{"gene":"LRSAM1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"LRSAM1 (Tal) is a RING finger E3 ubiquitin ligase that specifically mediates multiple monoubiquitylation of TSG101. Bivalent binding of TSG101 to a tandem PTAP tetrapeptide motif and to a central region of LRSAM1 is required for LRSAM1-mediated ubiquitylation of TSG101. LRSAM1 regulates a TSG101-associated complex responsible for sorting cargo into multivesicular body vesicles and at the plasma membrane, impacting EGF receptor endocytosis and HIV budding.","method":"Co-immunoprecipitation, in vivo ubiquitylation assays, mutagenesis of PTAP motif, receptor endocytosis assays, retrovirus budding assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP, mutagenesis of binding motif, multiple functional readouts (endocytosis, viral budding) in a single rigorous study","pmids":["15256501"],"is_preprint":false},{"year":2012,"finding":"LRSAM1 is the E3 ubiquitin ligase responsible for generating the polyubiquitin signal around cytosolic Salmonella Typhimurium that triggers autophagy-mediated bacterial clearance. LRSAM1 localizes to intracellular bacteria; its leucine-rich repeat (LRR) domain is required for bacterial recognition/localization, and its RING domain is required for ubiquitin ligase activity generating the bacteria-associated ubiquitin signal. Using cells from LRSAM1-deficient individuals confirmed LRSAM1 is required for ubiquitination of intracellular bacteria but dispensable for ubiquitination of aggregated proteins.","method":"Loss-of-function studies using LRSAM1-deficient human cells, domain deletion mutagenesis (LRR and RING), immunofluorescence localization, ubiquitination assays, bacterial survival assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — patient-derived loss-of-function cells, domain mutagenesis, multiple orthogonal methods (localization, ubiquitination assay, bacterial clearance), rigorous controls","pmids":["23245322"],"is_preprint":false},{"year":2010,"finding":"A homozygous intronic splice-site mutation in LRSAM1 causes autosomal recessive axonal Charcot-Marie-Tooth disease (CMT2P). The mutation causes aberrant splicing with obligatory frameshift and premature truncation, resulting in complete absence of LRSAM1 protein. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and in proper adhesion of neuronal cells in culture.","method":"Homozygosity mapping, SNP genotyping, direct DNA sequencing, RNA analysis (aberrant splicing), Western blotting of patient-derived immortalized cells","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — patient genetics with RNA and protein validation in patient cells, single lab, multiple methods confirming loss of function","pmids":["20865121"],"is_preprint":false},{"year":2011,"finding":"A frameshift mutation (p.Leu708Argfx28) in the C-terminal RING finger motif of LRSAM1 causes autosomal dominant axonal Charcot-Marie-Tooth disease. The patient mutation impairs ubiquitin ligase activity as measured by elevated abundance of TSG101 (LRSAM1's reported substrate) in transfected cells. Morpholino knockdown of zebrafish Lrsam1 disturbs neural structure and tail formation, confirming a neurodevelopmental role.","method":"Linkage analysis, next-generation sequencing, Sanger confirmation, ubiquitin ligase activity assay in transfected cells (TSG101 levels), zebrafish morpholino knockdown","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional assay of mutant ligase activity, zebrafish loss-of-function, single lab with multiple methods","pmids":["22012984"],"is_preprint":false},{"year":2013,"finding":"In transfected cells, LRSAM1 primarily localizes to a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome-to-lysosome trafficking pathway. Mouse Lrsam1 is abundantly expressed in motor and sensory neurons of the peripheral nervous system. Lrsam1 knockout mice show increased sensitivity to acrylamide-induced axon degeneration, indicating compromised axons, though baseline neuropathy phenotype is mild.","method":"Subcellular localization by immunofluorescence in transfected cells, colocalization with organelle markers, Lrsam1 knockout mouse generation, acrylamide challenge assay, neuromuscular performance testing","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in cells, genetic knockout mouse with functional challenge, single lab with multiple orthogonal