{"gene":"LARS1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1982,"finding":"The human leuS gene (encoding leucyl-tRNA synthetase, LARS1) was localized to human chromosome 5, and shown to be syntenic with emtB and chr genes; the human leucyl-tRNA synthetase complemented a temperature-sensitive lethal leuS mutation in Chinese hamster cells, establishing functional conservation.","method":"Interspecific somatic cell hybrid complementation; segregation analysis; cytogenetic mapping","journal":"Somatic cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation in hybrid cells plus chromosomal mapping, single lab but two orthogonal approaches","pmids":["9732752"],"is_preprint":false},{"year":1982,"finding":"Deletion mapping in human-Chinese hamster hybrids established the gene order of leuS (LARS1), hexB, emtB, and chr on the long arm of human chromosome 5, demonstrating conserved synteny between human chromosome 5 and Chinese hamster chromosome 2.","method":"Selective segregation in interspecific hybrid cells; cytogenetic and biochemical analysis of terminal deletions","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion mapping with selective pressures and cytogenetic validation, single lab","pmids":["7177110"],"is_preprint":false},{"year":2008,"finding":"siRNA-mediated knockdown of LARS1 in A549 lung cancer cells reduced cell migration (transwell assay) and colony formation (soft agar and culture plate), establishing a functional role for LARS1 in lung cancer cell growth and migration.","method":"siRNA knockdown; transwell migration assay; soft agar colony formation assay","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined cellular phenotype readouts, single lab, multiple assays","pmids":["18446061"],"is_preprint":false},{"year":2024,"finding":"MOTS-c (a mitochondrial-derived peptide) physically interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. USP7 was identified as a deubiquitinase of LARS1; MOTS-c competes with USP7 for binding to LARS1, thereby attenuating USP7-mediated LARS1 deubiquitination.","method":"Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor rescue; competition binding assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and functional ubiquitination/deubiquitination experiments, single lab","pmids":["39321430"],"is_preprint":false},{"year":2023,"finding":"LARS1 acts as a leucine sensor mediating amino acid-induced activation of mTORC1. The LARS1 inhibitor BC-LI-0186 paradoxically activated MAPK signaling in NSCLC cells; combining BC-LI-0186 with the MEK inhibitor trametinib synergistically inhibited S6, MEK, and ERK phosphorylation and suppressed tumor growth in a xenograft model.","method":"Immunoblotting (phospho-protein analysis); RNA sequencing; combination index analysis; mouse xenograft model","journal":"Cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with mechanistic pathway readouts in vitro and in vivo, single lab","pmids":["36960627"],"is_preprint":false},{"year":2025,"finding":"LARS1 lactylation at the K970 site (induced by high-glucose/elevated lactate conditions) activates mTORC1, which inhibits autophagy and promotes apoptosis in podocytes, contributing to diabetic kidney disease. LARS1 siRNA knockdown in vivo improved renal function and reduced podocyte injury.","method":"Protein modification omics (lactylation proteomics); site-specific mutagenesis (K970); mTORC1 signaling readout; siRNA knockdown in diabetic mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM site identified by omics with in vivo siRNA validation, single lab, multiple orthogonal methods","pmids":["40545110"],"is_preprint":false},{"year":2025,"finding":"In TGF-β1-stimulated tubular epithelial cells, LARS1 activates mTORC1 and suppresses lipophagy, leading to lipid accumulation and epithelial-mesenchymal transition (EMT). Lars1+/- mice showed significantly reduced lipid deposition and tubulointerstitial fibrosis.","method":"siRNA/genetic knockdown (Lars1+/- mice); mTORC1 signaling assay; lipophagy/autophagy flux assay; EMT marker analysis","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway placement plus in vivo genetic model, single lab","pmids":["40397353"],"is_preprint":false},{"year":2025,"finding":"HIF-1α transcriptionally upregulates LARS1 expression under hypoxic conditions in