{"year":2024,"claim":"Provided human genetic evidence that LRRC45 loss-of-function impairs ciliogenesis, linking the gene to disease through reduced cilia frequency and length in patient cells.","evidence":"Exome sequencing, RT-PCR splicing analysis, Western blot, and immunofluorescence in patient-derived fibroblasts","pmids":["39638757"],"confidence":"Medium","gaps":["Full clinical phenotype spectrum not delineated in this corpus","Rescue of the cilia defect not demonstrated"]},{"year":2024,"claim":"Identified a non-centriolar function: LRRC45 competitively binds KEAP1 to stabilize NRF2, defining a mechanism for its anti-ferroptotic, pro-tumorigenic activity.","evidence":"Co-IP, siRNA knockdown, NRF2 stability/degradation assay, nuclear fractionation, and ferroptosis assay in bladder cancer cells","pmids":["39522565"],"confidence":"Medium","gaps":["KEAP1 binding interface and competitive site not mapped","Relationship between centriolar and KEAP1-NRF2 functions unknown"]},{"year":2024,"claim":"Placed c-MYC/Slug and MMP2/MMP9 downstream of LRRC45 in driving proliferation and metastasis in lung adenocarcinoma via rescue epistasis.","evidence":"siRNA knockdown, western blot, colony formation, migration assay, rescue overexpression, and xenograft mouse model","pmids":["39326735"],"confidence":"Medium","gaps":["Direct molecular link between LRRC45 and c-MYC/Slug induction not defined","Whether this acts through the KEAP1-NRF2 axis untested"]},{"year":null,"claim":"How LRRC45's centriolar/ciliary scaffolding role mechanistically relates to its KEAP1-NRF2 and oncogenic signaling functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connecting centrosomal and cancer-signaling roles","No structural model of LRRC45 interactions","Substrate or enzymatic activity, if any, undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,3,5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2]},{"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":[0,1,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,9]}],"complexes":["centrosome linker","mother centriole distal appendages"],"partners":["CEP83","SCLT1","FBF1","CCDC102B","CEP250","KEAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CN5","full_name":"Leucine-rich repeat-containing protein 45","aliases":[],"length_aa":670,"mass_kda":76.0,"function":"Component of the proteinaceous fiber-like linker between two centrioles, required for centrosome cohesion","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q96CN5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC45","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC45","total_profiled":1310},"omim":[{"mim_id":"621312","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 45; LRRC45","url":"https://www.omim.org/entry/621312"},{"mim_id":"621147","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 102B; CCDC102B","url":"https://www.omim.org/entry/621147"},{"mim_id":"611399","title":"SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1","url":"https://www.omim.org/entry/611399"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRRC45"},"hgnc":{"alias_symbol":["MGC20806"],"prev_symbol":[]},"alphafold":{"accession":"Q96CN5","domains":[{"cath_id":"3.80.10.10","chopping":"33-252","consensus_level":"medium","plddt":92.4432,"start":33,"end":252},{"cath_id":"1.20.5","chopping":"566-611","consensus_level":"medium","plddt":77.1857,"start":566,"end":611}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CN5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CN5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CN5-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC45","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC45"},"sequence":{"accession":"Q96CN5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CN5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CN5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CN5"}},"corpus_meta":[{"pmid":"30131441","id":"PMC_30131441","title":"LRRC45 contributes to early steps of axoneme extension.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30131441","citation_count":42,"is_preprint":false},{"pmid":"39882846","id":"PMC_39882846","title":"A hierarchical pathway for assembly of the distal appendages that organize primary cilia.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39882846","citation_count":25,"is_preprint":false},{"pmid":"30404835","id":"PMC_30404835","title":"CCDC102B functions in centrosome linker assembly and centrosome cohesion.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30404835","citation_count":21,"is_preprint":false},{"pmid":"31260916","id":"PMC_31260916","title":"Association between long-term air pollution exposure and DNA methylation: The REGICOR study.","date":"2019","source":"Environmental research","url":"https://pubmed.ncbi.nlm.nih.gov/31260916","citation_count":20,"is_preprint":false},{"pmid":"34716235","id":"PMC_34716235","title":"Molecular diagnoses in the congenital malformations caused by ciliopathies cohort of the 100,000 Genomes Project.