methods","pmids":["23519028"],"is_preprint":false},{"year":2014,"finding":"PHF23 (PHD finger protein 23) negatively regulates autophagy by interacting with LRSAM1 and promoting its ubiquitination and proteasomal degradation, thereby reducing LRSAM1 protein levels. The PHD finger domain of PHF23 is required for interaction with LRSAM1. PHF23 overexpression impairs autophagy (decreased LC3B-II levels), while PHF23 knockdown enhances autophagy through increased LRSAM1 availability.","method":"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, LC3B-II autophagy flux assays, domain deletion mutagenesis of PHF23, siRNA knockdown","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, domain mutagenesis, autophagy readouts, single lab with multiple methods","pmids":["25484098"],"is_preprint":false},{"year":2020,"finding":"Berberine (BBR) induces autophagic lysosomal degradation of BCR-ABL and BCR-ABL T315I by recruiting LRSAM1 as an E3 ubiquitin ligase. BBR binds to the tyrosine kinase domain of BCR-ABL, and LRSAM1 is required for BBR-mediated ubiquitination and autophagic degradation of BCR-ABL.","method":"Molecular docking, surface plasmon resonance, NMR, thermoshift assays for BBR-BCR-ABL binding; Western blotting for protein degradation; autophagy pathway inhibitors; LRSAM1 involvement assessed in cell lines and mouse models","journal":"Clinical cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — LRSAM1 recruitment inferred from association studies without direct reconstitution of ubiquitination of BCR-ABL by LRSAM1; single lab","pmids":["32098768"],"is_preprint":false},{"year":2024,"finding":"LRSAM1 ubiquitinates and promotes proteasomal degradation of SLC40A1 (ferroportin), a ferrous iron exporter that inhibits ferroptosis. In glioma stem cells, the transcription repressor REST suppresses LRSAM1 expression; erianin inhibits REST's repressive function, upregulates LRSAM1, which then ubiquitinates and degrades SLC40A1, causing iron accumulation and ferroptosis.","method":"Co-immunoprecipitation, ubiquitination assays, protein stability assays, ChIP assays, luciferase reporter assays, ferroptosis markers (ROS, GSH, MDA, BODIPY C11), TEM, ferrostatin-1 rescue","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and ubiquitination assay identifying SLC40A1 as LRSAM1 substrate, multiple orthogonal mechanistic methods, single lab","pmids":["39039049"],"is_preprint":false}],"current_model":"LRSAM1 is an E3 ubiquitin ligase whose LRR domain mediates recognition of intracellular bacteria and whose RING domain catalyzes polyubiquitin chain formation on cytosolic Salmonella to initiate selective autophagy; it also monoubiquitylates TSG101 via a bivalent PTAP-docking mechanism to regulate multivesicular body sorting and viral budding, ubiquitinates SLC40A1 to regulate ferroptosis, and is regulated by PHF23-mediated proteasomal degradation, with mutations in its RING domain causing both dominant and recessive forms of Charcot-Marie-Tooth disease type 2P."},"narrative":{"mechanistic_narrative":"LRSAM1 is a RING-finger E3 ubiquitin ligase that couples substrate recognition to polyubiquitin chain formation across membrane trafficking, antibacterial autophagy, and iron homeostasis [PMID:15256501, PMID:23245322]. Its two functional modules underlie this versatility: the leucine-rich repeat (LRR) domain mediates target recognition—localizing the ligase to cytosolic Salmonella Typhimurium—while the C-terminal RING domain catalyzes ubiquitin transfer to generate the bacteria-associated polyubiquitin signal that triggers selective autophagy and bacterial clearance [PMID:23245322]. In its founding role, LRSAM1 multiply monoubiquitylates TSG101 through a bivalent docking mechanism requiring both a tandem PTAP tetrapeptide motif and a central region of LRSAM1, thereby regulating TSG101-dependent sorting of cargo into multivesicular bodies, EGF receptor endocytosis, and HIV budding [PMID:15256501]. LRSAM1 also ubiquitinates and drives proteasomal degradation of the iron exporter SLC40A1 (ferroportin), promoting iron accumulation and ferroptosis [PMID:39039049]. LRSAM1 protein levels are themselves controlled by PHF23, which interacts with LRSAM1 via its PHD finger domain and promotes its ubiquitination and proteasomal degradation, thereby restraining autophagy [PMID:25484098]. Loss-of-function and RING-domain frameshift