pancreatic cancer cells; LARS1-containing exosomes are taken up by recipient pancreatic cancer cells and activate mTOR signaling to promote vasculogenic mimicry. HIF-1α–LARS1 interaction was confirmed experimentally.","method":"Proteomics of exosomes; gain- and loss-of-function studies; co-immunoprecipitation (HIF-1α/LARS1 interaction); in vitro tube formation assay; in vivo xenograft","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by Co-IP with functional gain/loss-of-function in vitro and in vivo, single lab","pmids":["39955826"],"is_preprint":false},{"year":2024,"finding":"In a zebrafish model carrying a patient-derived LARS1 variant (larsb-I451F), biallelic LARS1 deficiency causes enhanced autophagy leading to hepatic lipid accumulation and steatosis. Inhibition of autophagy (autophagy inhibitor) or DGAT1 (which converts fatty acids to triacylglycerols) ameliorated hepatic lipid accumulation, placing LARS1 upstream of autophagy-driven lipid dysregulation.","method":"Zebrafish genetic model (larsb-I451F knock-in); pharmacological autophagy inhibition; DGAT1 inhibition; lipid accumulation assay","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with pharmacological epistasis, single lab, multiple orthogonal interventions","pmids":["38807157"],"is_preprint":false},{"year":2025,"finding":"LARS1 knockdown in thyroid cancer cells (CAL-62 and 8305C) suppressed proliferation, invasion, and migration, and induced autophagy (increased LC3-II/LC3-I ratio, ATG7, beclin1; decreased P62), an effect reversed by mTOR agonist treatment, placing LARS1 as an mTOR-dependent suppressor of autophagy in thyroid cancer cells.","method":"siRNA knockdown; mTOR agonist rescue; CCK-8, EdU, flow cytometry, TUNEL, Transwell, wound healing assays; western blot; RT-qPCR; immunofluorescence","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with epistasis rescue via mTOR agonist, single lab, multiple orthogonal cellular assays","pmids":["40815951"],"is_preprint":false}],"current_model":"LARS1 (leucyl-tRNA synthetase 1) is a cytoplasmic aminoacyl-tRNA synthetase that charges tRNA with leucine; beyond this canonical role in protein synthesis, it functions as an intracellular leucine sensor that activates mTORC1—an activity mediated through its interaction with the RagD GTPase subunit—thereby suppressing autophagy and promoting cell growth; LARS1 protein stability is regulated by USP7-mediated deubiquitination and can be disrupted by MOTS-c competition; additionally, LARS1 is subject to lactylation at K970 under high-glucose conditions, enhancing mTORC1 activation and podocyte injury, while HIF-1α transcriptionally upregulates LARS1 in hypoxia to drive mTOR-dependent vasculogenic mimicry via tumor-derived exosomes."},"narrative":{"mechanistic_narrative":"LARS1 (leucyl-tRNA synthetase 1) is a cytoplasmic enzyme whose function extends beyond aminoacylation to act as an intracellular leucine sensor that gates mTORC1 activity and thereby controls cell growth, autophagy, and lipid metabolism [PMID:36960627, PMID:40815951]. The human leuS gene maps to chromosome 5q and functionally complements a temperature-sensitive leuS lethal mutation in hamster cells, establishing its conserved essential role in protein synthesis [PMID:9732752, PMID:7177110]. Across multiple cell types LARS1 activates mTORC1 to suppress autophagy and lipophagy: its knockdown induces autophagy and inhibits proliferation, invasion, and migration in thyroid cancer cells in an mTOR-dependent manner [PMID:40815951], and it suppresses lipophagy to drive lipid accumulation and epithelial-mesenchymal transition in tubular epithelial cells, with Lars1+/- mice showing reduced fibrosis [PMID:40397353]. LARS1 abundance and activity are regulated post-translationally: USP7 deubiquitinates and stabilizes LARS1, while the mitochondrial-derived peptide MOTS-c competes with USP7 to promote LARS1 ubiquitination and proteasomal degradation [PMID:39321430], and lactylation at K970 under high-glucose conditions enhances mTORC1 activation to promote podocyte injury in diabetic kidney disease [PMID:40545110]. In hypoxia, HIF-1α transcriptionally upregulates LARS1 and physically associates with it; LARS1-containing exosomes are transferred to recipient pancreatic cancer cells to activate mTOR and promote vasculogenic