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34716235","citation_count":18,"is_preprint":false},{"pmid":"31974111","id":"PMC_31974111","title":"Cep44 functions in centrosome cohesion by stabilizing rootletin.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31974111","citation_count":14,"is_preprint":false},{"pmid":"36711481","id":"PMC_36711481","title":"A hierarchical pathway for assembly of the distal appendages that organize primary cilia.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36711481","citation_count":12,"is_preprint":false},{"pmid":"32599975","id":"PMC_32599975","title":"Genome-Wide Association Study for the Identification of Novel Genetic Variants Associated with the Risk of Neuroblastoma in Korean Children.","date":"2020","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/32599975","citation_count":11,"is_preprint":false},{"pmid":"39522565","id":"PMC_39522565","title":"LRRC45 accelerates bladder cancer development and ferroptosis inhibition via stabilizing NRF2 by competitively KEAP1 interaction.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39522565","citation_count":6,"is_preprint":false},{"pmid":"39326735","id":"PMC_39326735","title":"LRRC45 promotes lung cancer proliferation and progression by enhancing c-MYC, slug, MMP2, and MMP9 expression.","date":"2024","source":"Advances in medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39326735","citation_count":5,"is_preprint":false},{"pmid":"41227295","id":"PMC_41227295","title":"Astrocyte Transcriptomics in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41227295","citation_count":2,"is_preprint":false},{"pmid":"39638757","id":"PMC_39638757","title":"Biallelic Variants in LRRC45 Impair Ciliogenesis and Cause a Severe Neurological Disorder.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39638757","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8169,"output_tokens":2200,"usd":0.028754,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9202,"output_tokens":3096,"usd":0.061705,"stage2_stop_reason":"end_turn"},"total_usd":0.090459,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRC45 is recruited to the mother centriole distal appendages by the core appendage proteins Cep83 and SCLT1, and in turn recruits the keratin-binding protein FBF1.\",\n      \"method\": \"Localization studies and epistasis analysis in cultured cells (loss-of-function/recruitment hierarchy experiments)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal recruitment hierarchy established with multiple protein markers in a focused mechanistic study, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRC45 promotes early ciliogenesis in CP110-uncapped centrioles by organising centriolar satellites, establishing the transition zone, and promoting docking of Rab8 GTPase-positive vesicles; it is not required for docking of early ciliary vesicles or for removal of CP110 (negative finding for those two steps).\",\n      \"method\": \"siRNA knockdown with functional readouts: transition zone assembly, centriolar satellite organisation, Rab8 vesicle docking, CP110 removal assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with multiple specific phenotypic readouts in a single focused study\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LRRC45 localizes to the basal body of primary and motile cilia in both differentiated and stem cells, indicating a broad role in ciliogenesis.\",\n      \"method\": \"Immunofluorescence localization in multiple cell types including stem cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization established across multiple cell contexts in single lab study\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CCDC102B interacts with the centrosome linker component LRRC45 and is required for centrosome cohesion; CCDC102B is recruited by C-Nap1 (CEP250) and facilitates rootletin filament formation.\",\n      \"method\": \"Co-immunoprecipitation, localization studies, siRNA knockdown with centrosome cohesion phenotype\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction with LRRC45 established, multiple methods in single lab study\",\n      \"pmids\": [\"30404835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cep44 does not impinge on the stability or centrosomal recruitment of LRRC45, and LRRC45 does not impinge on Cep44 — these proteins are independently recruited to the centrosome (negative finding establishing pathway independence).\",\n      \"method\": \"siRNA knockdown with immunofluorescence readout of centrosomal protein levels\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD/KO with defined protein-level readout, single lab single method\",\n      \"pmids\": [\"31974111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Comprehensive CRISPR-Cas9 knockout analysis places LRRC45 within the distal appendage hierarchy; its precise position and requirement for each cilia-formation step (vesicle recruitment, IFT initiation, CP110 removal) was mapped relative to other distal appendage proteins including CEP83, SCLT1, CEP164, TTBK2, FBF1, CEP89.