{"gene":"LGALS8","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2012,"finding":"Galectin-8 (LGALS8) acts as a cytosolic danger receptor that detects host glycans exposed on damaged Salmonella-containing vacuoles, then recruits the autophagy adaptor NDP52 (CALCOCO2) to activate antibacterial selective autophagy, restricting Salmonella proliferation in human cells.","method":"Co-immunoprecipitation, live-cell fluorescence imaging, siRNA knockdown with bacterial proliferation assay, endosomal damage assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, live imaging, KD with defined phenotype; foundational paper replicated by multiple subsequent studies","pmids":["22246324"],"is_preprint":false},{"year":2017,"finding":"During picornavirus entry, galectin-8 detects permeated endosomes and marks them for autophagic degradation (pore-activated clearance pathway); PLA2G16 competes with this clearance by facilitating viral genome translocation, placing LGALS8-mediated autophagy as an antiviral defense mechanism suppressible by PLA2G16.","method":"Genome-wide haploid genetic screen, suppressor screen, siRNA knockdown, viral infection assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genome-wide screen plus epistasis suppressor screen; strong mechanistic placement of LGALS8 in antiviral pathway","pmids":["28077878"],"is_preprint":false},{"year":2018,"finding":"Upon lysosomal membrane damage, cytosolic galectin-8 (LGALS8) inhibits MTOR and activates AMPK, functioning as an active signal transducer (not merely a passive damage tag) that controls master regulators of autophagy in response to endomembrane damage.","method":"APEX2 proximity labeling proteomics, kinase activity assays (MTOR, AMPK), lysosomal damage assays with galectin KO/KD","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proximity proteomics, kinase assays, KO); mechanistic link between LGALS8 and MTOR/AMPK established","pmids":["30081722"],"is_preprint":false},{"year":2019,"finding":"Galectin-8-marked damaged Salmonella-containing vacuoles recruit CALCOCO2/NDP52, which then assembles a trimeric complex with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1 (components of ULK and TBK1 kinase complexes) to initiate phagophore formation at the cargo site, establishing LGALS8 as the upstream 'eat-me' signal that nucleates the autophagy-initiation machinery.","method":"Co-immunoprecipitation, fluorescence microscopy, mutagenesis of CALCOCO2 binding domains, KD with phenotypic rescue","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, mutagenesis, and defined phenotypic readout; mechanistic pathway placement of LGALS8→NDP52→ULK/TBK1","pmids":["31258038"],"is_preprint":false},{"year":2016,"finding":"Galectin-8 promotes pathological lymphangiogenesis through a mechanism involving crosstalk among VEGF-C, podoplanin, and integrin pathways (α1β1 and α5β1), independently of VEGFR-3; Lgals8-/- mice show reduced inflammatory lymphangiogenesis and improved corneal graft survival.","method":"Lgals8-/- mouse model, Pdpn-/- mouse model, VEGFR-3 knockdown, integrin inhibition assays, corneal transplant model, herpes simplex keratitis model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO models with multiple orthogonal pathway dissection experiments; replicated across disease models","pmids":["27066737"],"is_preprint":false},{"year":2022,"finding":"Upon lysosomal damage, galectin-8 contributes to MTOR inactivation via the Ragulator-RRAGA-RRAGB complex together with NUFIP2, and this function is coordinated by GABARAPs/Atg8ylation at the damaged lysosome membrane, linking membrane Atg8ylation to MTOR regulation.","method":"Lysosome immunopurification (LysoIP), proteomics, GABARAP interaction assays, Co-IP, MTOR activity assays, KD experiments","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — LysoIP proteomics plus Co-IP and MTOR activity assays; mechanistic placement of LGALS8 in Ragulator-RRAGA-RRAGB complex regulation","pmids":["36394332"],"is_preprint":false},{"year":2015,"finding":"CALCOCO2/NDP52 binds galectin-8 (LGALS8) adsorbed on damaged Salmonella-containing vacuoles via one domain to mediate bacterial targeting to phagophores, while a distinct domain mediates LC3A/B/GABARAPL2 and MYO6 binding for autophagosome maturation, demonstrating dual separable functions of the LGALS8-NDP52 interaction.","method":"Domain mutagenesis of NDP52, Co-IP, fluorescence microscopy, bacterial infection assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis with Co-IP; single lab reviewing own findings with partial new data","pmids":["25998689"],"is_preprint":false},{"year":2017,"finding":"Exogenous galectin-8 activates dendritic cells to express MHCII, CD80, CD86, and secrete pro-inflammatory cytokines (particularly IL-6); Lgals8-/- bone marrow-derived DCs display reduced CD86 and IL-6 expression and impaired antigen-specific CD4+ T cell activation, demonstrating an endogenous role of LGALS8 in DC maturation and adaptive immune priming.","method":"Flow cytometry, cytokine ELISA, Lgals8-/- mouse DC cultures, antigen-specific T cell proliferation assay, in vivo FMDV immunization model","journal":"Journal of Leukocyte Biology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with multiple readouts (flow cytometry, cytokines, T cell assays, in vivo protection); mechanistic role in DC activation