mimicry [PMID:39955826]. Consistent with its role upstream of autophagy, a patient-derived biallelic LARS1 variant modeled in zebrafish causes enhanced autophagy and hepatic steatosis, rescued by autophagy or DGAT1 inhibition [PMID:38807157]. The LARS1 inhibitor BC-LI-0186 paradoxically activates MAPK signaling, and combining it with MEK inhibition synergistically suppresses tumor growth [PMID:36960627].","teleology":[{"year":1982,"claim":"Establishing the chromosomal location and functional conservation of the human leuS gene confirmed it encodes a bona fide leucyl-tRNA synthetase essential for viability.","evidence":"Interspecific somatic cell hybrid complementation of a temperature-sensitive lethal leuS mutation and cytogenetic deletion mapping on chromosome 5","pmids":["9732752","7177110"],"confidence":"Medium","gaps":["Did not characterize enzymatic mechanism or any non-canonical signaling function","Gene order established but regulatory elements not defined"]},{"year":2008,"claim":"Loss-of-function established that LARS1 contributes to cancer cell growth and migration beyond housekeeping translation.","evidence":"siRNA knockdown in A549 lung cancer cells with transwell migration and soft-agar colony formation assays","pmids":["18446061"],"confidence":"Medium","gaps":["No molecular mechanism linking LARS1 to migration identified","Did not distinguish aminoacylation from signaling roles"]},{"year":2023,"claim":"Positioning LARS1 as a leucine sensor for mTORC1 activation provided a pharmacological handle and revealed compensatory MAPK signaling upon its inhibition.","evidence":"BC-LI-0186 inhibition with phospho-protein immunoblotting, RNA-seq, combination index analysis, and xenograft in NSCLC","pmids":["36960627"],"confidence":"Medium","gaps":["Molecular basis of paradoxical MAPK activation not resolved","Direct sensing mechanism not structurally defined in this study"]},{"year":2024,"claim":"Defining USP7 as a LARS1 deubiquitinase and MOTS-c as a competitor revealed how LARS1 protein stability is dynamically controlled.","evidence":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, and competition binding","pmids":["39321430"],"confidence":"Medium","gaps":["Ubiquitin ligase for LARS1 not identified","Physiological triggers of MOTS-c–LARS1 competition unclear"]},{"year":2024,"claim":"A patient-derived variant modeled in zebrafish placed LARS1 deficiency upstream of autophagy-driven hepatic lipid accumulation, linking the gene to a disease phenotype.","evidence":"larsb-I451F knock-in zebrafish with pharmacological autophagy and DGAT1 inhibition epistasis","pmids":["38807157"],"confidence":"Medium","gaps":["Human disease causation rests on a model organism variant","Mechanism by which deficiency enhances autophagy not detailed"]},{"year":2025,"claim":"Multiple disease contexts converged on LARS1–mTORC1 control of autophagy/lipophagy, with PTM (lactylation), transcriptional (HIF-1α), and exosomal regulation defining tissue-specific outputs.","evidence":"K970 lactylation proteomics and diabetic mouse siRNA; TGF-β1 tubular cells and Lars1+/- mice; HIF-1α Co-IP and exosome proteomics in pancreatic cancer; mTOR-agonist rescue in thyroid cancer","pmids":["40545110","40397353","39955826","40815951"],"confidence":"Medium","gaps":["Whether RagD-mediated sensing underlies all these contexts not directly tested in each","Each finding from a single lab without independent replication"]},{"year":null,"claim":"How LARS1 structurally couples leucine occupancy to mTORC1 activation and which E3 ligase counteracts USP7 remain open.","evidence":"No timeline discovery resolves the structural sensing mechanism or the cognate ubiquitin ligase","pmids":[],"confidence":"Medium","gaps":["No structural model of LARS1 leucine-sensing in the corpus","E3 ligase opposing USP7 unidentified","RagD interaction not directly demonstrated in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[4,9]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,8,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":[],"partners":["USP7","MOTS-C","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P2J5","full_name":"Leucine--tRNA ligase, cytoplasmic","aliases":["Leucyl-tRNA synthetase","LeuRS","cLRS"],"length_aa":1176,"mass_kda":134.5,"function":"Aminoacyl-tRNA synthetase