\",\n      \"method\": \"CRISPR-Cas9 knockout panel, localization, and functional assays for four ciliary steps\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive CRISPR KO panel with multiple functional assays, replicated from preprint in peer-reviewed journal\",\n      \"pmids\": [\"39882846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR-Cas9 knockout analysis (preprint version) confirms LRRC45 as a distal appendage protein in a complex hierarchical assembly network; its localization depends on upstream components and it participates in multiple steps of cilia formation.\",\n      \"method\": \"CRISPR-Cas9 knockouts, localization, functional cilia-formation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint, multiple KO experiments with functional assays, but superseded by published version\",\n      \"pmids\": [\"36711481\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic loss-of-function variants in LRRC45 impair ciliogenesis: patient fibroblasts with a splicing variant causing exon 14 skipping show drastically reduced LRRC45 mRNA and protein and a significant reduction in primary cilia frequency and length.\",\n      \"method\": \"Exome sequencing, RT-PCR splicing analysis, Western blot, immunofluorescence cilia frequency/length measurement in patient-derived fibroblasts\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional validation in patient-derived cells with multiple methods, single study\",\n      \"pmids\": [\"39638757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRRC45 competitively interacts with KEAP1, inhibiting ubiquitin-proteasome-mediated degradation of NRF2, thereby enhancing nuclear translocation of NRF2 and its anti-ferroptotic activity in bladder cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, NRF2 protein stability/degradation assay, nuclear fractionation, ferroptosis assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — competitive binding and functional pathway established by Co-IP and KD with defined readouts, single lab study\",\n      \"pmids\": [\"39522565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRRC45 knockdown in lung adenocarcinoma cells reduces c-MYC, Slug, MMP2, and MMP9 expression; overexpression of c-MYC/Slug or MMP2/MMP9 in LRRC45-deficient cells partially or fully rescues proliferation and metastasis defects, placing these downstream of LRRC45.\",\n      \"method\": \"siRNA knockdown, western blot, colony formation, migration assay, rescue overexpression, xenograft mouse model\",\n      \"journal\": \"Advances in medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiments with multiple readouts, single lab\",\n      \"pmids\": [\"39326735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC45 is a centrosomal protein with dual roles: at the proximal centriole it forms part of the proteinaceous centrosome linker (interacting with rootletin, CCDC102B, and C-Nap1/CEP250) to maintain centrosome cohesion, and at the distal appendages of the mother centriole it is recruited by Cep83-SCLT1 to recruit FBF1, organize centriolar satellites, establish the transition zone, and promote Rab8-vesicle docking during early axoneme extension—but is dispensable for CP110 removal or early ciliary vesicle docking; additionally, LRRC45 can interact with KEAP1 to stabilize NRF2 against proteasomal degradation and promote downstream oncogenic transcriptional programs in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRC45 is a centriolar protein that functions in centrosome architecture and ciliogenesis [#0, #5]. At the distal appendages of the mother centriole it is recruited by the core appendage proteins Cep83 and SCLT1 and in turn recruits the keratin-binding protein FBF1, placing it within the hierarchical distal-appendage assembly network [#0, #5]. Functionally, LRRC45 promotes early ciliogenesis in CP110-uncapped centrioles by organizing centriolar satellites, establishing the transition zone, and promoting docking of Rab8-positive vesicles, while being dispensable for CP110 removal and for docking of early ciliary vesicles [#1]. It also acts as a centrosome linker component, interacting with CCDC102B downstream of C-Nap1/CEP250 to support rootletin filament formation and centrosome cohesion [#3], and localizes to the basal body of both primary and motile cilia across differentiated and stem cell types [#2]. Biallelic loss-of-function variants in LRRC45 impair ciliogenesis, with patient fibroblasts showing reduced LRRC45 mRNA/protein and reduced cilia frequency and length, establishing a ciliopathy-associated role [#7]. Independently of its centriolar function, LRRC45 competitively binds KEAP1 to inhibit ubiquitin-proteasome degradation of NRF2, enhancing NRF2 nuclear translocation and anti-ferroptotic activity in bladder cancer [#8], and drives proliferation and metastasis through c-MYC/Slug and MMP2/MMP9 in lung adenocarcinoma [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established where LRRC45 sits in the distal-appendage recruitment hierarchy, answering how it is targeted to the mother centriole and what it recruits in turn.