{"gene":"RIBC2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2025,"finding":"RIBC2 (and its paralog RIBC1) are microtubule inner proteins (MIPs) localized in the inner lumen of doublet microtubules (DMTs) of mouse sperm flagella. Loss of both RIBC1 and RIBC2 (double knockout) significantly decreases sperm motility and litter size, while single knockouts have milder or no fertility effects. No gross axonemal structural abnormalities were detected by TEM in double-KO sperm, indicating RIBC2 contributes to flagellar motility through a mechanism not detectable at the gross ultrastructural level. RIBC2 function in sperm motility depends on RIBC1.","method":"CRISPR/Cas9 knockout mice (single and double KO), sperm motility analysis, transmission electron microscopy, cryo-EM/AI-based localization","journal":"Andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype (sperm motility, fertility), cryo-EM localization, but single lab and localization data partially from prior AI/cryo-EM studies cited rather than fully described in this abstract","pmids":["40265983"],"is_preprint":false},{"year":2022,"finding":"Ribc2 physically interacts with Ckb (creatine kinase B) and Ybx2 in multi-ciliated cells, as identified by immunoprecipitation and mass spectrometry. Both Ckb and Ybx2 localize to the axoneme of motile cilia in Xenopus laevis embryonic epithelium. Depletion of Ribc2 reduces the axonemal localization of Ckb and Ybx2. Knockdown of Ckb or Ybx2 causes abnormal ciliary beating and reduced cilia-driven fluid flow, placing these proteins downstream of or co-functional with Ribc2 in ciliary beating.","method":"Immunoprecipitation/mass spectrometry (IP/MS), antisense morpholino knockdown in Xenopus, fluorescent bead flow assay, immunostaining, western blot","journal":"Genes & Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal IP/MS identification of binding partners, localization experiments, functional knockdown with defined ciliary beating phenotype in Xenopus; single lab","pmids":["36508087"],"is_preprint":false},{"year":2020,"finding":"RIBC2 protein localizes to motile ciliated cells, consistent with a role as a motile cilia-associated protein. New localization experiments confirmed RIBC2 mRNA and protein are present in motile ciliated cells.","method":"Transcriptomics network deconvolution, in situ localization of mRNA and protein in motile ciliated cells","journal":"Scientific Reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization experiment without functional consequence established; single lab, single method type","pmids":["32616903"],"is_preprint":false},{"year":2026,"finding":"Silencing RIBC2 in esophageal cancer cells (transformed epithelial cells and established EC lines) significantly inhibited cell proliferation, migration, and invasion in vitro and in vivo, establishing a functional role for RIBC2 in tumor cell growth and motility.","method":"RNAi/siRNA silencing, cell proliferation assays, migration and invasion assays, in vivo experiments, transcriptome sequencing","journal":"PLoS One","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional KD with cellular phenotype but no pathway placement or molecular mechanism identified; single lab","pmids":["41666178"],"is_preprint":false}],"current_model":"RIBC2 is a RIB43A domain-containing coiled-coil protein that localizes as a microtubule inner protein within the doublet microtubules of motile cilia and sperm flagella, where it cooperates with its paralog RIBC1 to support sperm motility; in multi-ciliated epithelial cells, RIBC2 physically binds Ckb and Ybx2, recruiting them to the ciliary axoneme to sustain ciliary beating and cilia-driven fluid flow."},"narrative":{"mechanistic_narrative":"RIBC2 is a microtubule inner protein (MIP) of the doublet microtubules of motile cilia and sperm flagella, where it supports ciliary and flagellar motility [PMID:40265983]. In mouse sperm flagella, RIBC2 and its paralog RIBC1 reside in the inner lumen of doublet microtubules, and concurrent loss of both proteins reduces sperm motility and fertility without producing gross axonemal ultrastructural defects, indicating that RIBC2 contributes to motility through a mechanism not resolvable at the level of overall axonemal architecture; its function in this context depends on RIBC1 [PMID:40265983]. In multi-ciliated epithelial cells, RIBC2 physically interacts with creatine kinase B (Ckb) and Ybx2 and is required for their localization to the ciliary axoneme, and loss of either partner disrupts ciliary beating and cilia-driven fluid flow, placing RIBC2 upstream of an axonemal beating module [PMID:36508087]. Beyond these motile-cilia roles, no further biochemical mechanism for RIBC2 has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Established