that catalyzes the specific attachment of leucine to its cognate tRNA (tRNA(Leu)) (PubMed:25051973, PubMed:32232361). It performs tRNA aminoacylation in a two-step reaction: Leu is initially activated by ATP to form a leucyl-adenylate (Leu-AMP) intermediate; then the leucyl moiety is transferred to the acceptor 3' end of the tRNA to yield leucyl-tRNA (PubMed:25051973). To improve the fidelity of catalytic reactions, it is also able to hydrolyze misactivated aminoacyl-adenylate intermediates (pre-transfer editing) and mischarged aminoacyl-tRNAs (post-transfer editing) (PubMed:25051973)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9P2J5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LARS1","classification":"Common Essential","n_dependent_lines":1202,"n_total_lines":1208,"dependency_fraction":0.9950331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LARS1","total_profiled":1310},"omim":[{"mim_id":"615438","title":"INFANTILE LIVER FAILURE SYNDROME 1; ILFS1","url":"https://www.omim.org/entry/615438"},{"mim_id":"603168","title":"UNC51-LIKE AUTOPHAGY-ACTIVATING KINASE 1; ULK1","url":"https://www.omim.org/entry/603168"},{"mim_id":"151350","title":"LEUCYL-tRNA SYNTHETASE 1; LARS1","url":"https://www.omim.org/entry/151350"},{"mim_id":"134935","title":"FIBROBLAST GROWTH FACTOR RECEPTOR 4; FGFR4","url":"https://www.omim.org/entry/134935"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LARS1"},"hgnc":{"alias_symbol":["HSPC192","FLJ10595","FLJ21788","LEUS","RNTLS"],"prev_symbol":["LARS"]},"alphafold":{"accession":"Q9P2J5","domains":[{"cath_id":"3.40.50.620","chopping":"50-95_187-229_595-728","consensus_level":"medium","plddt":96.3535,"start":50,"end":728},{"cath_id":"3.90.740.10","chopping":"262-511","consensus_level":"medium","plddt":93.6204,"start":262,"end":511},{"cath_id":"1.10.730.10","chopping":"757-892","consensus_level":"medium","plddt":96.7244,"start":757,"end":892},{"cath_id":"-","chopping":"946-1011","consensus_level":"medium","plddt":92.6827,"start":946,"end":1011},{"cath_id":"3.10.20.90","chopping":"1066-1176","consensus_level":"medium","plddt":85.478,"start":1066,"end":1176}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2J5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2J5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2J5-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LARS1","jax_strain_url":"https://www.jax.org/strain/search?query=LARS1"},"sequence":{"accession":"Q9P2J5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2J5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2J5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2J5"}},"corpus_meta":[{"pmid":"9732752","id":"PMC_9732752","title":"Linkage of the leuS, emtB, and chr genes on chromosome 5 in humans and expression of human genes encoding protein synthetic components in human--Chinese hamster hybrids.","date":"1982","source":"Somatic cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9732752","citation_count":83,"is_preprint":false},{"pmid":"6451612","id":"PMC_6451612","title":"Defective and plaque-forming lambda transducing bacteriophage carrying penicillin-binding protein-cell shape genes: genetic and physical mapping and identification of gene products from the lip-dacA-rodA-pbpA-leuS region of the Escherichia coli chromosome.","date":"1980","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/6451612","citation_count":76,"is_preprint":false},{"pmid":"7177110","id":"PMC_7177110","title":"Selective linkage disruption in human-Chinese hamster cell hybrids: deletion mapping of the leuS, hexB, emtB, and chr genes on human chromosome 5.","date":"1982","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7177110","citation_count":62,"is_preprint":false},{"pmid":"3316191","id":"PMC_3316191","title":"Genes encoding two lipoproteins in the leuS-dacA region of the Escherichia coli chromosome.","date":"1987","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/3316191","citation_count":60,"is_preprint":false},{"pmid":"18446061","id":"PMC_18446061","title":"Implication of leucyl-tRNA synthetase 1 (LARS1) over-expression in growth and migration of lung cancer cells detected by siRNA targeted knock-down analysis.","date":"2008","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18446061","citation_count":45,"is_preprint":false},{"pmid":"7193212","id":"PMC_7193212","title":"Linkage in cultured Chinese hamster cells of two genes, emtB and leuS, involved in protein synthesis and isolation of cell lines with mutations in three linked genes.","date":"1980","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7193212","citation_count":36,"is_preprint":false},{"pmid":"39321430","id":"PMC_39321430","title":"Mitochondrial-Derived Peptide MOTS-c Suppresses Ovarian Cancer Progression by Attenuating USP7-Mediated LARS1 Deubiquitination.