{"gene":"MRPL4","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2023,"finding":"mRpL4 (MRPL4) physically interacts with the WD40 repeat protein Wap (the Drosophila ortholog) and is required in Notch signal-receiving cells to activate transcription of Notch signaling target genes during Drosophila wing development; genetic epistasis placed mRpL4 upstream of target gene transcription in the Notch pathway.","method":"Genetic epistasis analysis, physical interaction (co-immunoprecipitation/pulldown implied by 'physically interacts'), rescue experiments with human MRPL4 replacing fly mRpL4, zebrafish mrpl4 knockout showing downregulated Notch signaling components","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic epistasis in Drosophila, physical interaction data, cross-species rescue with human MRPL4, and independent zebrafish knockout validation, multiple orthogonal methods across two model organisms in one study","pmids":["37009823"],"is_preprint":false},{"year":2026,"finding":"Zebrafish mrpl4 knockout causes defects in intestinal growth and maturation, disruption of intestinal epithelial integrity, and inflammatory responses; Notch signaling is downregulated in mrpl4 knockout fish, and reactivation of Notch signaling partially rescues intestinal defects, placing Mrpl4 upstream of Notch signaling in intestinal development.","method":"mrpl4 knockout in zebrafish, phenotypic analysis of intestinal development, Notch signaling pathway analysis, pharmacological Notch reactivation rescue experiment","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined cellular phenotype, pathway placement via epistasis (Notch rescue), consistent with parallel Drosophila findings from the same group","pmids":["41709118"],"is_preprint":false},{"year":1995,"finding":"Yeast MRP-L4 (encoding mt ribosomal protein YmL4) is indispensable for mitochondrial function in cells on non-fermentable carbon sources; unlike nearly all other MRPs, disruption of MRP-L4 also impairs growth on fermentable carbon sources, suggesting additional cytosolic and/or mt functions beyond mitochondrial protein biosynthesis.","method":"Yeast gene disruption (knockout), growth analysis on fermentable vs. non-fermentable carbon sources, protein sequence analysis identifying signal peptide and hydrophobic domains","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean yeast gene disruption with defined growth phenotype on two carbon source types, single lab but two distinct phenotypic readouts","pmids":["7828914"],"is_preprint":false}],"current_model":"MRPL4 (mRpL4/uL4m) is a mitochondrial large ribosomal subunit protein with an established function beyond mitochondrial translation: it physically interacts with the WD40 protein Wap and is required in Notch signal-receiving cells to activate Notch target gene transcription, a role conserved from Drosophila to zebrafish (where mrpl4 knockout disrupts intestinal development via downregulated Notch signaling); in yeast, its ortholog MRP-L4 is additionally required for growth on fermentable carbon sources, implying extra-mitoribosomal cytosolic or mitochondrial functions."},"narrative":{"mechanistic_narrative":"MRPL4 (mRpL4/uL4m) is a mitochondrial large ribosomal subunit protein that also functions as a positive regulator of Notch signaling required for epithelial development [PMID:37009823, PMID:41709118]. In Notch signal-receiving cells during Drosophila wing development, mRpL4 physically interacts with the WD40 repeat protein Wap and acts upstream of Notch target gene transcription, a requirement that is conserved: human MRPL4 rescues the fly phenotype, and zebrafish mrpl4 knockout downregulates Notch signaling [PMID:37009823]. In zebrafish, loss of mrpl4 disrupts intestinal growth, epithelial integrity, and maturation while triggering inflammatory responses, and pharmacological reactivation of Notch partially rescues these intestinal defects, placing Mrpl4 genetically upstream of Notch in gut development [PMID:41709118]. The yeast ortholog MRP-L4 is indispensable for growth on non-fermentable carbon sources, but unlike most mitochondrial ribosomal proteins its disruption also impairs growth on fermentable carbon sources, indicating functions beyond mitochondrial protein biosynthesis [PMID:7828914]. The biochemical mechanism by which a mitoribosomal protein influences Notch target gene transcription has not been characterized in the available corpus.","teleology":[{"year":1995,"claim":"Established that MRPL4 has functions beyond canonical mitochondrial translation, since unlike other mitochondrial ribosomal proteins its loss impairs growth even under fermentable conditions.","evidence":"Yeast MRP-L4 gene disruption with growth analysis on fermentable versus non-fermentable carbon sources, plus sequence analysis identifying signal peptide and hydrophobic domains","pmids":["7828914"],"confidence":"Medium","gaps":["The molecular nature of the extra-mitoribosomal function was not defined","Single lab; no identification of a non-translational partner or pathway","Whether the fermentable-growth defect reflects a cytosolic role was not resolved"]},{"year":2023,"claim":"Defined a specific non-canonical role for MRPL4 in Notch signaling by showing it physically binds the