that RIBC2 is expressed and localized specifically in motile ciliated cells, first placing it in the motile cilia context.","evidence":"Transcriptomic network deconvolution plus in situ mRNA and protein localization in motile ciliated cells","pmids":["32616903"],"confidence":"Low","gaps":["Localization without functional consequence established","No interaction partners or molecular activity defined","Subcompartment within the cilium not resolved"]},{"year":2022,"claim":"Identified physical partners of RIBC2 and showed it is required to recruit them to the axoneme, linking RIBC2 to ciliary beating.","evidence":"Reciprocal IP/MS, morpholino knockdown in Xenopus, immunostaining, and fluorescent-bead flow assays","pmids":["36508087"],"confidence":"Medium","gaps":["Mechanism by which RIBC2 recruits Ckb/Ybx2 to the axoneme unknown","How partner localization translates into beating not defined","Single-lab Xenopus model only"]},{"year":2025,"claim":"Defined RIBC2 as a doublet-microtubule inner protein required, together with RIBC1, for sperm flagellar motility and fertility.","evidence":"Single and double CRISPR/Cas9 knockout mice, sperm motility and fertility analysis, TEM, and cryo-EM/AI-based localization","pmids":["40265983"],"confidence":"Medium","gaps":["No gross ultrastructural defect, so the molecular basis of motility loss is unresolved","Functional interdependence with RIBC1 not mechanistically explained","Whether the Ckb/Ybx2 module operates in flagella as in cilia untested"]},{"year":2026,"claim":"Extended RIBC2 function beyond cilia by showing it promotes esophageal cancer cell proliferation, migration, and invasion.","evidence":"siRNA silencing in esophageal cancer cell lines, proliferation/migration/invasion assays, in vivo experiments, transcriptome sequencing","pmids":["41666178"],"confidence":"Low","gaps":["No molecular mechanism or pathway placement for the tumor phenotype","Relationship to its ciliary MIP role unknown","Single-lab observation"]},{"year":null,"claim":"How RIBC2 as a microtubule inner protein mechanistically supports axonemal beating, and how its ciliary role relates to its proliferative role in cancer cells, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of how RIBC2 stabilizes or tunes doublet microtubules","Recruitment mechanism for Ckb/Ybx2 undefined","No link established between MIP function and tumor cell phenotype"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["CKB","YBX2","RIBC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H4K1","full_name":"RIB43A-like with coiled-coils protein 2","aliases":[],"length_aa":382,"mass_kda":45.4,"function":"Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, flagellum axoneme","url":"https://www.uniprot.org/uniprotkb/Q9H4K1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RIBC2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":77,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RIBC2","total_profiled":1310},"omim":[{"mim_id":"621115","title":"RIB43A DOMAIN WITH COILED-COILS PROTEIN 2; RIBC2","url":"https://www.omim.org/entry/621115"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Connecting piece","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"End piece","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":12.6},{"tissue":"fallopian tube","ntpm":9.2},{"tissue":"testis","ntpm":28.8}],"url":"https://www.proteinatlas.org/search/RIBC2"},"hgnc":{"alias_symbol":["DKFZp566F0546","FLJ25720"],"prev_symbol":["C22orf11"]},"alphafold":{"accession":"Q9H4K1","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4K1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4K1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H4K1-F1-predicted_aligned_error_v6.png","plddt_mean":86.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RIBC2","jax_strain_url":"https://www.jax.org/strain/search?query=RIBC2"},"sequence":{"accession":"Q9H4K1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H4K1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H4K1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H4K1"}},"corpus_meta":[{"pmid":"24424412","id":"PMC_24424412","title":"Coordinated genomic control of ciliogenesis and cell movement by RFX2.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24424412","citation_count":121,"is_preprint":false},{"pmid":"32616903","id":"PMC_32616903","title":"The transcriptional signature associated with human motile cilia.