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39321430","citation_count":17,"is_preprint":false},{"pmid":"25125967","id":"PMC_25125967","title":"An In-depth Analysis of a Multilocus Phylogeny Identifies leuS As a Reliable Phylogenetic Marker for the Genus Pantoea.","date":"2014","source":"Evolutionary bioinformatics online","url":"https://pubmed.ncbi.nlm.nih.gov/25125967","citation_count":17,"is_preprint":false},{"pmid":"34496286","id":"PMC_34496286","title":"Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34496286","citation_count":14,"is_preprint":false},{"pmid":"26154740","id":"PMC_26154740","title":"Orthogonal sampling in free-energy calculations of residue mutations in a tripeptide: TI versus λ-LEUS.","date":"2015","source":"Journal of computational chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26154740","citation_count":13,"is_preprint":false},{"pmid":"33300650","id":"PMC_33300650","title":"Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33300650","citation_count":12,"is_preprint":false},{"pmid":"40545110","id":"PMC_40545110","title":"LARS1 lactylation inhibits autophagy by activating mTORC1 to promote podocytes injury in diabetic kidney disease.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40545110","citation_count":11,"is_preprint":false},{"pmid":"39955826","id":"PMC_39955826","title":"Rg3 inhibits hypoxia-induced tumor exosomes from boosting pancreatic cancer vasculogenic mimicry through the HIF-1α/LARS1/mTOR axis.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39955826","citation_count":7,"is_preprint":false},{"pmid":"36960627","id":"PMC_36960627","title":"Combination of the LARS1 Inhibitor, BC-LI-0186 with a MEK1/2 Inhibitor Enhances the Anti-Tumor Effect in Non-Small Cell Lung Cancer.","date":"2023","source":"Cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/36960627","citation_count":4,"is_preprint":false},{"pmid":"36995308","id":"PMC_36995308","title":"Developing a comprehensive solution aimed to disrupt LARS1/RagD protein-protein interaction.","date":"2023","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/36995308","citation_count":3,"is_preprint":false},{"pmid":"40397353","id":"PMC_40397353","title":"LARS1 Promotes Tubular Epithelial Cells Epithelial Mesenchymal Transition in Chronic Kidney Disease by Inhibiting Lipophagy.","date":"2025","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/40397353","citation_count":3,"is_preprint":false},{"pmid":"38951950","id":"PMC_38951950","title":"MRI in LARS1 deficiency-Spectrum, patterns, and correlation with acute neurological deterioration.","date":"2024","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/38951950","citation_count":2,"is_preprint":false},{"pmid":"38807157","id":"PMC_38807157","title":"Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy.","date":"2024","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/38807157","citation_count":1,"is_preprint":false},{"pmid":"40815951","id":"PMC_40815951","title":"LARS1 knockdown suppresses the biological activities of thyroid cancer cells by stimulating autophagy.","date":"2025","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/40815951","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11236,"output_tokens":2493,"usd":0.035551,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9758,"output_tokens":2668,"usd":0.057745,"stage2_stop_reason":"end_turn"},"total_usd":0.093296,"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\": 1982,\n      \"finding\": \"The human leuS gene (encoding leucyl-tRNA synthetase, LARS1) was localized to human chromosome 5, and shown to be syntenic with emtB and chr genes; the human leucyl-tRNA synthetase complemented a temperature-sensitive lethal leuS mutation in Chinese hamster cells, establishing functional conservation.