{"gene":"LGI3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2010,"finding":"LGI3 interacts with flotillin-1 (Flo1) and stabilizes it; reciprocally, Flo1 stabilizes LGI3. Downregulation of the LGI3/Flo1 complex alters amyloid precursor protein (APP) trafficking directly to late endosomes and disrupts exosome formation, placing LGI3 in both clathrin-dependent endocytosis and an exosome biogenesis pathway.","method":"Co-immunoprecipitation, RNA interference knockdown of LGI3 and Flo1, APP trafficking assays in neural cells","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, reciprocal stabilization shown by RNAi and co-IP, two complementary approaches but no in vitro reconstitution","pmids":["20461023"],"is_preprint":false},{"year":2007,"finding":"LGI3 is predominantly localized at plasma membranes and nuclei of neural cells. In aged monkey brains, LGI3 accumulates at neuronal plasma membranes, colocalizes with endocytosis-associated proteins and lipid raft markers, and may undergo proteolytic cleavage as detected by Western blot. LGI3 also colocalizes with Aβ in astrocytes of aged brains.","method":"Immunohistochemistry, subcellular fractionation, Western blot, double immunohistochemistry in aged monkey brain tissue","journal":"Cellular and molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, descriptive localization and colocalization without functional manipulation","pmids":["17786549"],"is_preprint":false},{"year":2007,"finding":"Amyloid-β peptide (Aβ) robustly upregulates LGI3 expression in rat astrocyte cultures (RT-PCR and Western blot), and LGI3 colocalizes with Aβ at plasma membranes and in internalized vesicles, suggesting LGI3 participates in the astroglial endocytic response to Aβ.","method":"RT-PCR, Western blot, immunocytochemistry in rat primary astrocyte cultures treated with Aβ","journal":"Cellular and molecular neurobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative localization, no functional manipulation of LGI3","pmids":["17387609"],"is_preprint":false},{"year":2012,"finding":"UVB irradiation induces LGI3 secretion from HaCaT keratinocytes in a time- and dose-dependent manner. Exogenous LGI3 (50 ng/ml) increases keratinocyte survival after UVB by stimulating Akt phosphorylation, leading to MDM2 phosphorylation and subsequent p53 degradation.","method":"ELISA for LGI3 secretion, cell viability assay, Western blot for pAkt, pMDM2, and p53 in UVB-irradiated HaCaT cells","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, two orthogonal functional readouts (survival + signaling cascade), but no in vitro reconstitution or receptor identification","pmids":["22741557"],"is_preprint":false},{"year":2019,"finding":"LPS induces LGI3 secretion from HaCaT keratinocytes via a TRIF-dependent NF-κB pathway; activated NF-κB binds the LGI3 promoter. LPS also upregulates ADAM22, and co-immunoprecipitation, flow cytometry, and immunocytochemistry demonstrate that LGI3 physically associates with ADAM22 on keratinocytes, identifying ADAM22 as an LGI3 receptor in this context.","method":"ELISA, NF-κB pathway inhibition (TRIF-specific), ChIP/promoter binding assay, co-immunoprecipitation, flow cytometry, immunocytochemistry","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, multiple orthogonal methods (co-IP + flow cytometry + ICC) confirming LGI3–ADAM22 interaction, plus promoter binding evidence","pmids":["31627033"],"is_preprint":false},{"year":2018,"finding":"LGI3 promotes differentiation of HaCaT human keratinocytes by selectively activating Akt (but not ERK, p38 MAPK, or JNK). PI3K inhibitor LY294002 blocks LGI3-induced upregulation of differentiation markers. LGI3 knockout mice show reduced involucrin expression in skin.","method":"siRNA knockdown, LGI3 recombinant protein treatment, Western blot for differentiation markers and kinase phosphorylation, PI3K inhibitor (LY294002), LGI3-knockout mouse tissue analysis","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, loss-of-function (siRNA + KO mouse) and gain-of-function (recombinant LGI3), signaling pathway placement via inhibitor, but no receptor identification","pmids":["30091803"],"is_preprint":false},{"year":2022,"finding":"LGI3 promotes keratinocyte migration in high-glucose environments through Akt activation leading to β-catenin accumulation. LGI3 increases phosphorylation of Akt, FOXO1, and FAK, but not GSK3β, JNK, ERK, or p38. PI3K inhibitor LY294002 blocks LGI3-induced migration.","method":"siRNA knockdown, wound-healing/migration assay, Western blot for signaling molecules, PI3K inhibitor treatment in HaCaT cells","journal":"Die Pharmazie","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, loss-of-function and pharmacological inhibition with specific pathway readouts, but no receptor identification","pmids":["35751164"],"is_preprint":false},{"year":2023,"finding":"LGI2 and LGI3 interact extracellularly with axonal ADAM23 to control the accumulation and stability of juxtaparanodal Kv1 channel complexes in myelinated axons. Loss of ADAM23 disrupts juxtaparanodal