mutations in LRSAM1 cause both autosomal recessive and autosomal dominant axonal Charcot-Marie-Tooth disease type 2 [PMID:20865121, PMID:22012984], consistent with abundant expression in peripheral motor and sensory neurons and the increased axonal vulnerability of Lrsam1-deficient mice [PMID:23519028].","teleology":[{"year":2004,"claim":"Established LRSAM1 as a bona fide RING E3 ligase and defined its first substrate and trafficking role, answering what biochemical activity the protein carries.","evidence":"Reciprocal Co-IP, in vivo ubiquitylation assays, PTAP-motif mutagenesis, and endocytosis/retroviral budding readouts in cells","pmids":["15256501"],"confidence":"High","gaps":["Ubiquitin chain topology beyond multiple monoubiquitylation not resolved","Structural basis of the bivalent PTAP/central-region docking not determined"]},{"year":2010,"claim":"Linked complete loss of LRSAM1 to a human neurodegenerative disease, establishing physiological importance in peripheral nerve.","evidence":"Homozygosity mapping, sequencing, RNA splicing analysis, and Western blot of patient-derived cells","pmids":["20865121"],"confidence":"Medium","gaps":["Mechanism connecting ligase loss to axonal degeneration not defined","Single recessive pedigree"]},{"year":2011,"claim":"Showed a RING-domain frameshift causes dominant CMT and impairs catalytic activity, tying disease directly to defective ubiquitin ligase function.","evidence":"Linkage, NGS, TSG101-abundance ligase activity assay in transfected cells, and zebrafish morpholino knockdown","pmids":["22012984"],"confidence":"Medium","gaps":["Dominant-negative versus haploinsufficiency mechanism not distinguished","Neuronal substrate relevant to disease not identified"]},{"year":2012,"claim":"Defined the domain logic of LRSAM1 in antibacterial autophagy—LRR for recognition, RING for ubiquitination—answering how it targets intracellular pathogens.","evidence":"Patient-derived LRSAM1-deficient cells, LRR/RING domain deletions, immunofluorescence, ubiquitination and bacterial survival assays","pmids":["23245322"],"confidence":"High","gaps":["Direct bacterial ligand recognized by the LRR not identified","Ubiquitin chain type on bacteria and autophagy receptor coupling not fully resolved"]},{"year":2013,"claim":"Located LRSAM1 to a perinuclear post-Golgi compartment and demonstrated neuronal expression and axonal vulnerability, contextualizing where it acts and its in vivo requirement.","evidence":"Immunofluorescence colocalization in transfected cells and Lrsam1 knockout mouse with acrylamide axon-degeneration challenge","pmids":["23519028"],"confidence":"Medium","gaps":["Baseline knockout neuropathy phenotype mild, leaving disease mechanism incomplete","Functional significance of perinuclear localization not established"]},{"year":2014,"claim":"Identified PHF23 as an upstream regulator that controls LRSAM1 abundance, revealing how LRSAM1-dependent autophagy is tuned.","evidence":"Co-IP, ubiquitination and proteasome-inhibitor assays, PHD-domain mutagenesis, and LC3B-II autophagy flux readouts","pmids":["25484098"],"confidence":"Medium","gaps":["Whether PHF23 directly ubiquitinates LRSAM1 or recruits another ligase unresolved","Physiological contexts where this axis operates not defined"]},{"year":2024,"claim":"Identified SLC40A1 as a degradation substrate, expanding LRSAM1's role into iron homeostasis and ferroptosis control.","evidence":"Co-IP, ubiquitination and stability assays, ChIP/luciferase for REST regulation, and ferroptosis markers with ferrostatin-1 rescue in glioma stem cells","pmids":["39039049"],"confidence":"Medium","gaps":["Ubiquitin chain linkage on SLC40A1 not characterized","Generality beyond glioma stem cells not established"]},{"year":null,"claim":"How LRSAM1's distinct substrate-recognition modes are selected in different cellular contexts, and which substrate underlies its peripheral-nerve function, remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking LRR recognition to RING catalysis","Disease-relevant neuronal substrate unidentified","Chain-type specificity across substrates uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]}],"complexes":[],"partners":["TSG101","PHF23","SLC40A1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UWE0","full_name":"E3 ubiquitin-protein ligase LRSAM1","aliases":["Leucine-rich repeat and sterile alpha