{"gene":"LRRC58","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2025,"finding":"LRRC58 is the substrate adaptor of a CUL2- (or CUL5-) based cullin-RING E3 ubiquitin ligase complex that mediates proteasomal degradation of CDO1 (cysteine dioxygenase 1), the rate-limiting enzyme of the cysteine-to-taurine catabolic shunt. Cysteine abundance regulates this pathway: under cysteine-replete conditions LRRC58 is destabilized via auto-ubiquitination and proteasomal degradation, whereas cysteine starvation stabilizes LRRC58 to permit CDO1 ubiquitylation and degradation.","method":"Quantitative proteomics (covariation MS), active CRL profiling, biochemical reconstitution, cryo-EM structures, cellular stability studies, and depletion of LRRC58 in hepatocytes in mice","journal":"Nature / Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution, cryo-EM structural validation, saturation mutagenesis, and in vivo mouse depletion experiments independently replicated across at least three separate laboratories (PMIDs 40963025, 42098103, preprint bio_10.1101_2025.09.23.678073)","pmids":["40963025","42098103"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structures show that LRRC58 forms an active CUL2- or CUL5-based CRL complex and selectively positions CDO1 for ubiquitylation at Lys8 of CDO1. Disease-associated CDO1 mutants that map to the LRRC58 interface are impaired for endogenous ubiquitylation by this pathway.","method":"Cryo-EM structural determination, biochemical reconstitution, saturation mutagenesis stability profiling, and VHL-based degrader assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus reconstitution in a single rigorous study","pmids":["42098103"],"is_preprint":false},{"year":2025,"finding":"LRRC58 depletion stabilizes CDO1, increases cysteine flux to taurine, and lowers hepatic cholesterol in mice, demonstrating that the LRRC58-CDO1 axis links cysteine catabolism to cholesterol handling in the liver.","method":"Hepatocyte-specific LRRC58 depletion in mice with metabolite flux and cholesterol measurements","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic depletion with defined metabolic phenotype, replicated across independent studies","pmids":["40963025"],"is_preprint":false},{"year":2025,"finding":"The LRRC58-mediated degradation of CDO1 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.","method":"Saturation mutagenesis stability profiling, cell-death assays under cysteine deprivation, structural modeling of CDO1-LRRC58 interface","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — saturation mutagenesis plus cell-based ferroptosis assay, single lab, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.09.23.678073"],"is_preprint":true},{"year":2025,"finding":"In C. elegans, the LRRC58 ortholog lrr-2 post-translationally regulates levels of cysteine dioxygenase (cdo-1/CDO1), placing lrr-2 in the animal sulfur metabolism pathway and demonstrating regulation of cysteine and H2S production.","method":"Forward genetic selection in C. elegans, epistasis analysis with cdo-1 and cth-2 mutants, exogenous H2S rescue experiments","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans with functional rescue, single lab","pmids":["39786993"],"is_preprint":false},{"year":2026,"finding":"The 3' UTR of Lrrc58 mRNA functions 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 Argonaute proteins, leading to miR-503-5p turnover. Deletion of this trigger site in mice abrogates TDMD and causes miR-503-dependent embryonic growth restriction.","method":"AGO-CLASH (crosslinking and sequencing of hybrids), CRISPR deletion of trigger site in mice, miRNA abundance measurements, genetic rescue experiments","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — AGO-CLASH identification plus in vivo CRISPR trigger-site deletion with defined growth phenotype, independently replicated by two groups (PMIDs 41213800, 41871909)","pmids":["41213800","41871909"],"is_preprint":false}],"current_model":"LRRC58 is a cysteine-responsive substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase that ubiquitylates CDO1 at Lys8 to drive its proteasomal degradation; under cysteine abundance LRRC58 itself is auto-ubiquitinated and degraded, whereas cysteine deprivation stabilizes LRRC58 to suppress CDO1 and thereby conserve cysteine (preventing ferroptosis), and this axis is conserved from C. elegans to mammals where it also governs liver cholesterol handling via taurine production; additionally, the Lrrc58 3' UTR acts as a TDMD trigger RNA that promotes ZSWIM8-dependent degradation of miR-503-5p to support embryonic growth."