\",\n      \"method\": \"Interspecific somatic cell hybrid complementation; segregation analysis; cytogenetic mapping\",\n      \"journal\": \"Somatic cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation in hybrid cells plus chromosomal mapping, single lab but two orthogonal approaches\",\n      \"pmids\": [\"9732752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"Deletion mapping in human-Chinese hamster hybrids established the gene order of leuS (LARS1), hexB, emtB, and chr on the long arm of human chromosome 5, demonstrating conserved synteny between human chromosome 5 and Chinese hamster chromosome 2.\",\n      \"method\": \"Selective segregation in interspecific hybrid cells; cytogenetic and biochemical analysis of terminal deletions\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion mapping with selective pressures and cytogenetic validation, single lab\",\n      \"pmids\": [\"7177110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"siRNA-mediated knockdown of LARS1 in A549 lung cancer cells reduced cell migration (transwell assay) and colony formation (soft agar and culture plate), establishing a functional role for LARS1 in lung cancer cell growth and migration.\",\n      \"method\": \"siRNA knockdown; transwell migration assay; soft agar colony formation assay\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined cellular phenotype readouts, single lab, multiple assays\",\n      \"pmids\": [\"18446061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MOTS-c (a mitochondrial-derived peptide) physically interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. USP7 was identified as a deubiquitinase of LARS1; MOTS-c competes with USP7 for binding to LARS1, thereby attenuating USP7-mediated LARS1 deubiquitination.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; proteasome inhibitor rescue; competition binding assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and functional ubiquitination/deubiquitination experiments, single lab\",\n      \"pmids\": [\"39321430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LARS1 acts as a leucine sensor mediating amino acid-induced activation of mTORC1. The LARS1 inhibitor BC-LI-0186 paradoxically activated MAPK signaling in NSCLC cells; combining BC-LI-0186 with the MEK inhibitor trametinib synergistically inhibited S6, MEK, and ERK phosphorylation and suppressed tumor growth in a xenograft model.\",\n      \"method\": \"Immunoblotting (phospho-protein analysis); RNA sequencing; combination index analysis; mouse xenograft model\",\n      \"journal\": \"Cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with mechanistic pathway readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"36960627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARS1 lactylation at the K970 site (induced by high-glucose/elevated lactate conditions) activates mTORC1, which inhibits autophagy and promotes apoptosis in podocytes, contributing to diabetic kidney disease. LARS1 siRNA knockdown in vivo improved renal function and reduced podocyte injury.\",\n      \"method\": \"Protein modification omics (lactylation proteomics); site-specific mutagenesis (K970); mTORC1 signaling readout; siRNA knockdown in diabetic mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM site identified by omics with in vivo siRNA validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40545110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In TGF-β1-stimulated tubular epithelial cells, LARS1 activates mTORC1 and suppresses lipophagy, leading to lipid accumulation and epithelial-mesenchymal transition (EMT). Lars1+/- mice showed significantly reduced lipid deposition and tubulointerstitial fibrosis.\",\n      \"method\": \"siRNA/genetic knockdown (Lars1+/- mice); mTORC1 signaling assay; lipophagy/autophagy flux assay; EMT marker analysis\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway placement plus in vivo genetic model, single lab\",\n      \"pmids\": [\"40397353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF-1α transcriptionally upregulates LARS1 expression under hypoxic conditions in pancreatic cancer cells; LARS1-containing exosomes are taken up by recipient pancreatic cancer cells and activate mTOR signaling to promote vasculogenic mimicry. HIF-1α–LARS1 interaction was confirmed experimentally.