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32616903","citation_count":46,"is_preprint":false},{"pmid":"27517910","id":"PMC_27517910","title":"A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27517910","citation_count":30,"is_preprint":false},{"pmid":"36714595","id":"PMC_36714595","title":"Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36714595","citation_count":13,"is_preprint":false},{"pmid":"34674573","id":"PMC_34674573","title":"Identifying a cervical cancer survival signature based on mRNA expression and genome-wide copy number variations.","date":"2021","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34674573","citation_count":10,"is_preprint":false},{"pmid":"40265983","id":"PMC_40265983","title":"The absence of both RIBC1 and RIBC2 induces decreased sperm motility and litter size in male mice.","date":"2025","source":"Andrology","url":"https://pubmed.ncbi.nlm.nih.gov/40265983","citation_count":3,"is_preprint":false},{"pmid":"37394087","id":"PMC_37394087","title":"Epigenome-wide association study identifies Vogt-Koyanagi-Harada disease-associated DNA methylation loci in Chinese.","date":"2023","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/37394087","citation_count":3,"is_preprint":false},{"pmid":"22931212","id":"PMC_22931212","title":"Elucidation of the mechanism of ribose conjugation in a pyrazole-containing compound in rodent liver.","date":"2012","source":"Xenobiotica; the fate of foreign compounds in biological systems","url":"https://pubmed.ncbi.nlm.nih.gov/22931212","citation_count":3,"is_preprint":false},{"pmid":"36508087","id":"PMC_36508087","title":"Ckb and Ybx2 interact with Ribc2 and are necessary for the ciliary beating of multi-cilia.","date":"2022","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36508087","citation_count":2,"is_preprint":false},{"pmid":"41666178","id":"PMC_41666178","title":"Integrative bioinformatics and experiments identify RIBC2 as a key regulator in the esophageal cancer.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/41666178","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7694,"output_tokens":1195,"usd":0.020504,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7753,"output_tokens":1756,"usd":0.041333,"stage2_stop_reason":"end_turn"},"total_usd":0.061837,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"RIBC2 (and its paralog RIBC1) are microtubule inner proteins (MIPs) localized in the inner lumen of doublet microtubules (DMTs) of mouse sperm flagella. Loss of both RIBC1 and RIBC2 (double knockout) significantly decreases sperm motility and litter size, while single knockouts have milder or no fertility effects. No gross axonemal structural abnormalities were detected by TEM in double-KO sperm, indicating RIBC2 contributes to flagellar motility through a mechanism not detectable at the gross ultrastructural level. RIBC2 function in sperm motility depends on RIBC1.\",\n      \"method\": \"CRISPR/Cas9 knockout mice (single and double KO), sperm motility analysis, transmission electron microscopy, cryo-EM/AI-based localization\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype (sperm motility, fertility), cryo-EM localization, but single lab and localization data partially from prior AI/cryo-EM studies cited rather than fully described in this abstract\",\n      \"pmids\": [\"40265983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Ribc2 physically interacts with Ckb (creatine kinase B) and Ybx2 in multi-ciliated cells, as identified by immunoprecipitation and mass spectrometry. Both Ckb and Ybx2 localize to the axoneme of motile cilia in Xenopus laevis embryonic epithelium. Depletion of Ribc2 reduces the axonemal localization of Ckb and Ybx2. Knockdown of Ckb or Ybx2 causes abnormal ciliary beating and reduced cilia-driven fluid flow, placing these proteins downstream of or co-functional with Ribc2 in ciliary beating.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry (IP/MS), antisense morpholino knockdown in Xenopus, fluorescent bead flow assay, immunostaining, western blot\",\n      \"journal\": \"Genes & Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal IP/MS identification of binding partners, localization experiments, functional knockdown with defined ciliary beating phenotype in Xenopus; single lab\",\n      \"pmids\": [\"36508087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RIBC2 protein localizes to motile ciliated cells, consistent with a role as a motile cilia-associated protein. New localization experiments confirmed RIBC2 mRNA and protein are present in motile ciliated cells.\",\n      \"method\": \"Transcriptomics network deconvolution, in situ localization of mRNA and protein in motile ciliated cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization experiment without functional consequence established; single lab, single method type\",\n      \"pmids\": [\"32616903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Silencing RIBC2 in esophageal cancer cells (transformed epithelial cells and established EC lines) significantly inhibited cell proliferation, migration, and invasion in vitro and in vivo, establishing a functional role for RIBC2 in tumor cell growth and motility.