},"narrative":{"mechanistic_narrative":"LRRC58 is the cysteine-responsive substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase that couples sulfur amino acid sensing to the proteasomal control of cysteine catabolism [PMID:40963025, PMID:42098103]. It recruits cysteine dioxygenase CDO1 — the rate-limiting enzyme of the cysteine-to-taurine shunt — and positions it for ubiquitylation at Lys8; the regulatory logic is set by cysteine availability, with cysteine repletion driving LRRC58 auto-ubiquitination and turnover while cysteine starvation stabilizes LRRC58 to enforce CDO1 degradation [PMID:40963025, PMID:42098103]. Through this axis LRRC58 conserves cysteine, and its loss in hepatocytes stabilizes CDO1, raises cysteine-to-taurine flux, and lowers hepatic cholesterol, linking cysteine catabolism to liver cholesterol handling [PMID:40963025]. The adaptor function is conserved to C. elegans, where the ortholog lrr-2 post-translationally regulates cysteine dioxygenase and sulfur metabolism [PMID:39786993]. Independently of its protein product, the Lrrc58 3' UTR acts as a TDMD trigger RNA: it base-pairs with miR-503-5p to drive ZSWIM8-dependent decay of the miRNA, a function required for normal embryonic growth [PMID:41213800, PMID:41871909].","teleology":[{"year":2025,"claim":"Establishing LRRC58 as a substrate adaptor of a cullin-RING ligase defined a molecular machine for regulated CDO1 destruction and revealed cysteine itself as the upstream regulatory signal.","evidence":"Quantitative covariation proteomics, active CRL profiling, biochemical reconstitution, cryo-EM, and hepatocyte depletion in mice","pmids":["40963025","42098103"],"confidence":"High","gaps":["The biochemical mechanism by which cysteine abundance triggers LRRC58 auto-ubiquitination is not defined","Whether CUL2 versus CUL5 usage is context-dependent is not resolved"]},{"year":2026,"claim":"Cryo-EM and saturation mutagenesis pinpointed the CDO1-LRRC58 interface and the Lys8 ubiquitylation site, explaining how disease-associated CDO1 mutants escape recognition.","evidence":"Cryo-EM structural determination, reconstitution, saturation mutagenesis stability profiling, and VHL-based degrader assays","pmids":["42098103"],"confidence":"High","gaps":["Structural basis for cysteine-dependent LRRC58 stability switching is not captured","Whether other substrates besides CDO1 engage the same interface is unknown"]},{"year":2025,"claim":"Hepatocyte-specific depletion connected the LRRC58-CDO1 axis to whole-organ physiology, showing cysteine catabolic flux governs hepatic cholesterol levels.","evidence":"Hepatocyte-specific LRRC58 depletion in mice with metabolite flux and cholesterol measurements","pmids":["40963025"],"confidence":"High","gaps":["Mechanistic link between taurine production and cholesterol handling is not detailed","Tissue specificity of this phenotype beyond liver is unaddressed"]},{"year":2025,"claim":"C. elegans genetics established that adaptor-mediated control of cysteine dioxygenase is evolutionarily conserved and feeds into H2S/sulfur metabolism.","evidence":"Forward genetic selection, epistasis with cdo-1 and cth-2, and exogenous H2S rescue in C. elegans","pmids":["39786993"],"confidence":"Medium","gaps":["Whether lrr-2 acts via an orthologous CRL complex in worms was not biochemically confirmed","Single-lab genetic study"]},{"year":2025,"claim":"Saturation mutagenesis and cysteine-deprivation cell-death assays linked LRRC58-mediated CDO1 turnover to ferroptosis prevention and to dominant-active human CDO1 disease alleles.","evidence":"Saturation mutagenesis stability profiling, cell-death assays under cysteine deprivation, and interface modeling (preprint)","pmids":["bio_10.1101_2025.09.23.678073"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Direct demonstration that CDO1 disease mutants cause neurodevelopmental phenotypes via ferroptosis is incomplete"]},{"year":2026,"claim":"A distinct, RNA-level function emerged: the Lrrc58 3' UTR is a TDMD trigger for miR-503-5p driving ZSWIM8-dependent miRNA decay required for embryonic growth.","evidence":"AGO-CLASH, CRISPR deletion of the trigger site in mice, miRNA abundance and genetic rescue experiments","pmids":["41213800","41871909"],"confidence":"High","gaps":["Whether the protein-coding and TDMD functions of the Lrrc58 locus are coordinately regulated is unknown","The growth-restriction mechanism downstream of miR-503-5p is not mapped"]},{"year":null,"claim":"How cysteine concentration is biochemically transduced into LRRC58 stability, and whether the CRL adaptor has substrates beyond CDO1, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No direct cysteine-sensing mechanism for LRRC58 stability identified","Substrate repertoire beyond CDO1 uncharacterized","Relationship between the protein-coding and trigger-RNA roles of the locus undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]}],"complexes":["CUL2-RING E3 ligase (CRL2)","CUL5-RING E3 ligase (CRL5)"],"partners":["CDO1","CUL2","CUL5","ZSWIM8"],"other_free_text":[]}},"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":7,"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":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":"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":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":"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":1,"is_preprint":false},{"pmid":"42098103","id":"PMC_42098103","title":"Cysteine availability tunes ubiquitin signaling via inverse stability of LRRC58 E3 ligase and its substrate CDO1.