WD40 protein Wap and is required in receiving cells for Notch target gene transcription, with the function conserved to human and zebrafish.","evidence":"Drosophila genetic epistasis, physical interaction assays, cross-species rescue with human MRPL4, and zebrafish mrpl4 knockout","pmids":["37009823"],"confidence":"High","gaps":["The biochemical mechanism linking a mitoribosomal protein to Notch transcriptional activation is unknown","Whether MRPL4's mitoribosomal function and Notch role are mechanistically coupled or separable was not resolved","The subcellular site of the MRPL4–Wap interaction was not localized"]},{"year":2026,"claim":"Extended the Notch role to vertebrate organ development by showing mrpl4 loss disrupts intestinal growth and integrity via downregulated Notch signaling, with Notch reactivation partially rescuing the defect.","evidence":"Zebrafish mrpl4 knockout with intestinal phenotyping and pharmacological Notch reactivation rescue","pmids":["41709118"],"confidence":"High","gaps":["Partial rescue indicates Notch-independent contributions that were not characterized","The cellular target of MRPL4 within the intestinal epithelium was not pinpointed","The mechanistic basis of the accompanying inflammatory response was not defined"]},{"year":null,"claim":"How a mitochondrial large ribosomal subunit protein mechanistically activates Notch target gene transcription remains unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No molecular mechanism connecting MRPL4–Wap binding to transcriptional output","No structural or biochemical model of the non-mitoribosomal MRPL4 pool","Whether the role requires intact mitochondrial translation is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1]}],"complexes":["mitochondrial large ribosomal subunit"],"partners":["WAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYD3","full_name":"Large ribosomal subunit protein uL4m","aliases":["39S ribosomal protein L4, mitochondrial","L4mt","MRP-L4"],"length_aa":311,"mass_kda":34.9,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q9BYD3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPL4","classification":"Common Essential","n_dependent_lines":1036,"n_total_lines":1208,"dependency_fraction":0.8576158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HNRNPD","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MRPL4","total_profiled":1310},"omim":[{"mim_id":"611823","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L4; MRPL4","url":"https://www.omim.org/entry/611823"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPL4"},"hgnc":{"alias_symbol":["CGI-28","uL4m"],"prev_symbol":[]},"alphafold":{"accession":"Q9BYD3","domains":[{"cath_id":"3.40.1370.10","chopping":"46-107_164-277","consensus_level":"high","plddt":94.6809,"start":46,"end":277},{"cath_id":"-","chopping":"111-128_138-160","consensus_level":"medium","plddt":94.4744,"start":111,"end":160}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYD3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYD3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYD3-F1-predicted_aligned_error_v6.png","plddt_mean":83.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPL4","jax_strain_url":"https://www.jax.org/strain/search?query=MRPL4"},"sequence":{"accession":"Q9BYD3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYD3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYD3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYD3"}},"corpus_meta":[{"pmid":"21625490","id":"PMC_21625490","title":"Genome-wide association study for atopy and allergic rhinitis in a Singapore Chinese population.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21625490","citation_count":73,"is_preprint":false},{"pmid":"23472126","id":"PMC_23472126","title":"The association between polymorphisms in the MRPL4 and TNF-α genes and susceptibility to allergic rhinitis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23472126","citation_count":19,"is_preprint":false},{"pmid":"37009823","id":"PMC_37009823","title":"The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37009823","citation_count":14,"is_preprint":false},{"pmid":"31545431","id":"PMC_31545431","title":"miR‑126a‑5p‑Dbp and miR‑31a‑Crot/Mrpl4 interaction pairs crucial for the development of hypertension and stroke.","date":"2019","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/31545431","citation_count":13,"is_preprint":false},{"pmid":"34359804","id":"PMC_34359804","title":"Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34359804","citation_count":12,"is_preprint":false},{"pmid":"7828914","id":"PMC_7828914","title":"Gene MRP-L4, encoding mitochondrial ribosomal protein YmL4, is indispensable for proper non-respiratory cell functions in yeast.","date":"1995","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/7828914","citation_count":10,"is_preprint":false},{"pmid":"32344118","id":"PMC_32344118","title":"The effects of environmental stressors on candidate aging associated genes.","date":"2020","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/32344118","citation_count":10,"is_preprint":false},{"pmid":"36059095","id":"PMC_36059095","title":"Proteomics reveals MRPL4 as a high-risk factor and a potential diagnostic biomarker for prostate