motif-containing protein 1","RING-type E3 ubiquitin transferase LRSAM1","Tsg101-associated ligase","hTAL"],"length_aa":723,"mass_kda":83.6,"function":"E3 ubiquitin-protein ligase that mediates monoubiquitination of TSG101 at multiple sites, leading to inactivate the ability of TSG101 to sort endocytic (EGF receptors) and exocytic (HIV-1 viral proteins) cargos (PubMed:15256501). Bacterial recognition protein that defends the cytoplasm from invasive pathogens (PubMed:23245322). Localizes to several intracellular bacterial pathogens and generates the bacteria-associated ubiquitin signal leading to autophagy-mediated intracellular bacteria degradation (xenophagy) (PubMed:23245322, PubMed:25484098)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6UWE0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRSAM1","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/LRSAM1","total_profiled":1310},"omim":[{"mim_id":"614436","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P; CMT2P","url":"https://www.omim.org/entry/614436"},{"mim_id":"610933","title":"LEUCINE-RICH REPEAT- AND STERILE ALPHA MOTIF-CONTAINING 1; LRSAM1","url":"https://www.omim.org/entry/610933"},{"mim_id":"601387","title":"TUMOR SUSCEPTIBILITY GENE 101; TSG101","url":"https://www.omim.org/entry/601387"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRSAM1"},"hgnc":{"alias_symbol":["FLJ31641","CMT2P","RIFLE","TAL"],"prev_symbol":[]},"alphafold":{"accession":"Q6UWE0","domains":[{"cath_id":"3.80.10.10","chopping":"11-216","consensus_level":"medium","plddt":85.4365,"start":11,"end":216},{"cath_id":"1.10.150.50","chopping":"559-632","consensus_level":"high","plddt":77.1791,"start":559,"end":632},{"cath_id":"3.30.40.10","chopping":"674-723","consensus_level":"medium","plddt":83.5574,"start":674,"end":723}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWE0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWE0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UWE0-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRSAM1","jax_strain_url":"https://www.jax.org/strain/search?query=LRSAM1"},"sequence":{"accession":"Q6UWE0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UWE0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UWE0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UWE0"}},"corpus_meta":[{"pmid":"19933107","id":"PMC_19933107","title":"Breaking 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hematopoiesis.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18550854","citation_count":38,"is_preprint":false},{"pmid":"1450410","id":"PMC_1450410","title":"T-cell acute lymphoblastic leukemia--the associated gene SCL/tal codes for a 42-Kd nuclear phosphoprotein.","date":"1992","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/1450410","citation_count":38,"is_preprint":false},{"pmid":"24130757","id":"PMC_24130757","title":"Molecular dynamics simulations of DNA-free and DNA-bound TAL effectors.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24130757","citation_count":36,"is_preprint":false},{"pmid":"24312634","id":"PMC_24312634","title":"TAL effector specificity for base 0 of the DNA target is altered in a complex, effector- and assay-dependent manner by substitutions for the tryptophan in cryptic repeat -1.","date":"2013","source":"PloS 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haematology","url":"https://pubmed.ncbi.nlm.nih.gov/9432040","citation_count":34,"is_preprint":false},{"pmid":"7812000","id":"PMC_7812000","title":"Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism.","date":"1995","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7812000","citation_count":34,"is_preprint":false},{"pmid":"24228087","id":"PMC_24228087","title":"ULtiMATE system for rapid assembly of customized TAL effectors.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24228087","citation_count":34,"is_preprint":false},{"pmid":"28460076","id":"PMC_28460076","title":"The effect of increasing numbers of repeats on TAL effector DNA binding specificity.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28460076","citation_count":32,"is_preprint":false},{"pmid":"23888878","id":"PMC_23888878","title":"Genome engineering with TAL-effector nucleases and alternative modular nuclease technologies.","date":"2013","source":"Current gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/23888878","citation_count":31,"is_preprint":false},{"pmid":"32098768","id":"PMC_32098768","title":"Discovery of Berberine that Targetedly Induces Autophagic Degradation of both BCR-ABL and BCR-ABL T315I through Recruiting LRSAM1 for Overcoming Imatinib Resistance.