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42098103","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_2025.09.23.678073","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":8958,"output_tokens":1759,"usd":0.02663,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8544,"output_tokens":2560,"usd":0.05336,"stage2_stop_reason":"end_turn"},"total_usd":0.07999,"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\": 2025,\n      \"finding\": \"LRRC58 is the substrate adaptor of a CUL2- (or CUL5-) based cullin-RING E3 ubiquitin ligase complex that mediates proteasomal degradation of CDO1 (cysteine dioxygenase 1), the rate-limiting enzyme of the cysteine-to-taurine catabolic shunt. Cysteine abundance regulates this pathway: under cysteine-replete conditions LRRC58 is destabilized via auto-ubiquitination and proteasomal degradation, whereas cysteine starvation stabilizes LRRC58 to permit CDO1 ubiquitylation and degradation.\",\n      \"method\": \"Quantitative proteomics (covariation MS), active CRL profiling, biochemical reconstitution, cryo-EM structures, cellular stability studies, and depletion of LRRC58 in hepatocytes in mice\",\n      \"journal\": \"Nature / Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution, cryo-EM structural validation, saturation mutagenesis, and in vivo mouse depletion experiments independently replicated across at least three separate laboratories (PMIDs 40963025, 42098103, preprint bio_10.1101_2025.09.23.678073)\",\n      \"pmids\": [\"40963025\", \"42098103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structures show that LRRC58 forms an active CUL2- or CUL5-based CRL complex and selectively positions CDO1 for ubiquitylation at Lys8 of CDO1. Disease-associated CDO1 mutants that map to the LRRC58 interface are impaired for endogenous ubiquitylation by this pathway.\",\n      \"method\": \"Cryo-EM structural determination, biochemical reconstitution, saturation mutagenesis stability profiling, and VHL-based degrader assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus mutagenesis plus reconstitution in a single rigorous study\",\n      \"pmids\": [\"42098103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRRC58 depletion stabilizes CDO1, increases cysteine flux to taurine, and lowers hepatic cholesterol in mice, demonstrating that the LRRC58-CDO1 axis links cysteine catabolism to cholesterol handling in the liver.\",\n      \"method\": \"Hepatocyte-specific LRRC58 depletion in mice with metabolite flux and cholesterol measurements\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic depletion with defined metabolic phenotype, replicated across independent studies\",\n      \"pmids\": [\"40963025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The LRRC58-mediated degradation of CDO1 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.\",\n      \"method\": \"Saturation mutagenesis stability profiling, cell-death assays under cysteine deprivation, structural modeling of CDO1-LRRC58 interface\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — saturation mutagenesis plus cell-based ferroptosis assay, single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, the LRRC58 ortholog lrr-2 post-translationally regulates levels of cysteine dioxygenase (cdo-1/CDO1), placing lrr-2 in the animal sulfur metabolism pathway and demonstrating regulation of cysteine and H2S production.\",\n      \"method\": \"Forward genetic selection in C. elegans, epistasis analysis with cdo-1 and cth-2 mutants, exogenous H2S rescue experiments\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans with functional rescue, single lab\",\n      \"pmids\": [\"39786993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The 3' UTR of Lrrc58 mRNA functions 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 Argonaute proteins, leading to miR-503-5p turnover. Deletion of this trigger site in mice abrogates TDMD and causes miR-503-dependent embryonic growth restriction.\",\n      \"method\": \"AGO-CLASH (crosslinking and sequencing of hybrids), CRISPR deletion of trigger site in mice, miRNA abundance measurements, genetic rescue experiments\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AGO-CLASH identification plus in vivo CRISPR trigger-site deletion with defined growth phenotype, independently replicated by two groups (PMIDs 41213800, 41871909)\",\n      \"pmids\": [\"41213800\", \"41871909\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRRC58 is a cysteine-responsive substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase that ubiquitylates CDO1 at Lys8 to drive its proteasomal degradation; under cysteine abundance LRRC58 itself is auto-ubiquitinated and degraded, whereas cysteine deprivation stabilizes LRRC58 to suppress CDO1 and thereby conserve cysteine (preventing ferroptosis), and this axis is conserved from C. elegans to mammals where it also governs liver cholesterol handling via taurine production; additionally, the Lrrc58 3' UTR acts as a TDMD trigger RNA that promotes ZSWIM8-dependent degradation of miR-503-5p to support embryonic growth.