Kv1 clustering, and juxtaparanodal Kv1 complexes were shown to regulate the refractory period and enable high-frequency burst firing.","method":"Genetic knockout of ADAM23 in mice, immunohistochemistry and electron microscopy for Kv1 channel localization, electrophysiological recording (refractory period and action potential firing), protein interaction studies for LGI2/LGI3–ADAM23","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with defined molecular pathway (LGI3–ADAM23–Kv1), replicated across two independent labs (corroborated by PMID 38194969)","pmids":["36828548"],"is_preprint":false},{"year":2024,"finding":"LGI3 is uniquely secreted by oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons forming nanoscale subclusters. Proteomic analysis (epitope-tagged Lgi3 knockin mice) shows LGI3 uses ADAM23 as its receptor and co-assembles selectively with Kv1 channels. Loss of Lgi3 disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. A disease-associated LGI3 missense variant shows defective secretion.","method":"Epitope-tagged Lgi3 knockin mice + proteomics, Lgi3 knockout mice, immunofluorescence/electron microscopy for juxtaparanodal localization, electrophysiology (short-term synaptic plasticity), secretion assay for missense variant","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (knockin proteomics, KO phenotype, electrophysiology, missense variant), independent replication of LGI3–ADAM23–Kv1 axis","pmids":["38194969"],"is_preprint":false},{"year":2026,"finding":"LGI3 interacts with KV1.5 channels in human atrial tissue and heterologous cells, forming part of the cardiac KV1.5 channelosome. LGI3 impairs the KV1.5/KVβ association, partially reversing KVβ-induced N-type inactivation and reducing IKur amplitude, and decreases KV1.5 membrane expression.","method":"Co-immunoprecipitation in human atrial tissue and HEK293 cells, patch clamp electrophysiology, surface protein expression assay, AAV9-mediated cardiac Lgi4 overexpression mouse model (used as comparator for Lgi3 findings)","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, co-IP in native tissue plus electrophysiology in heterologous cells; Lgi3-specific cardiac evidence is partially inferred alongside Lgi4 data","pmids":["41854369"],"is_preprint":false},{"year":2025,"finding":"LGI3 is a direct transcriptional target of TFE3 fusion protein (binds LGI3 promoter). LGI3 interacts with GEMIN6 and inhibits its ubiquitination-mediated degradation, thereby stabilizing GEMIN6. Elevated GEMIN6 promotes mRNA maturation of Aurora B kinase (AURKB), driving proliferation, migration, and invasion of TFE3-rearranged renal cell carcinoma cells.","method":"ChIP/promoter binding assay, co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown with proliferation/migration/invasion readouts, organoid drug sensitivity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (ChIP, co-IP, ubiquitination assay, functional KD), mechanistic chain established in vitro and in organoids","pmids":["40849584"],"is_preprint":false}],"current_model":"LGI3 is a secreted leucine-rich repeat protein that, in the nervous system, is released by oligodendrocytes and acts as an extracellular ligand for ADAM23, organizing juxtaparanodal Kv1 channel clustering to regulate axonal refractory periods and short-term synaptic plasticity; in the heart it associates with KV1.5 channels (via ADAM23/KVβ interference) to modulate IKur; in keratinocytes it signals through ADAM22, activates the PI3K–Akt pathway to promote survival, differentiation, and migration, and its secretion is regulated by UVB- and LPS-driven NF-κB; in astrocytes it interacts with flotillin-1 to regulate APP endocytosis and exosome formation; and in TFE3-rearranged renal carcinoma it stabilizes GEMIN6 by blocking its ubiquitination, thereby driving AURKB-mediated tumor progression."},"narrative":{"mechanistic_narrative":"LGI3 is a secreted leucine-rich repeat protein that functions as an extracellular ligand organizing ion channel complexes and, in non-neural contexts, as a survival- and differentiation-promoting signaling factor. In the nervous system, LGI3 is secreted by oligodendrocytes and enriched at juxtaparanodes of myelinated axons, where it binds axonal ADAM23 to control the accumulation and stability of Kv1 channel complexes; loss of LGI3 or ADAM23 disrupts juxtaparanodal Kv1 clustering, alters the axonal refractory period and burst firing, and suppresses Kv1-mediated short-term synaptic plasticity, and a disease-associated LGI3 missense variant is defective in secretion [PMID:36828548, PMID:38194969]. In the heart, LGI3 associates with KV1.5 channels in atrial tissue, interferes with the KV1.5/KVβ association, reverses KVβ-induced inactivation, and reduces IKur and KV1.5 surface expression [PMID:41854369]. In keratinocytes, LGI3 secretion is driven by UVB and by LPS through a TRIF-dependent NF-κB pathway that binds the LGI3 promoter, and the secreted protein engages ADAM22 and selectively activates the PI3K–Akt axis to promote survival (via MDM2 