\",\n      \"evidence\": \"Localization and epistasis/recruitment-hierarchy experiments in cultured cells\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular nature of the Cep83-SCLT1 binding interface not defined\", \"Direct versus indirect recruitment of FBF1 not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined which specific ciliogenesis steps require LRRC45, distinguishing its role in transition zone and satellite organization and Rab8 vesicle docking from steps it does not control.\",\n      \"evidence\": \"siRNA knockdown with functional readouts for transition zone assembly, centriolar satellite organization, Rab8 vesicle docking, and CP110 removal\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LRRC45 organizes satellites unknown\", \"Direct effectors linking LRRC45 to Rab8 vesicle docking not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed LRRC45 broadly localizes to the basal body across primary and motile cilia and multiple cell types, indicating a general rather than cell-type-restricted ciliary function.\",\n      \"evidence\": \"Immunofluorescence across differentiated and stem cells\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional contribution in motile cilia not tested\", \"Quantitative localization dynamics across the cell cycle not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected LRRC45 to the centrosome cohesion machinery, showing it interacts with CCDC102B within the C-Nap1/rootletin linker, expanding its role beyond ciliogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation, localization, and siRNA knockdown with centrosome cohesion phenotype\",\n      \"pmids\": [\"30404835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between LRRC45 and CCDC102B not biochemically reconstituted\", \"Whether LRRC45 is required for rootletin filament formation independent of CCDC102B unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined pathway independence between LRRC45 and Cep44, ruling out mutual dependence in centrosomal recruitment and clarifying the modularity of the appendage network.\",\n      \"evidence\": \"siRNA knockdown with immunofluorescence readout of centrosomal protein levels\",\n      \"pmids\": [\"31974111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional interplay during ciliogenesis not tested\", \"Single-method negative finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Systematic CRISPR knockout mapping (preprint) positioned LRRC45 within the multi-step distal-appendage assembly network and its dependence on upstream components.\",\n      \"evidence\": \"CRISPR-Cas9 knockouts, localization, and functional cilia-formation assays (preprint)\",\n      \"pmids\": [\"36711481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Superseded by peer-reviewed version\", \"Precise step-by-step requirements still being resolved at this stage\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided human genetic evidence that LRRC45 loss-of-function impairs ciliogenesis, linking the gene to disease through reduced cilia frequency and length in patient cells.\",\n      \"evidence\": \"Exome sequencing, RT-PCR splicing analysis, Western blot, and immunofluorescence in patient-derived fibroblasts\",\n      \"pmids\": [\"39638757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full clinical phenotype spectrum not delineated in this corpus\", \"Rescue of the cilia defect not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a non-centriolar function: LRRC45 competitively binds KEAP1 to stabilize NRF2, defining a mechanism for its anti-ferroptotic, pro-tumorigenic activity.\",\n      \"evidence\": \"Co-IP, siRNA knockdown, NRF2 stability/degradation assay, nuclear fractionation, and ferroptosis assay in bladder cancer cells\",\n      \"pmids\": [\"39522565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KEAP1 binding interface and competitive site not mapped\", \"Relationship between centriolar and KEAP1-NRF2 functions unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed c-MYC/Slug and MMP2/MMP9 downstream of LRRC45 in driving proliferation and metastasis in lung adenocarcinoma via rescue epistasis.\",\n      \"evidence\": \"siRNA knockdown, western blot, colony formation, migration assay, rescue overexpression, and xenograft mouse model\",\n      \"pmids\": [\"39326735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between LRRC45 and c-MYC/Slug induction not defined\", \"Whether this acts through the KEAP1-NRF2 axis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRRC45's centriolar/ciliary scaffolding role mechanistically relates to its KEAP1-NRF2 and oncogenic signaling functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism connecting centrosomal and cancer-signaling roles\", \"No structural model of LRRC45 interactions\", \"Substrate or enzymatic activity, if any, undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 3, 5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"complexes\": [\"centrosome linker\", \"mother centriole distal appendages\"],\n    \"partners\": [\"CEP83\", \"SCLT1\", \"FBF1\", \"CCDC102B\", \"CEP250\", \"KEAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}