\",\n      \"method\": \"Proteomics of exosomes; gain- and loss-of-function studies; co-immunoprecipitation (HIF-1α/LARS1 interaction); in vitro tube formation assay; in vivo xenograft\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by Co-IP with functional gain/loss-of-function in vitro and in vivo, single lab\",\n      \"pmids\": [\"39955826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a zebrafish model carrying a patient-derived LARS1 variant (larsb-I451F), biallelic LARS1 deficiency causes enhanced autophagy leading to hepatic lipid accumulation and steatosis. Inhibition of autophagy (autophagy inhibitor) or DGAT1 (which converts fatty acids to triacylglycerols) ameliorated hepatic lipid accumulation, placing LARS1 upstream of autophagy-driven lipid dysregulation.\",\n      \"method\": \"Zebrafish genetic model (larsb-I451F knock-in); pharmacological autophagy inhibition; DGAT1 inhibition; lipid accumulation assay\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with pharmacological epistasis, single lab, multiple orthogonal interventions\",\n      \"pmids\": [\"38807157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LARS1 knockdown in thyroid cancer cells (CAL-62 and 8305C) suppressed proliferation, invasion, and migration, and induced autophagy (increased LC3-II/LC3-I ratio, ATG7, beclin1; decreased P62), an effect reversed by mTOR agonist treatment, placing LARS1 as an mTOR-dependent suppressor of autophagy in thyroid cancer cells.\",\n      \"method\": \"siRNA knockdown; mTOR agonist rescue; CCK-8, EdU, flow cytometry, TUNEL, Transwell, wound healing assays; western blot; RT-qPCR; immunofluorescence\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with epistasis rescue via mTOR agonist, single lab, multiple orthogonal cellular assays\",\n      \"pmids\": [\"40815951\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LARS1 (leucyl-tRNA synthetase 1) is a cytoplasmic aminoacyl-tRNA synthetase that charges tRNA with leucine; beyond this canonical role in protein synthesis, it functions as an intracellular leucine sensor that activates mTORC1—an activity mediated through its interaction with the RagD GTPase subunit—thereby suppressing autophagy and promoting cell growth; LARS1 protein stability is regulated by USP7-mediated deubiquitination and can be disrupted by MOTS-c competition; additionally, LARS1 is subject to lactylation at K970 under high-glucose conditions, enhancing mTORC1 activation and podocyte injury, while HIF-1α transcriptionally upregulates LARS1 in hypoxia to drive mTOR-dependent vasculogenic mimicry via tumor-derived exosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LARS1 (leucyl-tRNA synthetase 1) is a cytoplasmic enzyme whose function extends beyond aminoacylation to act as an intracellular leucine sensor that gates mTORC1 activity and thereby controls cell growth, autophagy, and lipid metabolism [#4, #9]. The human leuS gene maps to chromosome 5q and functionally complements a temperature-sensitive leuS lethal mutation in hamster cells, establishing its conserved essential role in protein synthesis [#0, #1]. Across multiple cell types LARS1 activates mTORC1 to suppress autophagy and lipophagy: its knockdown induces autophagy and inhibits proliferation, invasion, and migration in thyroid cancer cells in an mTOR-dependent manner [#9], and it suppresses lipophagy to drive lipid accumulation and epithelial-mesenchymal transition in tubular epithelial cells, with Lars1+/- mice showing reduced fibrosis [#6]. LARS1 abundance and activity are regulated post-translationally: USP7 deubiquitinates and stabilizes LARS1, while the mitochondrial-derived peptide MOTS-c competes with USP7 to promote LARS1 ubiquitination and proteasomal degradation [#3], and lactylation at K970 under high-glucose conditions enhances mTORC1 activation to promote podocyte injury in diabetic kidney disease [#5]. In hypoxia, HIF-1\\u03b1 transcriptionally upregulates LARS1 and physically associates with it; LARS1-containing exosomes are transferred to recipient pancreatic cancer cells to activate mTOR and promote vasculogenic mimicry [#7]. Consistent with its role upstream of autophagy, a patient-derived biallelic LARS1 variant modeled in zebrafish causes enhanced autophagy and hepatic steatosis, rescued by autophagy or DGAT1 inhibition [#8]. The LARS1 inhibitor BC-LI-0186 paradoxically activates MAPK signaling, and combining it with MEK inhibition synergistically suppresses tumor growth [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Establishing the chromosomal location and functional conservation of the human leuS gene confirmed it encodes a bona fide leucyl-tRNA synthetase essential for viability.