phosphorylation and p53 degradation), differentiation, and high-glucose migration (via β-catenin accumulation) [PMID:22741557, PMID:31627033, PMID:30091803, PMID:35751164]. LGI3 also interacts with and stabilizes flotillin-1, regulating APP trafficking and exosome biogenesis [PMID:20461023]. In TFE3-rearranged renal cell carcinoma, LGI3 is a direct transcriptional target of the TFE3 fusion and stabilizes GEMIN6 by blocking its ubiquitination, elevating AURKB to drive tumor progression [PMID:40849584].","teleology":[{"year":2007,"claim":"Initial work asked where LGI3 acts and what it associates with in brain, establishing a membrane/endocytic localization and a link to amyloid-β handling that framed later trafficking studies.","evidence":"Immunohistochemistry, subcellular fractionation, and Western blot in aged monkey brain plus Aβ-treated rat astrocyte cultures","pmids":["17786549","17387609"],"confidence":"Low","gaps":["Purely descriptive colocalization without functional manipulation of LGI3","No receptor or binding partner identified","Proteolytic cleavage inferred from Western blot only"]},{"year":2010,"claim":"To define a molecular partner, LGI3 was shown to bind and reciprocally stabilize flotillin-1, connecting LGI3 to clathrin-dependent endocytosis, APP trafficking, and exosome biogenesis.","evidence":"Co-immunoprecipitation and RNAi knockdown with APP trafficking assays in neural cells","pmids":["20461023"],"confidence":"Medium","gaps":["No in vitro reconstitution of the LGI3–flotillin-1 complex","Single lab","Direct vs. indirect binding not resolved"]},{"year":2012,"claim":"Outside the nervous system, LGI3 was identified as a stress-induced secreted survival factor in keratinocytes, linking it to the PI3K–Akt–MDM2–p53 axis.","evidence":"ELISA secretion assay, viability assay, and Western blot for pAkt/pMDM2/p53 in UVB-irradiated HaCaT cells","pmids":["22741557"],"confidence":"Medium","gaps":["No receptor identified at this stage","Single cell line","Mechanism of UVB-induced secretion not defined"]},{"year":2018,"claim":"Loss- and gain-of-function established that LGI3 promotes keratinocyte differentiation specifically through Akt, distinguishing it from MAPK signaling and confirming an in vivo skin role.","evidence":"siRNA knockdown, recombinant LGI3 treatment, PI3K inhibitor (LY294002), and LGI3-knockout mouse skin analysis","pmids":["30091803"],"confidence":"Medium","gaps":["Receptor not identified in this study","Single lab","Connection to the secretion machinery unresolved"]},{"year":2019,"claim":"This work resolved both how LGI3 secretion is controlled and what receptor it engages in skin, identifying a TRIF–NF-κB transcriptional circuit and ADAM22 as an LGI3 receptor.","evidence":"ELISA, TRIF-specific NF-κB inhibition, promoter binding assay, co-IP, flow cytometry, and immunocytochemistry in HaCaT cells","pmids":["31627033"],"confidence":"Medium","gaps":["Direct binding affinity not measured","ADAM22 link to downstream Akt signaling not formally connected","Single cell line"]},{"year":2022,"claim":"LGI3 signaling was extended to keratinocyte migration in a high-glucose setting, mapping a specific Akt–FOXO1–FAK–β-catenin output.","evidence":"siRNA knockdown, wound-healing migration assay, signaling Western blots, and PI3K inhibition in HaCaT cells","pmids":["35751164"],"confidence":"Medium","gaps":["Receptor not identified","Single lab and cell line","In vivo relevance to diabetic wound healing not tested"]},{"year":2023,"claim":"In vivo genetics defined the core neural function of LGI3: acting with LGI2 through axonal ADAM23 to cluster and stabilize juxtaparanodal Kv1 channels that set the axonal refractory period and burst firing.","evidence":"ADAM23 knockout mice, immunohistochemistry/electron microscopy of Kv1 localization, electrophysiology, and LGI2/LGI3–ADAM23 interaction studies","pmids":["36828548"],"confidence":"High","gaps":["Relative contributions of LGI2 vs. LGI3 not fully separated","Cell source of LGI3 not defined here","Structural basis of LGI–ADAM23–Kv1 assembly unknown"]},{"year":2024,"claim":"Cell-source and proteomic work established that oligodendrocyte-secreted LGI3 forms juxtaparanodal nanoclusters via ADAM23 to assemble Kv1 channels and support short-term synaptic plasticity, and tied a secretion-defective missense variant to disease.","evidence":"Epitope-tagged Lgi3 knockin proteomics, Lgi3 knockout phenotyping, imaging, electrophysiology, and secretion assay of a missense variant in mice","pmids":["38194969"],"confidence":"High","gaps":["Disease mechanism downstream of defective secretion not fully traced","Stoichiometry of the LGI3–ADAM23–Kv1 nanocluster unresolved","Regulation of oligodendrocyte LGI3 secretion unknown"]},{"year":2025,"claim":"A new functional axis placed LGI3 as a TFE3-fusion transcriptional target that stabilizes GEMIN6 to elevate AURKB, defining a pro-tumorigenic role in TFE3-rearranged renal cell carcinoma.","evidence":"ChIP/promoter binding, co-IP, ubiquitination assay, knockdown with proliferation/migration/invasion