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32098768","citation_count":30,"is_preprint":false},{"pmid":"8255100","id":"PMC_8255100","title":"tal-1 deletions in T-cell acute lymphoblastic leukemia as PCR target for detection of minimal residual disease.","date":"1993","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/8255100","citation_count":30,"is_preprint":false},{"pmid":"39039049","id":"PMC_39039049","title":"Erianin induces ferroptosis in GSCs via REST/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39039049","citation_count":28,"is_preprint":false},{"pmid":"22384209","id":"PMC_22384209","title":"The TAL effector PthA4 interacts with nuclear factors involved in RNA-dependent processes including a HMG protein that selectively binds poly(U) RNA.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22384209","citation_count":28,"is_preprint":false},{"pmid":"29026078","id":"PMC_29026078","title":"Deciphering TAL effectors for 5-methylcytosine and 5-hydroxymethylcytosine recognition.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29026078","citation_count":27,"is_preprint":false},{"pmid":"22781092","id":"PMC_22781092","title":"A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease.","date":"2012","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/22781092","citation_count":26,"is_preprint":false},{"pmid":"27965000","id":"PMC_27965000","title":"TAL Effectors Drive Transcription Bidirectionally in Plants.","date":"2016","source":"Molecular plant","url":"https://pubmed.ncbi.nlm.nih.gov/27965000","citation_count":26,"is_preprint":false},{"pmid":"26900582","id":"PMC_26900582","title":"A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease.","date":"2015","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26900582","citation_count":26,"is_preprint":false},{"pmid":"25484098","id":"PMC_25484098","title":"PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25484098","citation_count":25,"is_preprint":false},{"pmid":"29677397","id":"PMC_29677397","title":"Two ancestral genes shaped the Xanthomonas campestris TAL effector gene repertoire.","date":"2018","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/29677397","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45359,"output_tokens":3056,"usd":0.090958,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9690,"output_tokens":2820,"usd":0.059475,"stage2_stop_reason":"end_turn"},"total_usd":0.150433,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the canonical human/mammalian protein LRSAM1 (also known as TAL, RIFLE, FLJ31641, CMT2P).\n\nThe vast majority of papers in this corpus are about:\n1. TAL effectors from Xanthomonas bacteria (plant pathology/genome engineering) - NOT LRSAM1\n2. TAL-1/SCL (a bHLH transcription factor involved in T-cell leukemia and hematopoiesis) - NOT LRSAM1\n3. Schistosoma TAL proteins - NOT LRSAM1\n\nThe relevant papers about LRSAM1 (the E3 ubiquitin ligase) are:\n- PMID 23245322 (Huett et al., 2012) - LRSAM1 as E3 ligase for anti-Salmonella autophagy\n- PMID 15256501 (Amit et al., 2004) - Tal/LRSAM1 as Tsg101-specific E3 ligase\n- PMID 20865121 (Guernsey et al., 2010) - LRSAM1 mutation in CMT disease\n- PMID 22012984 (Weterman et al., 2011) - Frameshift mutation in LRSAM1 causing dominant CMT\n- PMID 23519028 (Bogdanik et al., 2013) - Mouse model of LRSAM1\n- PMID 22781092 (Nicolaou et al., 2012) - Novel LRSAM1 mutation in CMT2\n- PMID 26900582 (Aerts et al., 2015) - LRSAM1 mutation linking CMT2 to Parkinson's\n- PMID 25484098 (Wang et al., 2014) - PHF23 regulates LRSAM1\n- PMID 32098768 (Yin et al., 2020) - BBR recruits LRSAM1\n- PMID 39039049 (Mansuer et al., 2024) - LRSAM1 ubiquitinates SLC40A1\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"LRSAM1 (Tal) is a RING finger E3 ubiquitin ligase that specifically mediates multiple monoubiquitylation of TSG101. Bivalent binding of TSG101 to a tandem PTAP tetrapeptide motif and to a central region of LRSAM1 is required for LRSAM1-mediated ubiquitylation of TSG101. LRSAM1 regulates a TSG101-associated complex responsible for sorting cargo into multivesicular body vesicles and at the plasma membrane, impacting EGF receptor endocytosis and HIV budding.