\",\n      \"evidence\": \"Interspecific somatic cell hybrid complementation of a temperature-sensitive lethal leuS mutation and cytogenetic deletion mapping on chromosome 5\",\n      \"pmids\": [\"9732752\", \"7177110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not characterize enzymatic mechanism or any non-canonical signaling function\", \"Gene order established but regulatory elements not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Loss-of-function established that LARS1 contributes to cancer cell growth and migration beyond housekeeping translation.\",\n      \"evidence\": \"siRNA knockdown in A549 lung cancer cells with transwell migration and soft-agar colony formation assays\",\n      \"pmids\": [\"18446061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking LARS1 to migration identified\", \"Did not distinguish aminoacylation from signaling roles\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioning LARS1 as a leucine sensor for mTORC1 activation provided a pharmacological handle and revealed compensatory MAPK signaling upon its inhibition.\",\n      \"evidence\": \"BC-LI-0186 inhibition with phospho-protein immunoblotting, RNA-seq, combination index analysis, and xenograft in NSCLC\",\n      \"pmids\": [\"36960627\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of paradoxical MAPK activation not resolved\", \"Direct sensing mechanism not structurally defined in this study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining USP7 as a LARS1 deubiquitinase and MOTS-c as a competitor revealed how LARS1 protein stability is dynamically controlled.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor rescue, and competition binding\",\n      \"pmids\": [\"39321430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase for LARS1 not identified\", \"Physiological triggers of MOTS-c\\u2013LARS1 competition unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A patient-derived variant modeled in zebrafish placed LARS1 deficiency upstream of autophagy-driven hepatic lipid accumulation, linking the gene to a disease phenotype.\",\n      \"evidence\": \"larsb-I451F knock-in zebrafish with pharmacological autophagy and DGAT1 inhibition epistasis\",\n      \"pmids\": [\"38807157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human disease causation rests on a model organism variant\", \"Mechanism by which deficiency enhances autophagy not detailed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple disease contexts converged on LARS1\\u2013mTORC1 control of autophagy/lipophagy, with PTM (lactylation), transcriptional (HIF-1\\u03b1), and exosomal regulation defining tissue-specific outputs.\",\n      \"evidence\": \"K970 lactylation proteomics and diabetic mouse siRNA; TGF-\\u03b21 tubular cells and Lars1+/- mice; HIF-1\\u03b1 Co-IP and exosome proteomics in pancreatic cancer; mTOR-agonist rescue in thyroid cancer\",\n      \"pmids\": [\"40545110\", \"40397353\", \"39955826\", \"40815951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RagD-mediated sensing underlies all these contexts not directly tested in each\", \"Each finding from a single lab without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LARS1 structurally couples leucine occupancy to mTORC1 activation and which E3 ligase counteracts USP7 remain open.\",\n      \"evidence\": \"No timeline discovery resolves the structural sensing mechanism or the cognate ubiquitin ligase\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LARS1 leucine-sensing in the corpus\", \"E3 ligase opposing USP7 unidentified\", \"RagD interaction not directly demonstrated in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 8, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"USP7\", \"MOTS-c\", \"HIF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"loss","faith_supported":7,"faith_total":7,"faith_pct":100.0}}