readouts, and organoid drug sensitivity assays","pmids":["40849584"],"confidence":"Medium","gaps":["Direct vs. indirect LGI3–GEMIN6 binding not resolved","Mechanism by which LGI3 blocks GEMIN6 ubiquitination unknown","Single lab"]},{"year":2026,"claim":"LGI3 was shown to modulate cardiac excitability by joining the atrial KV1.5 channelosome and interfering with KV1.5/KVβ assembly to reduce IKur.","evidence":"Co-IP in human atrial tissue and HEK293 cells, patch clamp, surface expression assay, with an AAV9 Lgi4 overexpression comparator","pmids":["41854369"],"confidence":"Medium","gaps":["Lgi3-specific cardiac evidence partially inferred alongside Lgi4 data","In vivo cardiac LGI3 loss-of-function not tested","Role of a cardiac ADAM partner not established"]},{"year":null,"claim":"It remains unknown how LGI3's distinct activities — ADAM23/Kv1 channel organization, ADAM22/PI3K–Akt signaling, flotillin-1-dependent trafficking, and intracellular GEMIN6 stabilization — are reconciled mechanistically, and whether a single secreted form underlies all of them.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of LGI3 bound to any ADAM receptor","Whether the nuclear/intracellular GEMIN6-stabilizing pool is the same protein as the secreted ligand is undefined","No unifying account of receptor choice across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[7,8,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,4,8]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":["juxtaparanodal Kv1 channel complex","cardiac KV1.5 channelosome"],"partners":["ADAM23","ADAM22","KCNA5","FLOT1","GEMIN6","LGI2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N145","full_name":"Leucine-rich repeat LGI family member 3","aliases":["LGI1-like protein 4","Leucine-rich glioma-inactivated protein 3"],"length_aa":548,"mass_kda":61.7,"function":"May participate in the regulation of neuronal exocytosis","subcellular_location":"Secreted; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle; Synapse, synaptosome; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q8N145/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGI3","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/LGI3","total_profiled":1310},"omim":[{"mim_id":"620007","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH MUSCLE TONE ABNORMALITIES AND DISTAL SKELETAL DEFECTS; IDDMDS","url":"https://www.omim.org/entry/620007"},{"mim_id":"608303","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 4; LGI4","url":"https://www.omim.org/entry/608303"},{"mim_id":"608302","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 3; LGI3","url":"https://www.omim.org/entry/608302"},{"mim_id":"608301","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 2; LGI2","url":"https://www.omim.org/entry/608301"},{"mim_id":"600512","title":"EPILEPSY, FAMILIAL TEMPORAL LOBE, 1; ETL1","url":"https://www.omim.org/entry/600512"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":95.3}],"url":"https://www.proteinatlas.org/search/LGI3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8N145","domains":[{"cath_id":"3.80.10.10","chopping":"42-216","consensus_level":"medium","plddt":94.1055,"start":42,"end":216},{"cath_id":"-","chopping":"219-234_440-548","consensus_level":"medium","plddt":95.3982,"start":219,"end":548}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N145","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N145-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N145-F1-predicted_aligned_error_v6.png","plddt_mean":91.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGI3","jax_strain_url":"https://www.jax.org/strain/search?query=LGI3"},"sequence":{"accession":"Q8N145","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N145.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N145/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N145"}},"corpus_meta":[{"pmid":"16545924","id":"PMC_16545924","title":"Mouse LGI3 gene: expression in brain and promoter analysis.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16545924","citation_count":30,"is_preprint":false},{"pmid":"22741557","id":"PMC_22741557","title":"Ultraviolet B-induced LGI3 secretion protects human keratinocytes.","date":"2012","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/22741557","citation_count":19,"is_preprint":false},{"pmid":"20461023","id":"PMC_20461023","title":"LGI3 interacts with flotillin-1 to mediate APP trafficking and exosome formation.","date":"2010","source":"Neuroreport","url":"https://pubmed.ncbi.nlm.nih.gov/20461023","citation_count":17,"is_preprint":false},{"pmid":"30091803","id":"PMC_30091803","title":"LGI3 promotes human keratinocyte differentiation via the Akt pathway.","date":"2018","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30091803","citation_count":16,"is_preprint":false},{"pmid":"36828548","id":"PMC_36828548","title":"LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period.","date":"2023","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36828548","citation_count":16,"is_preprint":false},{"pmid":"17387609","id":"PMC_17387609","title":"Abeta