{"gene":"LRRC58","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2025,"finding":"LRRC58 is the substrate adaptor of a CUL2-based (and CUL5-based) E3 ubiquitin ligase complex (CRL) that mediates proteasomal degradation of CDO1 (cysteine dioxygenase 1), the rate-limiting enzyme of cysteine catabolism to taurine. Cysteine abundance regulates LRRC58 stability inversely: under cysteine-replete conditions, LRRC58 undergoes auto-ubiquitination and proteasomal self-degradation; under cysteine deprivation, LRRC58 is stabilized and promotes CDO1 ubiquitylation specifically at Lys8.","method":"Covariation mass spectrometry (metabolite-protein covariation architecture), biochemical reconstitution of CRL complex, cryo-EM structural analysis, saturation mutagenesis stability profiling, quantitative proteomics, active cullin-RING ligase profiling, cellular depletion experiments in hepatocytes/mice","journal":"Nature / bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — multiple independent labs with reconstitution, cryo-EM structure, mutagenesis, and in vivo mouse experiments; replicated across at least three independent studies","pmids":["40963025","bio_10.1101_2025.11.14.688510","bio_10.1101_2025.09.23.678073","41270722"],"is_preprint":false},{"year":2025,"finding":"Depletion of LRRC58 in hepatocytes stabilizes CDO1, driving increased cysteine flux to taurine, which promotes bile acid conjugation and lowers hepatic cholesterol in mice, demonstrating that the LRRC58-CDO1 axis controls liver cysteine utilization and cholesterol handling.","method":"Hepatocyte-specific LRRC58 depletion in mice, metabolite flux measurements, cholesterol assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo KD with defined metabolic phenotype, orthogonal biochemical measurements in a rigorous study","pmids":["40963025"],"is_preprint":false},{"year":2025,"finding":"LRRC58-mediated CDO1 degradation is essential to prevent ferroptotic cell death under conditions of cysteine scarcity; CDO1 mutations causing human neurodevelopmental defects encode dominant-active proteins refractory to LRRC58 recognition, placing LRRC58-CDO1 as a critical regulator of cysteine homeostasis safeguarding neural development.","method":"Cell death assays under cysteine deprivation, saturation mutagenesis of CDO1-LRRC58 interface, analysis of patient-derived CDO1 mutations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — functional loss-of-pathway assay with mechanistic mutagenesis in a single preprint lab","pmids":["bio_10.1101_2025.09.23.678073"],"is_preprint":true},{"year":2025,"finding":"The 3' UTR of Lrrc58 mRNA acts as a TDMD (target-directed microRNA degradation) trigger for miR-503-5p: binding of miR-503-5p to the Lrrc58 3' UTR induces ZSWIM8-dependent ubiquitylation and decay of associated AGO proteins, leading to miR-503-5p turnover. Deletion of this trigger site in mice abrogates TDMD of miR-503-5p and causes miR-503-dependent embryonic growth restriction.","method":"AGO cross-linking and sequencing of hybrids (AGO-CLASH), CRISPR deletion of trigger site in mouse 3' UTR, mouse body size phenotyping, miRNA quantification","journal":"Genes & development / bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 — independently replicated by two labs (Mendell and Bartel groups) using AGO-CLASH, in vivo mouse genetics with trigger-site deletion, and miRNA quantification","pmids":["41213800","40631113","41871909","41279844","bio_10.1101_2025.11.06.686990","bio_10.1101_2025.06.30.662380"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, the ortholog lrr-2/LRRC58 post-translationally regulates levels of cysteine dioxygenase (cdo-1/CDO1), placing lrr-2 in the animal sulfur metabolism pathway controlling cysteine and H2S production, as established by genetic epistasis in a forward selection screen.","method":"Forward genetic selection, genetic epistasis in C. elegans, mutant allele analysis, exogenous H2S rescue experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in a model organism ortholog with functional rescue, single lab","pmids":["39786993"],"is_preprint":false}],"current_model":"LRRC58 functions as a substrate adaptor of a CUL2/CUL5-based E3 ubiquitin ligase that ubiquitylates CDO1 (at Lys8) for proteasomal degradation, with LRRC58 stability itself inversely regulated by cysteine abundance via auto-ubiquitination; additionally, the Lrrc58 3' UTR acts as a TDMD trigger RNA that drives ZSWIM8-dependent degradation of miR-503-5p to promote embryonic body growth."