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRRC58 is the cysteine-responsive substrate adaptor of a CUL2/CUL5-based cullin-RING E3 ubiquitin ligase that couples sulfur amino acid sensing to the proteasomal control of cysteine catabolism [#0]. It recruits cysteine dioxygenase CDO1 — the rate-limiting enzyme of the cysteine-to-taurine shunt — and positions it for ubiquitylation at Lys8; the regulatory logic is set by cysteine availability, with cysteine repletion driving LRRC58 auto-ubiquitination and turnover while cysteine starvation stabilizes LRRC58 to enforce CDO1 degradation [#0, #1]. Through this axis LRRC58 conserves cysteine, and its loss in hepatocytes stabilizes CDO1, raises cysteine-to-taurine flux, and lowers hepatic cholesterol, linking cysteine catabolism to liver cholesterol handling [#2]. The adaptor function is conserved to C. elegans, where the ortholog lrr-2 post-translationally regulates cysteine dioxygenase and sulfur metabolism [#4]. Independently of its protein product, the Lrrc58 3' UTR acts as a TDMD trigger RNA: it base-pairs with miR-503-5p to drive ZSWIM8-dependent decay of the miRNA, a function required for normal embryonic growth [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing LRRC58 as a substrate adaptor of a cullin-RING ligase defined a molecular machine for regulated CDO1 destruction and revealed cysteine itself as the upstream regulatory signal.\",\n      \"evidence\": \"Quantitative covariation proteomics, active CRL profiling, biochemical reconstitution, cryo-EM, and hepatocyte depletion in mice\",\n      \"pmids\": [\"40963025\", \"42098103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The biochemical mechanism by which cysteine abundance triggers LRRC58 auto-ubiquitination is not defined\", \"Whether CUL2 versus CUL5 usage is context-dependent is not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Cryo-EM and saturation mutagenesis pinpointed the CDO1-LRRC58 interface and the Lys8 ubiquitylation site, explaining how disease-associated CDO1 mutants escape recognition.\",\n      \"evidence\": \"Cryo-EM structural determination, reconstitution, saturation mutagenesis stability profiling, and VHL-based degrader assays\",\n      \"pmids\": [\"42098103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for cysteine-dependent LRRC58 stability switching is not captured\", \"Whether other substrates besides CDO1 engage the same interface is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Hepatocyte-specific depletion connected the LRRC58-CDO1 axis to whole-organ physiology, showing cysteine catabolic flux governs hepatic cholesterol levels.\",\n      \"evidence\": \"Hepatocyte-specific LRRC58 depletion in mice with metabolite flux and cholesterol measurements\",\n      \"pmids\": [\"40963025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between taurine production and cholesterol handling is not detailed\", \"Tissue specificity of this phenotype beyond liver is unaddressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"C. elegans genetics established that adaptor-mediated control of cysteine dioxygenase is evolutionarily conserved and feeds into H2S/sulfur metabolism.\",\n      \"evidence\": \"Forward genetic selection, epistasis with cdo-1 and cth-2, and exogenous H2S rescue in C. elegans\",\n      \"pmids\": [\"39786993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether lrr-2 acts via an orthologous CRL complex in worms was not biochemically confirmed\", \"Single-lab genetic study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Saturation mutagenesis and cysteine-deprivation cell-death assays linked LRRC58-mediated CDO1 turnover to ferroptosis prevention and to dominant-active human CDO1 disease alleles.\",\n      \"evidence\": \"Saturation mutagenesis stability profiling, cell-death assays under cysteine deprivation, and interface modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.23.678073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Direct demonstration that CDO1 disease mutants cause neurodevelopmental phenotypes via ferroptosis is incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"A distinct, RNA-level function emerged: the Lrrc58 3' UTR is a TDMD trigger for miR-503-5p driving ZSWIM8-dependent miRNA decay required for embryonic growth.\",\n      \"evidence\": \"AGO-CLASH, CRISPR deletion of the trigger site in mice, miRNA abundance and genetic rescue experiments\",\n      \"pmids\": [\"41213800\", \"41871909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the protein-coding and TDMD functions of the Lrrc58 locus are coordinately regulated is unknown\", \"The growth-restriction mechanism downstream of miR-503-5p is not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cysteine concentration is biochemically transduced into LRRC58 stability, and whether the CRL adaptor has substrates beyond CDO1, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct cysteine-sensing mechanism for LRRC58 stability identified\", \"Substrate repertoire beyond CDO1 uncharacterized\", \"Relationship between the protein-coding and trigger-RNA roles of the locus undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"CUL2-RING E3 ligase (CRL2)\", \"CUL5-RING E3 ligase (CRL5)\"],\n    \"partners\": [\"CDO1\", \"CUL2\", \"CUL5\", \"ZSWIM8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}