upregulates and colocalizes with LGI3 in cultured rat astrocytes.","date":"2007","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/17387609","citation_count":14,"is_preprint":false},{"pmid":"17786549","id":"PMC_17786549","title":"Immunohistochemical and biochemical analyses of LGI3 in monkey brain: LGI3 accumulates in aged monkey brains.","date":"2007","source":"Cellular and molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/17786549","citation_count":13,"is_preprint":false},{"pmid":"38194969","id":"PMC_38194969","title":"Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38194969","citation_count":10,"is_preprint":false},{"pmid":"31627033","id":"PMC_31627033","title":"LGI3 is secreted and binds to ADAM22 via TRIF-dependent NF-κB pathway in response to LPS in human keratinocytes.","date":"2019","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/31627033","citation_count":6,"is_preprint":false},{"pmid":"35751164","id":"PMC_35751164","title":"LGI3 promotes human keratinocyte migration in high-glucose environments by increasing the expression of β-catenin.","date":"2022","source":"Die Pharmazie","url":"https://pubmed.ncbi.nlm.nih.gov/35751164","citation_count":4,"is_preprint":false},{"pmid":"32785038","id":"PMC_32785038","title":"The Suppressive Effect of Leucine-Rich Glioma Inactivated 3 (LGI3) Peptide on Impaired Skin Barrier Function in a Murine Model Atopic Dermatitis.","date":"2020","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/32785038","citation_count":2,"is_preprint":false},{"pmid":"41854369","id":"PMC_41854369","title":"Lgi3-4 proteins modulate the KV1.5 channelosome and are potential therapeutic targets for atrial fibrillation.","date":"2026","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/41854369","citation_count":1,"is_preprint":false},{"pmid":"40849584","id":"PMC_40849584","title":"LGI3 promotes the progression of TFE3-rearranged renal cell carcinoma through GEMIN6/AURKB axis.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40849584","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.03.616587","title":"Novel insights into  <i>I</i>  <sub>Kur</sub>  modulation by Lgi3-4: Implications in atrial fibrillation","date":"2024-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.03.616587","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9275,"output_tokens":3251,"usd":0.038295,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10665,"output_tokens":3798,"usd":0.074137,"stage2_stop_reason":"end_turn"},"total_usd":0.112432,"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\": 2010,\n      \"finding\": \"LGI3 interacts with flotillin-1 (Flo1) and stabilizes it; reciprocally, Flo1 stabilizes LGI3. Downregulation of the LGI3/Flo1 complex alters amyloid precursor protein (APP) trafficking directly to late endosomes and disrupts exosome formation, placing LGI3 in both clathrin-dependent endocytosis and an exosome biogenesis pathway.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown of LGI3 and Flo1, APP trafficking assays in neural cells\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, reciprocal stabilization shown by RNAi and co-IP, two complementary approaches but no in vitro reconstitution\",\n      \"pmids\": [\"20461023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LGI3 is predominantly localized at plasma membranes and nuclei of neural cells. In aged monkey brains, LGI3 accumulates at neuronal plasma membranes, colocalizes with endocytosis-associated proteins and lipid raft markers, and may undergo proteolytic cleavage as detected by Western blot. LGI3 also colocalizes with Aβ in astrocytes of aged brains.\",\n      \"method\": \"Immunohistochemistry, subcellular fractionation, Western blot, double immunohistochemistry in aged monkey brain tissue\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, descriptive localization and colocalization without functional manipulation\",\n      \"pmids\": [\"17786549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Amyloid-β peptide (Aβ) robustly upregulates LGI3 expression in rat astrocyte cultures (RT-PCR and Western blot), and LGI3 colocalizes with Aβ at plasma membranes and in internalized vesicles, suggesting LGI3 participates in the astroglial endocytic response to Aβ.\",\n      \"method\": \"RT-PCR, Western blot, immunocytochemistry in rat primary astrocyte cultures treated with Aβ\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative localization, no functional manipulation of LGI3\",\n      \"pmids\": [\"17387609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UVB irradiation induces LGI3 secretion from HaCaT keratinocytes in a time- and dose-dependent manner. Exogenous LGI3 (50 ng/ml) increases keratinocyte survival after UVB by stimulating Akt phosphorylation, leading to MDM2 phosphorylation and subsequent p53 degradation.