\",\n      \"method\": \"RNAi/siRNA silencing, cell proliferation assays, migration and invasion assays, in vivo experiments, transcriptome sequencing\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional KD with cellular phenotype but no pathway placement or molecular mechanism identified; single lab\",\n      \"pmids\": [\"41666178\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RIBC2 is a RIB43A domain-containing coiled-coil protein that localizes as a microtubule inner protein within the doublet microtubules of motile cilia and sperm flagella, where it cooperates with its paralog RIBC1 to support sperm motility; in multi-ciliated epithelial cells, RIBC2 physically binds Ckb and Ybx2, recruiting them to the ciliary axoneme to sustain ciliary beating and cilia-driven fluid flow.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RIBC2 is a microtubule inner protein (MIP) of the doublet microtubules of motile cilia and sperm flagella, where it supports ciliary and flagellar motility [#0]. In mouse sperm flagella, RIBC2 and its paralog RIBC1 reside in the inner lumen of doublet microtubules, and concurrent loss of both proteins reduces sperm motility and fertility without producing gross axonemal ultrastructural defects, indicating that RIBC2 contributes to motility through a mechanism not resolvable at the level of overall axonemal architecture; its function in this context depends on RIBC1 [#0]. In multi-ciliated epithelial cells, RIBC2 physically interacts with creatine kinase B (Ckb) and Ybx2 and is required for their localization to the ciliary axoneme, and loss of either partner disrupts ciliary beating and cilia-driven fluid flow, placing RIBC2 upstream of an axonemal beating module [#1]. Beyond these motile-cilia roles, no further biochemical mechanism for RIBC2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that RIBC2 is expressed and localized specifically in motile ciliated cells, first placing it in the motile cilia context.\",\n      \"evidence\": \"Transcriptomic network deconvolution plus in situ mRNA and protein localization in motile ciliated cells\",\n      \"pmids\": [\"32616903\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization without functional consequence established\", \"No interaction partners or molecular activity defined\", \"Subcompartment within the cilium not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified physical partners of RIBC2 and showed it is required to recruit them to the axoneme, linking RIBC2 to ciliary beating.\",\n      \"evidence\": \"Reciprocal IP/MS, morpholino knockdown in Xenopus, immunostaining, and fluorescent-bead flow assays\",\n      \"pmids\": [\"36508087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which RIBC2 recruits Ckb/Ybx2 to the axoneme unknown\", \"How partner localization translates into beating not defined\", \"Single-lab Xenopus model only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined RIBC2 as a doublet-microtubule inner protein required, together with RIBC1, for sperm flagellar motility and fertility.\",\n      \"evidence\": \"Single and double CRISPR/Cas9 knockout mice, sperm motility and fertility analysis, TEM, and cryo-EM/AI-based localization\",\n      \"pmids\": [\"40265983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No gross ultrastructural defect, so the molecular basis of motility loss is unresolved\", \"Functional interdependence with RIBC1 not mechanistically explained\", \"Whether the Ckb/Ybx2 module operates in flagella as in cilia untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended RIBC2 function beyond cilia by showing it promotes esophageal cancer cell proliferation, migration, and invasion.\",\n      \"evidence\": \"siRNA silencing in esophageal cancer cell lines, proliferation/migration/invasion assays, in vivo experiments, transcriptome sequencing\",\n      \"pmids\": [\"41666178\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No molecular mechanism or pathway placement for the tumor phenotype\", \"Relationship to its ciliary MIP role unknown\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RIBC2 as a microtubule inner protein mechanistically supports axonemal beating, and how its ciliary role relates to its proliferative role in cancer cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of how RIBC2 stabilizes or tunes doublet microtubules\", \"Recruitment mechanism for Ckb/Ybx2 undefined\", \"No link established between MIP function and tumor cell phenotype\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"CKB\", \"YBX2\", \"RIBC1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}