},"narrative":{"teleology":[{"year":2025,"claim":"Establishing that LRRC58 ortholog lrr-2 post-translationally controls CDO1 levels in C. elegans revealed a conserved regulatory axis in sulfur amino acid metabolism, answering the question of how cysteine dioxygenase abundance is tuned across metazoans.","evidence":"Forward genetic selection and epistasis analysis in C. elegans with H₂S rescue experiments","pmids":["39786993"],"confidence":"Medium","gaps":["Single-lab genetic study in a model organism; biochemical mechanism of regulation not defined","Direct physical interaction between lrr-2 and cdo-1 not demonstrated","No mammalian validation at that time"]},{"year":2025,"claim":"Identification of LRRC58 as the substrate adaptor of a CUL2/CUL5 E3 ligase complex that ubiquitylates CDO1 at Lys8, combined with cryo-EM structure and demonstration that cysteine abundance inversely regulates LRRC58 stability via auto-ubiquitination, established the complete molecular logic of a nutrient-sensing degradation switch for cysteine homeostasis.","evidence":"Metabolite-protein covariation mass spectrometry, cryo-EM structural analysis, biochemical reconstitution of CRL complex, saturation mutagenesis stability profiling, active CRL profiling, and in vivo hepatocyte depletion in mice across multiple independent laboratories","pmids":["40963025","41270722"],"confidence":"High","gaps":["Structural basis for cysteine sensing by LRRC58 (how cysteine triggers auto-ubiquitination) not fully resolved","Whether additional substrates beyond CDO1 are targeted by the LRRC58-CRL complex is unknown","Tissue-specific regulation outside liver not characterized"]},{"year":2025,"claim":"Demonstrating that LRRC58-mediated CDO1 degradation prevents ferroptosis under cysteine scarcity, and that patient CDO1 mutations causing neurodevelopmental defects escape LRRC58 recognition, linked this ubiquitin ligase axis to human disease and cell survival.","evidence":"Cell death assays under cysteine deprivation, saturation mutagenesis of CDO1-LRRC58 binding interface, analysis of patient-derived CDO1 mutations (preprint)","pmids":["bio_10.1101_2025.09.23.678073"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed; disease-causative CDO1 mutations need independent clinical validation","Whether LRRC58 loss alone is sufficient for ferroptosis in vivo is untested","Mechanism by which dominant-active CDO1 mutants evade LRRC58 recognition not structurally defined"]},{"year":2025,"claim":"Discovery that the Lrrc58 3′ UTR functions as a TDMD trigger RNA for miR-503-5p, driving ZSWIM8-dependent AGO degradation and miRNA turnover, revealed a second, protein-coding-independent biological function of the LRRC58 locus in controlling embryonic body growth.","evidence":"AGO-CLASH, CRISPR deletion of the trigger site in the mouse Lrrc58 3′ UTR, body size phenotyping, miRNA quantification; independently replicated by two laboratories","pmids":["41213800","40631113","41871909","41279844"],"confidence":"High","gaps":["Whether the TDMD function and the CRL adaptor function interact or are independently regulated is unknown","The full spectrum of miRNAs regulated by the Lrrc58 3′ UTR beyond miR-503-5p is not defined","Mechanism linking miR-503-5p to embryonic growth restriction at the target mRNA level is uncharacterized"]},{"year":null,"claim":"Open questions remain about how cysteine is sensed to toggle LRRC58 auto-ubiquitination, whether LRRC58 targets substrates beyond CDO1, and how the dual functions of the LRRC58 locus (CRL adaptor protein and TDMD trigger mRNA) are coordinated in physiology.","evidence":"","pmids":[],"confidence":"High","gaps":["Cysteine-sensing mechanism upstream of LRRC58 stabilization is undefined","No systematic substrate profiling beyond CDO1","Interplay between LRRC58 protein function and 3′ UTR TDMD activity unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3]}],"complexes":["CUL2-LRRC58 CRL complex","CUL5-LRRC58 CRL complex"],"partners":["CUL2","CUL5","CDO1","ZSWIM8","AGO2"],"other_free_text":[]},"mechanistic_narrative":"LRRC58 is a leucine-rich repeat protein that functions as the substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase complex, targeting cysteine dioxygenase 1 (CDO1) for proteasomal degradation at Lys8 to maintain cysteine homeostasis [PMID:40963025, PMID:41270722]. LRRC58 stability is itself inversely regulated by cysteine availability: cysteine-replete conditions trigger LRRC58 auto-ubiquitination and self-degradation, whereas cysteine deprivation stabilizes LRRC58 to promote CDO1 turnover, thereby preventing ferroptotic cell death caused by futile cysteine catabolism [PMID:40963025]. In mice, hepatocyte-specific LRRC58 depletion stabilizes CDO1, redirecting cysteine flux toward taurine and bile acid conjugation and lowering hepatic cholesterol [PMID:40963025]. Independently of its protein-coding function, the Lrrc58 3′ UTR serves as a target-directed miRNA degradation (TDMD) trigger RNA that recruits miR-503-5p to AGO for ZSWIM8-dependent destruction, and deletion of this trigger site in mice causes miR-503-dependent embryonic growth restriction [PMID:41213800, PMID:40631113]."