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitylation assays, mutagenesis of PTAP motif, receptor endocytosis assays, retrovirus budding assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP, mutagenesis of binding motif, multiple functional readouts (endocytosis, viral budding) in a single rigorous study\",\n      \"pmids\": [\"15256501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LRSAM1 is the E3 ubiquitin ligase responsible for generating the polyubiquitin signal around cytosolic Salmonella Typhimurium that triggers autophagy-mediated bacterial clearance. LRSAM1 localizes to intracellular bacteria; its leucine-rich repeat (LRR) domain is required for bacterial recognition/localization, and its RING domain is required for ubiquitin ligase activity generating the bacteria-associated ubiquitin signal. Using cells from LRSAM1-deficient individuals confirmed LRSAM1 is required for ubiquitination of intracellular bacteria but dispensable for ubiquitination of aggregated proteins.\",\n      \"method\": \"Loss-of-function studies using LRSAM1-deficient human cells, domain deletion mutagenesis (LRR and RING), immunofluorescence localization, ubiquitination assays, bacterial survival assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — patient-derived loss-of-function cells, domain mutagenesis, multiple orthogonal methods (localization, ubiquitination assay, bacterial clearance), rigorous controls\",\n      \"pmids\": [\"23245322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A homozygous intronic splice-site mutation in LRSAM1 causes autosomal recessive axonal Charcot-Marie-Tooth disease (CMT2P). The mutation causes aberrant splicing with obligatory frameshift and premature truncation, resulting in complete absence of LRSAM1 protein. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and in proper adhesion of neuronal cells in culture.\",\n      \"method\": \"Homozygosity mapping, SNP genotyping, direct DNA sequencing, RNA analysis (aberrant splicing), Western blotting of patient-derived immortalized cells\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — patient genetics with RNA and protein validation in patient cells, single lab, multiple methods confirming loss of function\",\n      \"pmids\": [\"20865121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A frameshift mutation (p.Leu708Argfx28) in the C-terminal RING finger motif of LRSAM1 causes autosomal dominant axonal Charcot-Marie-Tooth disease. The patient mutation impairs ubiquitin ligase activity as measured by elevated abundance of TSG101 (LRSAM1's reported substrate) in transfected cells. Morpholino knockdown of zebrafish Lrsam1 disturbs neural structure and tail formation, confirming a neurodevelopmental role.\",\n      \"method\": \"Linkage analysis, next-generation sequencing, Sanger confirmation, ubiquitin ligase activity assay in transfected cells (TSG101 levels), zebrafish morpholino knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional assay of mutant ligase activity, zebrafish loss-of-function, single lab with multiple methods\",\n      \"pmids\": [\"22012984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In transfected cells, LRSAM1 primarily localizes to a perinuclear compartment immediately beyond the Golgi and shows little colocalization with components of the endosome-to-lysosome trafficking pathway. Mouse Lrsam1 is abundantly expressed in motor and sensory neurons of the peripheral nervous system. Lrsam1 knockout mice show increased sensitivity to acrylamide-induced axon degeneration, indicating compromised axons, though baseline neuropathy phenotype is mild.\",\n      \"method\": \"Subcellular localization by immunofluorescence in transfected cells, colocalization with organelle markers, Lrsam1 knockout mouse generation, acrylamide challenge assay, neuromuscular performance testing\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in cells, genetic knockout mouse with functional challenge, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23519028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PHF23 (PHD finger protein 23) negatively regulates autophagy by interacting with LRSAM1 and promoting its ubiquitination and proteasomal degradation, thereby reducing LRSAM1 protein levels. The PHD finger domain of PHF23 is required for