cancer.","date":"2022","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/36059095","citation_count":8,"is_preprint":false},{"pmid":"37158323","id":"PMC_37158323","title":"Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia.","date":"2023","source":"The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37158323","citation_count":5,"is_preprint":false},{"pmid":"38336623","id":"PMC_38336623","title":"Comprehensive genotyping analysis of single nucleotide polymorphisms responsible for beef marbling in Japanese Black cattle.","date":"2024","source":"BMC genomic data","url":"https://pubmed.ncbi.nlm.nih.gov/38336623","citation_count":3,"is_preprint":false},{"pmid":"39170385","id":"PMC_39170385","title":"MicroRNA-2861 regulates the proliferation and apoptosis of human retinal vascular endothelial cells treated with high glucose by targeting NDUFB7.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39170385","citation_count":2,"is_preprint":false},{"pmid":"37990886","id":"PMC_37990886","title":"Epigenetic signature discriminates lymphatic metastasis in BRAF wild-type thyroid carcinoma: methylation role of GRIK2.","date":"2023","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/37990886","citation_count":1,"is_preprint":false},{"pmid":"40311750","id":"PMC_40311750","title":"Proteomics suggests the role of Cxcl12 secreted by hucMSCs in the treatment of lipopolysaccharide-acute lung injury.","date":"2025","source":"Microvascular research","url":"https://pubmed.ncbi.nlm.nih.gov/40311750","citation_count":1,"is_preprint":false},{"pmid":"41318970","id":"PMC_41318970","title":"A Six-Gene Signature Related to Mitochondrial Dysfunction as a Potential Diagnostic Biomarker for Sarcopenia.","date":"2025","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41318970","citation_count":1,"is_preprint":false},{"pmid":"41709118","id":"PMC_41709118","title":"Mitochondrial protein Mrpl4 is required for zebrafish intestinal development.","date":"2026","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/41709118","citation_count":0,"is_preprint":false},{"pmid":"40989695","id":"PMC_40989695","title":"Identification of MAEA protein as a potential target for chemoresistance in osteosarcoma using bioinformatics and proteomic analysis.","date":"2025","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40989695","citation_count":0,"is_preprint":false},{"pmid":"41616541","id":"PMC_41616541","title":"Comprehensive characterization of transcriptional regulation during HCG-induced follicle maturation in mandarin fish (Siniperca chuatsi): Insights from transcriptomics.","date":"2026","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/41616541","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.10.24315152","title":"Biallelic variants in<i>MRPL49</i>cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency","date":"2024-10-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.10.24315152","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11062,"output_tokens":946,"usd":0.023688,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7466,"output_tokens":1769,"usd":0.040778,"stage2_stop_reason":"end_turn"},"total_usd":0.064466,"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\": 2023,\n      \"finding\": \"mRpL4 (MRPL4) physically interacts with the WD40 repeat protein Wap (the Drosophila ortholog) and is required in Notch signal-receiving cells to activate transcription of Notch signaling target genes during Drosophila wing development; genetic epistasis placed mRpL4 upstream of target gene transcription in the Notch pathway.\",\n      \"method\": \"Genetic epistasis analysis, physical interaction (co-immunoprecipitation/pulldown implied by 'physically interacts'), rescue experiments with human MRPL4 replacing fly mRpL4, zebrafish mrpl4 knockout showing downregulated Notch signaling components\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic epistasis in Drosophila, physical interaction data, cross-species rescue with human MRPL4, and independent zebrafish knockout validation, multiple orthogonal methods across two model organisms in one study\",\n      \"pmids\": [\"37009823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Zebrafish mrpl4 knockout causes defects in intestinal growth and maturation, disruption of intestinal epithelial integrity, and inflammatory responses; Notch signaling is downregulated in mrpl4 knockout fish, and reactivation of Notch signaling partially rescues intestinal defects, placing Mrpl4 upstream of Notch signaling in intestinal development.\",\n      \"method\": \"mrpl4 knockout in zebrafish, phenotypic analysis of intestinal development, Notch signaling pathway analysis, pharmacological Notch reactivation rescue experiment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined cellular phenotype, pathway placement via epistasis (Notch rescue), consistent with parallel Drosophila findings from the same group\",\n      \"pmids\": [\"41709118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast MRP-L4 (encoding mt ribosomal protein YmL4) is indispensable for mitochondrial function in cells on non-fermentable carbon sources; unlike nearly all other MRPs, disruption of MRP-L4 also impairs growth on fermentable carbon sources, suggesting additional cytosolic and/or mt functions beyond mitochondrial protein biosynthesis.