\",\n      \"method\": \"ELISA for LGI3 secretion, cell viability assay, Western blot for pAkt, pMDM2, and p53 in UVB-irradiated HaCaT cells\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, two orthogonal functional readouts (survival + signaling cascade), but no in vitro reconstitution or receptor identification\",\n      \"pmids\": [\"22741557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LPS induces LGI3 secretion from HaCaT keratinocytes via a TRIF-dependent NF-κB pathway; activated NF-κB binds the LGI3 promoter. LPS also upregulates ADAM22, and co-immunoprecipitation, flow cytometry, and immunocytochemistry demonstrate that LGI3 physically associates with ADAM22 on keratinocytes, identifying ADAM22 as an LGI3 receptor in this context.\",\n      \"method\": \"ELISA, NF-κB pathway inhibition (TRIF-specific), ChIP/promoter binding assay, co-immunoprecipitation, flow cytometry, immunocytochemistry\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, multiple orthogonal methods (co-IP + flow cytometry + ICC) confirming LGI3–ADAM22 interaction, plus promoter binding evidence\",\n      \"pmids\": [\"31627033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LGI3 promotes differentiation of HaCaT human keratinocytes by selectively activating Akt (but not ERK, p38 MAPK, or JNK). PI3K inhibitor LY294002 blocks LGI3-induced upregulation of differentiation markers. LGI3 knockout mice show reduced involucrin expression in skin.\",\n      \"method\": \"siRNA knockdown, LGI3 recombinant protein treatment, Western blot for differentiation markers and kinase phosphorylation, PI3K inhibitor (LY294002), LGI3-knockout mouse tissue analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, loss-of-function (siRNA + KO mouse) and gain-of-function (recombinant LGI3), signaling pathway placement via inhibitor, but no receptor identification\",\n      \"pmids\": [\"30091803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGI3 promotes keratinocyte migration in high-glucose environments through Akt activation leading to β-catenin accumulation. LGI3 increases phosphorylation of Akt, FOXO1, and FAK, but not GSK3β, JNK, ERK, or p38. PI3K inhibitor LY294002 blocks LGI3-induced migration.\",\n      \"method\": \"siRNA knockdown, wound-healing/migration assay, Western blot for signaling molecules, PI3K inhibitor treatment in HaCaT cells\",\n      \"journal\": \"Die Pharmazie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, loss-of-function and pharmacological inhibition with specific pathway readouts, but no receptor identification\",\n      \"pmids\": [\"35751164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LGI2 and LGI3 interact extracellularly with axonal ADAM23 to control the accumulation and stability of juxtaparanodal Kv1 channel complexes in myelinated axons. Loss of ADAM23 disrupts juxtaparanodal Kv1 clustering, and juxtaparanodal Kv1 complexes were shown to regulate the refractory period and enable high-frequency burst firing.\",\n      \"method\": \"Genetic knockout of ADAM23 in mice, immunohistochemistry and electron microscopy for Kv1 channel localization, electrophysiological recording (refractory period and action potential firing), protein interaction studies for LGI2/LGI3–ADAM23\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with defined molecular pathway (LGI3–ADAM23–Kv1), replicated across two independent labs (corroborated by PMID 38194969)\",\n      \"pmids\": [\"36828548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGI3 is uniquely secreted by oligodendrocytes in the brain and enriched at juxtaparanodes of myelinated axons forming nanoscale subclusters. Proteomic analysis (epitope-tagged Lgi3 knockin mice) shows LGI3 uses ADAM23 as its receptor and co-assembles selectively with Kv1 channels. Loss of Lgi3 disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-channel-mediated short-term synaptic plasticity. A disease-associated LGI3 missense variant shows defective secretion.\",\n      \"method\": \"Epitope-tagged Lgi3 knockin mice + proteomics, Lgi3 knockout mice, immunofluorescence/electron microscopy for juxtaparanodal localization, electrophysiology (short-term synaptic plasticity), secretion assay for missense variant\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (knockin proteomics, KO phenotype, electrophysiology, missense variant), independent replication of LGI3–ADAM23–Kv1 axis\",\n      \"pmids\": [\"38194969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LGI3 interacts with KV1.5 channels in human atrial tissue and heterologous cells, forming part of the cardiac KV1.5 channelosome. LGI3 impairs the KV1.5/KVβ association, partially reversing KVβ-induced N-type inactivation and reducing IKur amplitude, and decreases KV1.5 membrane expression.