interaction with LRSAM1. PHF23 overexpression impairs autophagy (decreased LC3B-II levels), while PHF23 knockdown enhances autophagy through increased LRSAM1 availability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, LC3B-II autophagy flux assays, domain deletion mutagenesis of PHF23, siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, domain mutagenesis, autophagy readouts, single lab with multiple methods\",\n      \"pmids\": [\"25484098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Berberine (BBR) induces autophagic lysosomal degradation of BCR-ABL and BCR-ABL T315I by recruiting LRSAM1 as an E3 ubiquitin ligase. BBR binds to the tyrosine kinase domain of BCR-ABL, and LRSAM1 is required for BBR-mediated ubiquitination and autophagic degradation of BCR-ABL.\",\n      \"method\": \"Molecular docking, surface plasmon resonance, NMR, thermoshift assays for BBR-BCR-ABL binding; Western blotting for protein degradation; autophagy pathway inhibitors; LRSAM1 involvement assessed in cell lines and mouse models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — LRSAM1 recruitment inferred from association studies without direct reconstitution of ubiquitination of BCR-ABL by LRSAM1; single lab\",\n      \"pmids\": [\"32098768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LRSAM1 ubiquitinates and promotes proteasomal degradation of SLC40A1 (ferroportin), a ferrous iron exporter that inhibits ferroptosis. In glioma stem cells, the transcription repressor REST suppresses LRSAM1 expression; erianin inhibits REST's repressive function, upregulates LRSAM1, which then ubiquitinates and degrades SLC40A1, causing iron accumulation and ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, protein stability assays, ChIP assays, luciferase reporter assays, ferroptosis markers (ROS, GSH, MDA, BODIPY C11), TEM, ferrostatin-1 rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and ubiquitination assay identifying SLC40A1 as LRSAM1 substrate, multiple orthogonal mechanistic methods, single lab\",\n      \"pmids\": [\"39039049\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRSAM1 is an E3 ubiquitin ligase whose LRR domain mediates recognition of intracellular bacteria and whose RING domain catalyzes polyubiquitin chain formation on cytosolic Salmonella to initiate selective autophagy; it also monoubiquitylates TSG101 via a bivalent PTAP-docking mechanism to regulate multivesicular body sorting and viral budding, ubiquitinates SLC40A1 to regulate ferroptosis, and is regulated by PHF23-mediated proteasomal degradation, with mutations in its RING domain causing both dominant and recessive forms of Charcot-Marie-Tooth disease type 2P.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRSAM1 is a RING-finger E3 ubiquitin ligase that couples substrate recognition to polyubiquitin chain formation across membrane trafficking, antibacterial autophagy, and iron homeostasis [#0, #1]. Its two functional modules underlie this versatility: the leucine-rich repeat (LRR) domain mediates target recognition—localizing the ligase to cytosolic Salmonella Typhimurium—while the C-terminal RING domain catalyzes ubiquitin transfer to generate the bacteria-associated polyubiquitin signal that triggers selective autophagy and bacterial clearance [#1]. In its founding role, LRSAM1 multiply monoubiquitylates TSG101 through a bivalent docking mechanism requiring both a tandem PTAP tetrapeptide motif and a central region of LRSAM1, thereby regulating TSG101-dependent sorting of cargo into multivesicular bodies, EGF receptor endocytosis, and HIV budding [#0]. LRSAM1 also ubiquitinates and drives proteasomal degradation of the iron exporter SLC40A1 (ferroportin), promoting iron accumulation and ferroptosis [#7]. LRSAM1 protein levels are themselves controlled by PHF23, which interacts with LRSAM1 via its PHD finger domain and promotes its ubiquitination and proteasomal degradation, thereby restraining autophagy [#5]. Loss-of-function and RING-domain frameshift mutations in LRSAM1 cause both autosomal recessive and autosomal dominant axonal Charcot-Marie-Tooth disease type 2 [#2, #3], consistent with abundant expression in peripheral motor and sensory neurons and the increased axonal vulnerability of Lrsam1-deficient mice [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established LRSAM1 as a bona fide RING E3 ligase and defined its first substrate and trafficking role, answering what biochemical activity the protein carries.