},"prefetch_data":{"uniprot":{"accession":"Q96CX6","full_name":"Leucine-rich repeat-containing protein 58","aliases":[],"length_aa":371,"mass_kda":40.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96CX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRRC58","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRRC58","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRRC58"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q96CX6","domains":[{"cath_id":"3.80.10.10","chopping":"16-253","consensus_level":"medium","plddt":91.5504,"start":16,"end":253}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96CX6-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRRC58","jax_strain_url":"https://www.jax.org/strain/search?query=LRRC58"},"sequence":{"accession":"Q96CX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96CX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96CX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96CX6"}},"corpus_meta":[{"pmid":"27434957","id":"PMC_27434957","title":"[IDENTIFICATION OF A NEW DIAGNOSTIC MARKERS OF PROSTATIC CANCER, USING NOTI-MICROCHIPS].","date":"2016","source":"Klinichna khirurhiia","url":"https://pubmed.ncbi.nlm.nih.gov/27434957","citation_count":7,"is_preprint":false},{"pmid":"39786993","id":"PMC_39786993","title":"Hydrogen sulfide mediates the interaction between C. elegans and Actinobacteria from its natural microbial environment.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39786993","citation_count":6,"is_preprint":false},{"pmid":"35969671","id":"PMC_35969671","title":"Evaluation of a Pooling Chemoproteomics Strategy with an FDA-Approved Drug Library.","date":"2022","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35969671","citation_count":5,"is_preprint":false},{"pmid":"40963025","id":"PMC_40963025","title":"Covariation MS uncovers a protein that controls cysteine catabolism.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40963025","citation_count":4,"is_preprint":false},{"pmid":"36324506","id":"PMC_36324506","title":"Identification of genes modified by N6-methyladenosine in patients with colorectal cancer recurrence.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36324506","citation_count":4,"is_preprint":false},{"pmid":"41213800","id":"PMC_41213800","title":"Plagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503.","date":"2026","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/41213800","citation_count":2,"is_preprint":false},{"pmid":"40631113","id":"PMC_40631113","title":"Plagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40631113","citation_count":2,"is_preprint":false},{"pmid":"41279844","id":"PMC_41279844","title":"mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279844","citation_count":2,"is_preprint":false},{"pmid":"41871909","id":"PMC_41871909","title":"mRNA 3' UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth.","date":"2026","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/41871909","citation_count":0,"is_preprint":false},{"pmid":"41270722","id":"PMC_41270722","title":"Leveraging biochemical covariance to better understand biology.","date":"2025","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/41270722","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.14.688510","title":"Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1","date":"2025-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688510","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.23.678073","title":"LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance","date":"2025-09-24","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.23.678073","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.06.686990","title":"mRNA 3′ UTRs direct microRNA degradation to participate in imprinted gene networks and regulate growth","date":"2025-11-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.06.686990","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.30.662380","title":"<i>Plagl1</i> and <i>Lrrc58</i> control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503","date":"2025-07-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.30.662380","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8239,"output_tokens":1583,"usd":0.024231},"stage2":{"model":"claude-opus-4-6","input_tokens":4817,"output_tokens":1946,"usd":0.109103},"total_usd":0.133334,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 is the substrate adaptor of a CUL2-based (and CUL5-based) E3 ubiquitin ligase complex (CRL) that mediates proteasomal degradation of CDO1 (cysteine dioxygenase 1), the rate-limiting enzyme of cysteine catabolism to taurine. Cysteine abundance regulates LRRC58 stability inversely: under cysteine-replete conditions, LRRC58 undergoes auto-ubiquitination and proteasomal self-degradation; under cysteine deprivation, LRRC58 is stabilized and promotes CDO1 ubiquitylation specifically at Lys8.