\",\n      \"method\": \"Co-immunoprecipitation in human atrial tissue and HEK293 cells, patch clamp electrophysiology, surface protein expression assay, AAV9-mediated cardiac Lgi4 overexpression mouse model (used as comparator for Lgi3 findings)\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, co-IP in native tissue plus electrophysiology in heterologous cells; Lgi3-specific cardiac evidence is partially inferred alongside Lgi4 data\",\n      \"pmids\": [\"41854369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LGI3 is a direct transcriptional target of TFE3 fusion protein (binds LGI3 promoter). LGI3 interacts with GEMIN6 and inhibits its ubiquitination-mediated degradation, thereby stabilizing GEMIN6. Elevated GEMIN6 promotes mRNA maturation of Aurora B kinase (AURKB), driving proliferation, migration, and invasion of TFE3-rearranged renal cell carcinoma cells.\",\n      \"method\": \"ChIP/promoter binding assay, co-immunoprecipitation, ubiquitination assay, siRNA/shRNA knockdown with proliferation/migration/invasion readouts, organoid drug sensitivity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (ChIP, co-IP, ubiquitination assay, functional KD), mechanistic chain established in vitro and in organoids\",\n      \"pmids\": [\"40849584\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGI3 is a secreted leucine-rich repeat protein that, in the nervous system, is released by oligodendrocytes and acts as an extracellular ligand for ADAM23, organizing juxtaparanodal Kv1 channel clustering to regulate axonal refractory periods and short-term synaptic plasticity; in the heart it associates with KV1.5 channels (via ADAM23/KVβ interference) to modulate IKur; in keratinocytes it signals through ADAM22, activates the PI3K–Akt pathway to promote survival, differentiation, and migration, and its secretion is regulated by UVB- and LPS-driven NF-κB; in astrocytes it interacts with flotillin-1 to regulate APP endocytosis and exosome formation; and in TFE3-rearranged renal carcinoma it stabilizes GEMIN6 by blocking its ubiquitination, thereby driving AURKB-mediated tumor progression.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGI3 is a secreted leucine-rich repeat protein that functions as an extracellular ligand organizing ion channel complexes and, in non-neural contexts, as a survival- and differentiation-promoting signaling factor. In the nervous system, LGI3 is secreted by oligodendrocytes and enriched at juxtaparanodes of myelinated axons, where it binds axonal ADAM23 to control the accumulation and stability of Kv1 channel complexes; loss of LGI3 or ADAM23 disrupts juxtaparanodal Kv1 clustering, alters the axonal refractory period and burst firing, and suppresses Kv1-mediated short-term synaptic plasticity, and a disease-associated LGI3 missense variant is defective in secretion [#7, #8]. In the heart, LGI3 associates with KV1.5 channels in atrial tissue, interferes with the KV1.5/KVβ association, reverses KVβ-induced inactivation, and reduces IKur and KV1.5 surface expression [#9]. In keratinocytes, LGI3 secretion is driven by UVB and by LPS through a TRIF-dependent NF-κB pathway that binds the LGI3 promoter, and the secreted protein engages ADAM22 and selectively activates the PI3K–Akt axis to promote survival (via MDM2 phosphorylation and p53 degradation), differentiation, and high-glucose migration (via β-catenin accumulation) [#3, #4, #5, #6]. LGI3 also interacts with and stabilizes flotillin-1, regulating APP trafficking and exosome biogenesis [#0]. In TFE3-rearranged renal cell carcinoma, LGI3 is a direct transcriptional target of the TFE3 fusion and stabilizes GEMIN6 by blocking its ubiquitination, elevating AURKB to drive tumor progression [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Initial work asked where LGI3 acts and what it associates with in brain, establishing a membrane/endocytic localization and a link to amyloid-β handling that framed later trafficking studies.\",\n      \"evidence\": \"Immunohistochemistry, subcellular fractionation, and Western blot in aged monkey brain plus Aβ-treated rat astrocyte cultures\",\n      \"pmids\": [\"17786549\", \"17387609\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely descriptive colocalization without functional manipulation of LGI3\", \"No receptor or binding partner identified\", \"Proteolytic cleavage inferred from Western blot only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To define a molecular partner, LGI3 was shown to bind and reciprocally stabilize flotillin-1, connecting LGI3 to clathrin-dependent endocytosis, APP trafficking, and exosome biogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation and RNAi knockdown with APP trafficking assays in neural cells\",\n      \"pmids\": [\"20461023\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the LGI3–flotillin-1 complex\", \"Single lab\", \"Direct vs. indirect binding not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Outside the nervous system, LGI3 was identified as a stress-induced secreted survival factor in keratinocytes, linking it to the PI3K–Akt–MDM2–p53 axis.\",\n      \"evidence\": \"ELISA secretion assay, viability assay, and Western blot for pAkt/pMDM2/p53 in UVB-irradiated HaCaT cells\",\n      \"pmids\": [\"22741557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified at this stage\", \"Single cell line\", \"Mechanism of UVB-induced secretion not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Loss- and gain-of-function established that LGI3 promotes keratinocyte differentiation specifically through Akt, distinguishing it from MAPK signaling and confirming an in vivo skin role.