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo ubiquitylation assays, PTAP-motif mutagenesis, and endocytosis/retroviral budding readouts in cells\",\n      \"pmids\": [\"15256501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Ubiquitin chain topology beyond multiple monoubiquitylation not resolved\",\n        \"Structural basis of the bivalent PTAP/central-region docking not determined\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked complete loss of LRSAM1 to a human neurodegenerative disease, establishing physiological importance in peripheral nerve.\",\n      \"evidence\": \"Homozygosity mapping, sequencing, RNA splicing analysis, and Western blot of patient-derived cells\",\n      \"pmids\": [\"20865121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism connecting ligase loss to axonal degeneration not defined\",\n        \"Single recessive pedigree\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed a RING-domain frameshift causes dominant CMT and impairs catalytic activity, tying disease directly to defective ubiquitin ligase function.\",\n      \"evidence\": \"Linkage, NGS, TSG101-abundance ligase activity assay in transfected cells, and zebrafish morpholino knockdown\",\n      \"pmids\": [\"22012984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Dominant-negative versus haploinsufficiency mechanism not distinguished\",\n        \"Neuronal substrate relevant to disease not identified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the domain logic of LRSAM1 in antibacterial autophagy—LRR for recognition, RING for ubiquitination—answering how it targets intracellular pathogens.\",\n      \"evidence\": \"Patient-derived LRSAM1-deficient cells, LRR/RING domain deletions, immunofluorescence, ubiquitination and bacterial survival assays\",\n      \"pmids\": [\"23245322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct bacterial ligand recognized by the LRR not identified\",\n        \"Ubiquitin chain type on bacteria and autophagy receptor coupling not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Located LRSAM1 to a perinuclear post-Golgi compartment and demonstrated neuronal expression and axonal vulnerability, contextualizing where it acts and its in vivo requirement.\",\n      \"evidence\": \"Immunofluorescence colocalization in transfected cells and Lrsam1 knockout mouse with acrylamide axon-degeneration challenge\",\n      \"pmids\": [\"23519028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Baseline knockout neuropathy phenotype mild, leaving disease mechanism incomplete\",\n        \"Functional significance of perinuclear localization not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified PHF23 as an upstream regulator that controls LRSAM1 abundance, revealing how LRSAM1-dependent autophagy is tuned.\",\n      \"evidence\": \"Co-IP, ubiquitination and proteasome-inhibitor assays, PHD-domain mutagenesis, and LC3B-II autophagy flux readouts\",\n      \"pmids\": [\"25484098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PHF23 directly ubiquitinates LRSAM1 or recruits another ligase unresolved\",\n        \"Physiological contexts where this axis operates not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SLC40A1 as a degradation substrate, expanding LRSAM1's role into iron homeostasis and ferroptosis control.\",\n      \"evidence\": \"Co-IP, ubiquitination and stability assays, ChIP/luciferase for REST regulation, and ferroptosis markers with ferrostatin-1 rescue in glioma stem cells\",\n      \"pmids\": [\"39039049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitin chain linkage on SLC40A1 not characterized\",\n        \"Generality beyond glioma stem cells not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRSAM1's distinct substrate-recognition modes are selected in different cellular contexts, and which substrate underlies its peripheral-nerve function, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model linking LRR recognition to RING catalysis\",\n        \"Disease-relevant neuronal substrate unidentified\",\n        \"Chain-type specificity across substrates uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TSG101\", \"PHF23\", \"SLC40A1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}