\",\n      \"method\": \"Covariation mass spectrometry (metabolite-protein covariation architecture), biochemical reconstitution of CRL complex, cryo-EM structural analysis, saturation mutagenesis stability profiling, quantitative proteomics, active cullin-RING ligase profiling, cellular depletion experiments in hepatocytes/mice\",\n      \"journal\": \"Nature / bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple independent labs with reconstitution, cryo-EM structure, mutagenesis, and in vivo mouse experiments; replicated across at least three independent studies\",\n      \"pmids\": [\"40963025\", \"bio_10.1101_2025.11.14.688510\", \"bio_10.1101_2025.09.23.678073\", \"41270722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Depletion of LRRC58 in hepatocytes stabilizes CDO1, driving increased cysteine flux to taurine, which promotes bile acid conjugation and lowers hepatic cholesterol in mice, demonstrating that the LRRC58-CDO1 axis controls liver cysteine utilization and cholesterol handling.\",\n      \"method\": \"Hepatocyte-specific LRRC58 depletion in mice, metabolite flux measurements, cholesterol assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KD with defined metabolic phenotype, orthogonal biochemical measurements in a rigorous study\",\n      \"pmids\": [\"40963025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58-mediated CDO1 degradation is essential to prevent ferroptotic cell death under conditions of cysteine scarcity; CDO1 mutations causing human neurodevelopmental defects encode dominant-active proteins refractory to LRRC58 recognition, placing LRRC58-CDO1 as a critical regulator of cysteine homeostasis safeguarding neural development.\",\n      \"method\": \"Cell death assays under cysteine deprivation, saturation mutagenesis of CDO1-LRRC58 interface, analysis of patient-derived CDO1 mutations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional loss-of-pathway assay with mechanistic mutagenesis in a single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The 3' UTR of Lrrc58 mRNA acts as a TDMD (target-directed microRNA degradation) trigger for miR-503-5p: binding of miR-503-5p to the Lrrc58 3' UTR induces ZSWIM8-dependent ubiquitylation and decay of associated AGO proteins, leading to miR-503-5p turnover. Deletion of this trigger site in mice abrogates TDMD of miR-503-5p and causes miR-503-dependent embryonic growth restriction.\",\n      \"method\": \"AGO cross-linking and sequencing of hybrids (AGO-CLASH), CRISPR deletion of trigger site in mouse 3' UTR, mouse body size phenotyping, miRNA quantification\",\n      \"journal\": \"Genes & development / bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — independently replicated by two labs (Mendell and Bartel groups) using AGO-CLASH, in vivo mouse genetics with trigger-site deletion, and miRNA quantification\",\n      \"pmids\": [\"41213800\", \"40631113\", \"41871909\", \"41279844\", \"bio_10.1101_2025.11.06.686990\", \"bio_10.1101_2025.06.30.662380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, the ortholog lrr-2/LRRC58 post-translationally regulates levels of cysteine dioxygenase (cdo-1/CDO1), placing lrr-2 in the animal sulfur metabolism pathway controlling cysteine and H2S production, as established by genetic epistasis in a forward selection screen.\",\n      \"method\": \"Forward genetic selection, genetic epistasis in C. elegans, mutant allele analysis, exogenous H2S rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in a model organism ortholog with functional rescue, single lab\",\n      \"pmids\": [\"39786993\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC58 functions as a substrate adaptor of a CUL2/CUL5-based E3 ubiquitin ligase that ubiquitylates CDO1 (at Lys8) for proteasomal degradation, with LRRC58 stability itself inversely regulated by cysteine abundance via auto-ubiquitination; additionally, the Lrrc58 3' UTR acts as a TDMD trigger RNA that drives ZSWIM8-dependent degradation of miR-503-5p to promote embryonic body growth.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRRC58 is a leucine-rich repeat protein that functions as the substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase complex, targeting cysteine dioxygenase 1 (CDO1) for proteasomal degradation at Lys8 to maintain cysteine homeostasis [PMID:40963025, PMID:41270722]. LRRC58 stability is itself inversely regulated by cysteine availability: cysteine-replete conditions trigger LRRC58 auto-ubiquitination and self-degradation, whereas cysteine deprivation stabilizes LRRC58 to promote CDO1 turnover, thereby preventing ferroptotic cell death caused by futile cysteine catabolism [PMID:40963025]. In mice, hepatocyte-specific LRRC58 depletion stabilizes CDO1, redirecting cysteine flux toward taurine and bile acid conjugation and lowering hepatic cholesterol [PMID:40963025]. Independently of its protein-coding function, the Lrrc58 3′ UTR serves as a target-directed miRNA degradation (TDMD) trigger RNA that recruits miR-503-5p to AGO for ZSWIM8-dependent destruction, and deletion of this trigger site in mice causes miR-503-dependent embryonic growth restriction [PMID:41213800, PMID:40631113].