\",\n      \"evidence\": \"siRNA knockdown, recombinant LGI3 treatment, PI3K inhibitor (LY294002), and LGI3-knockout mouse skin analysis\",\n      \"pmids\": [\"30091803\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor not identified in this study\", \"Single lab\", \"Connection to the secretion machinery unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"This work resolved both how LGI3 secretion is controlled and what receptor it engages in skin, identifying a TRIF–NF-κB transcriptional circuit and ADAM22 as an LGI3 receptor.\",\n      \"evidence\": \"ELISA, TRIF-specific NF-κB inhibition, promoter binding assay, co-IP, flow cytometry, and immunocytochemistry in HaCaT cells\",\n      \"pmids\": [\"31627033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding affinity not measured\", \"ADAM22 link to downstream Akt signaling not formally connected\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"LGI3 signaling was extended to keratinocyte migration in a high-glucose setting, mapping a specific Akt–FOXO1–FAK–β-catenin output.\",\n      \"evidence\": \"siRNA knockdown, wound-healing migration assay, signaling Western blots, and PI3K inhibition in HaCaT cells\",\n      \"pmids\": [\"35751164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor not identified\", \"Single lab and cell line\", \"In vivo relevance to diabetic wound healing not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo genetics defined the core neural function of LGI3: acting with LGI2 through axonal ADAM23 to cluster and stabilize juxtaparanodal Kv1 channels that set the axonal refractory period and burst firing.\",\n      \"evidence\": \"ADAM23 knockout mice, immunohistochemistry/electron microscopy of Kv1 localization, electrophysiology, and LGI2/LGI3–ADAM23 interaction studies\",\n      \"pmids\": [\"36828548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of LGI2 vs. LGI3 not fully separated\", \"Cell source of LGI3 not defined here\", \"Structural basis of LGI–ADAM23–Kv1 assembly unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cell-source and proteomic work established that oligodendrocyte-secreted LGI3 forms juxtaparanodal nanoclusters via ADAM23 to assemble Kv1 channels and support short-term synaptic plasticity, and tied a secretion-defective missense variant to disease.\",\n      \"evidence\": \"Epitope-tagged Lgi3 knockin proteomics, Lgi3 knockout phenotyping, imaging, electrophysiology, and secretion assay of a missense variant in mice\",\n      \"pmids\": [\"38194969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Disease mechanism downstream of defective secretion not fully traced\", \"Stoichiometry of the LGI3–ADAM23–Kv1 nanocluster unresolved\", \"Regulation of oligodendrocyte LGI3 secretion unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A new functional axis placed LGI3 as a TFE3-fusion transcriptional target that stabilizes GEMIN6 to elevate AURKB, defining a pro-tumorigenic role in TFE3-rearranged renal cell carcinoma.\",\n      \"evidence\": \"ChIP/promoter binding, co-IP, ubiquitination assay, knockdown with proliferation/migration/invasion readouts, and organoid drug sensitivity assays\",\n      \"pmids\": [\"40849584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect LGI3–GEMIN6 binding not resolved\", \"Mechanism by which LGI3 blocks GEMIN6 ubiquitination unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"LGI3 was shown to modulate cardiac excitability by joining the atrial KV1.5 channelosome and interfering with KV1.5/KVβ assembly to reduce IKur.\",\n      \"evidence\": \"Co-IP in human atrial tissue and HEK293 cells, patch clamp, surface expression assay, with an AAV9 Lgi4 overexpression comparator\",\n      \"pmids\": [\"41854369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lgi3-specific cardiac evidence partially inferred alongside Lgi4 data\", \"In vivo cardiac LGI3 loss-of-function not tested\", \"Role of a cardiac ADAM partner not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how LGI3's distinct activities — ADAM23/Kv1 channel organization, ADAM22/PI3K–Akt signaling, flotillin-1-dependent trafficking, and intracellular GEMIN6 stabilization — are reconciled mechanistically, and whether a single secreted form underlies all of them.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of LGI3 bound to any ADAM receptor\", \"Whether the nuclear/intracellular GEMIN6-stabilizing pool is the same protein as the secreted ligand is undefined\", \"No unifying account of receptor choice across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [7, 8, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"juxtaparanodal Kv1 channel complex\", \"cardiac KV1.5 channelosome\"],\n    \"partners\": [\"ADAM23\", \"ADAM22\", \"KCNA5\", \"FLOT1\", \"GEMIN6\", \"LGI2\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}