\",\n      \"method\": \"Yeast gene disruption (knockout), growth analysis on fermentable vs. non-fermentable carbon sources, protein sequence analysis identifying signal peptide and hydrophobic domains\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean yeast gene disruption with defined growth phenotype on two carbon source types, single lab but two distinct phenotypic readouts\",\n      \"pmids\": [\"7828914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPL4 (mRpL4/uL4m) is a mitochondrial large ribosomal subunit protein with an established function beyond mitochondrial translation: it physically interacts with the WD40 protein Wap and is required in Notch signal-receiving cells to activate Notch target gene transcription, a role conserved from Drosophila to zebrafish (where mrpl4 knockout disrupts intestinal development via downregulated Notch signaling); in yeast, its ortholog MRP-L4 is additionally required for growth on fermentable carbon sources, implying extra-mitoribosomal cytosolic or mitochondrial functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MRPL4 (mRpL4/uL4m) is a mitochondrial large ribosomal subunit protein that also functions as a positive regulator of Notch signaling required for epithelial development [#0, #1]. In Notch signal-receiving cells during Drosophila wing development, mRpL4 physically interacts with the WD40 repeat protein Wap and acts upstream of Notch target gene transcription, a requirement that is conserved: human MRPL4 rescues the fly phenotype, and zebrafish mrpl4 knockout downregulates Notch signaling [#0]. In zebrafish, loss of mrpl4 disrupts intestinal growth, epithelial integrity, and maturation while triggering inflammatory responses, and pharmacological reactivation of Notch partially rescues these intestinal defects, placing Mrpl4 genetically upstream of Notch in gut development [#1]. The yeast ortholog MRP-L4 is indispensable for growth on non-fermentable carbon sources, but unlike most mitochondrial ribosomal proteins its disruption also impairs growth on fermentable carbon sources, indicating functions beyond mitochondrial protein biosynthesis [#2]. The biochemical mechanism by which a mitoribosomal protein influences Notch target gene transcription has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that MRPL4 has functions beyond canonical mitochondrial translation, since unlike other mitochondrial ribosomal proteins its loss impairs growth even under fermentable conditions.\",\n      \"evidence\": \"Yeast MRP-L4 gene disruption with growth analysis on fermentable versus non-fermentable carbon sources, plus sequence analysis identifying signal peptide and hydrophobic domains\",\n      \"pmids\": [\"7828914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular nature of the extra-mitoribosomal function was not defined\",\n        \"Single lab; no identification of a non-translational partner or pathway\",\n        \"Whether the fermentable-growth defect reflects a cytosolic role was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a specific non-canonical role for MRPL4 in Notch signaling by showing it physically binds the WD40 protein Wap and is required in receiving cells for Notch target gene transcription, with the function conserved to human and zebrafish.\",\n      \"evidence\": \"Drosophila genetic epistasis, physical interaction assays, cross-species rescue with human MRPL4, and zebrafish mrpl4 knockout\",\n      \"pmids\": [\"37009823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The biochemical mechanism linking a mitoribosomal protein to Notch transcriptional activation is unknown\",\n        \"Whether MRPL4's mitoribosomal function and Notch role are mechanistically coupled or separable was not resolved\",\n        \"The subcellular site of the MRPL4–Wap interaction was not localized\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the Notch role to vertebrate organ development by showing mrpl4 loss disrupts intestinal growth and integrity via downregulated Notch signaling, with Notch reactivation partially rescuing the defect.\",\n      \"evidence\": \"Zebrafish mrpl4 knockout with intestinal phenotyping and pharmacological Notch reactivation rescue\",\n      \"pmids\": [\"41709118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Partial rescue indicates Notch-independent contributions that were not characterized\",\n        \"The cellular target of MRPL4 within the intestinal epithelium was not pinpointed\",\n        \"The mechanistic basis of the accompanying inflammatory response was not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a mitochondrial large ribosomal subunit protein mechanistically activates Notch target gene transcription remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No molecular mechanism connecting MRPL4–Wap binding to transcriptional output\",\n        \"No structural or biochemical model of the non-mitoribosomal MRPL4 pool\",\n        \"Whether the role requires intact mitochondrial translation is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"mitochondrial large ribosomal subunit\"],\n    \"partners\": [\"Wap\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}