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing that LRRC58 ortholog lrr-2 post-translationally controls CDO1 levels in C. elegans revealed a conserved regulatory axis in sulfur amino acid metabolism, answering the question of how cysteine dioxygenase abundance is tuned across metazoans.\",\n      \"evidence\": \"Forward genetic selection and epistasis analysis in C. elegans with H₂S rescue experiments\",\n      \"pmids\": [\"39786993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab genetic study in a model organism; biochemical mechanism of regulation not defined\",\n        \"Direct physical interaction between lrr-2 and cdo-1 not demonstrated\",\n        \"No mammalian validation at that time\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of LRRC58 as the substrate adaptor of a CUL2/CUL5 E3 ligase complex that ubiquitylates CDO1 at Lys8, combined with cryo-EM structure and demonstration that cysteine abundance inversely regulates LRRC58 stability via auto-ubiquitination, established the complete molecular logic of a nutrient-sensing degradation switch for cysteine homeostasis.\",\n      \"evidence\": \"Metabolite-protein covariation mass spectrometry, cryo-EM structural analysis, biochemical reconstitution of CRL complex, saturation mutagenesis stability profiling, active CRL profiling, and in vivo hepatocyte depletion in mice across multiple independent laboratories\",\n      \"pmids\": [\"40963025\", \"41270722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for cysteine sensing by LRRC58 (how cysteine triggers auto-ubiquitination) not fully resolved\",\n        \"Whether additional substrates beyond CDO1 are targeted by the LRRC58-CRL complex is unknown\",\n        \"Tissue-specific regulation outside liver not characterized\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that LRRC58-mediated CDO1 degradation prevents ferroptosis under cysteine scarcity, and that patient CDO1 mutations causing neurodevelopmental defects escape LRRC58 recognition, linked this ubiquitin ligase axis to human disease and cell survival.\",\n      \"evidence\": \"Cell death assays under cysteine deprivation, saturation mutagenesis of CDO1-LRRC58 binding interface, analysis of patient-derived CDO1 mutations (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed; disease-causative CDO1 mutations need independent clinical validation\",\n        \"Whether LRRC58 loss alone is sufficient for ferroptosis in vivo is untested\",\n        \"Mechanism by which dominant-active CDO1 mutants evade LRRC58 recognition not structurally defined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Discovery that the Lrrc58 3′ UTR functions as a TDMD trigger RNA for miR-503-5p, driving ZSWIM8-dependent AGO degradation and miRNA turnover, revealed a second, protein-coding-independent biological function of the LRRC58 locus in controlling embryonic body growth.\",\n      \"evidence\": \"AGO-CLASH, CRISPR deletion of the trigger site in the mouse Lrrc58 3′ UTR, body size phenotyping, miRNA quantification; independently replicated by two laboratories\",\n      \"pmids\": [\"41213800\", \"40631113\", \"41871909\", \"41279844\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the TDMD function and the CRL adaptor function interact or are independently regulated is unknown\",\n        \"The full spectrum of miRNAs regulated by the Lrrc58 3′ UTR beyond miR-503-5p is not defined\",\n        \"Mechanism linking miR-503-5p to embryonic growth restriction at the target mRNA level is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Open questions remain about how cysteine is sensed to toggle LRRC58 auto-ubiquitination, whether LRRC58 targets substrates beyond CDO1, and how the dual functions of the LRRC58 locus (CRL adaptor protein and TDMD trigger mRNA) are coordinated in physiology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cysteine-sensing mechanism upstream of LRRC58 stabilization is undefined\",\n        \"No systematic substrate profiling beyond CDO1\",\n        \"Interplay between LRRC58 protein function and 3′ UTR TDMD activity unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"CUL2-LRRC58 CRL complex\",\n      \"CUL5-LRRC58 CRL complex\"\n    ],\n    \"partners\": [\n      \"CUL2\",\n      \"CUL5\",\n      \"CDO1\",\n      \"ZSWIM8\",\n      \"AGO2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}