established","pmids":["28811319"],"is_preprint":false},{"year":2020,"finding":"A network of three miRNAs (miR-125b, miR-221, miR-579) cooperatively downregulates LGALS8 in human macrophages to restrict Legionella pneumophila replication; LGALS8 protein functions as an antibacterial effector whose level is controlled post-transcriptionally by this miRNA network.","method":"miRNA overexpression/knockdown, proteome analysis (mass spectrometry), intracellular bacterial replication assays, ChIP-seq for chromatin changes","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 — proteomics plus functional bacterial replication assay; single lab but orthogonal methods","pmids":["32209695"],"is_preprint":false},{"year":2024,"finding":"In human osteoclasts, galectin-8 regulates bone resorption, osteoclast nuclearity, and mTORC1 signaling; the short isoform predominantly mediates bone resorption. LC-MS/MS proteomic analysis identified 22 shared interacting partners for both isoforms and 9 partners unique to the short isoform, including cell adhesion and lysosomal proteins (CLCN3, CLCN7, LAMP1, LAMP2), with interactions confirmed by Co-IP in human osteoclasts.","method":"Isoform-specific siRNA knockdown, LC-MS/MS proteomics, Co-immunoprecipitation, bone resorption assays, mTORC1 activity assays","journal":"Life Science Alliance","confidence":"High","confidence_rationale":"Tier 1/2 — proteomics plus Co-IP validation plus functional KD assays with multiple readouts; mechanistic isoform distinction established","pmids":["38395460"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 regulates LGALS8 mRNA stability through m6A modification; IGF2BP2 knockdown reduces LGALS8 expression and impairs angiogenesis in endothelial cells and zebrafish, establishing LGALS8 as a downstream effector of m6A-dependent mRNA regulation in vascular development.","method":"RNA-seq, MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular development assay, rescue experiments with LGALS8","journal":"Frontiers in Neurology","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics plus in vivo zebrafish rescue; single lab but orthogonal methods establishing m6A-LGALS8 axis","pmids":["39722688"],"is_preprint":false},{"year":2024,"finding":"LGALS8 inhibits MTOR and activates TFEB to promote ATG and lysosomal gene transcription in response to lysosomal membrane damage, functioning as part of the endomembrane damage response alongside LGALS3 and LGALS9.","method":"Review integrating published experimental data including MTOR assays, TFEB nuclear translocation assays, lysosomal damage models","journal":"Journal of Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 3 — review synthesis of prior experimental work; mechanistic model supported by primary papers (PMID 30081722, 36394332)","pmids":["38183492"],"is_preprint":false},{"year":2025,"finding":"Endogenous galectin-8 in mouse kidney is dispensable during the acute phase of AKI but protects against maladaptive repair by limiting extracellular matrix deposition (collagen I and III), fibrosis, and Th17 cell infiltration during the fibrotic phase, as demonstrated in Lgals8-/- mice.","method":"Lgals8-/- knockout mice, folic acid-induced AKI model, flow cytometry for immune cell characterization, histological fibrosis scoring, RT-qPCR","journal":"Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with defined phenotypic readouts at two phases; single lab, single study","pmids":["40375122"],"is_preprint":false}],"current_model":"LGALS8/Galectin-8 is a cytosolic lectin that functions as a danger receptor: it detects host glycans exposed on damaged endosomal/lysosomal membranes caused by bacterial invasion or sterile damage, recruits the autophagy adaptor NDP52/CALCOCO2 to initiate selective autophagy, and simultaneously inhibits MTOR while activating AMPK and TFEB via the Ragulator-RRAGA/B complex to drive lysosomal biogenesis; extracellularly, it promotes lymphangiogenesis through podoplanin-integrin crosstalk and activates dendritic cells to enhance adaptive immune responses, while its short isoform specifically regulates osteoclast bone resorption through interactions with lysosomal chloride channels and LAMP proteins."},"narrative":{"teleology":[{"year":2012,"claim":"Identifying LGALS8 as a cytosolic danger receptor solved the question of how cells detect bacteria-damaged vacuoles: galectin-8 recognizes exposed host glycans on Salmonella-containing vacuoles and recruits NDP52 to initiate selective autophagy, establishing the foundational 'eat-me' signaling axis for xenophagy.","evidence":"Co-immunoprecipitation, live-cell imaging, siRNA knockdown with Salmonella proliferation assays in human cells","pmids":["22246324"],"confidence":"High","gaps":["Mechanism by which galectin-8 specifically distinguishes damaged from intact endosomes was not resolved","Whether the same pathway operates against non-bacterial pathogens was unknown","Downstream signaling consequences beyond NDP52 recruitment were unexplored"]},{"year":2015,"claim":"Domain dissection of NDP52 revealed that LGALS8 binding and LC3/MYO6 engagement are structurally separable functions, establishing that NDP52 acts as a bifunctional bridge—one domain senses LGALS8-marked damage, and a distinct domain couples to autophagosome maturation machinery.","evidence":"Domain mutagenesis of NDP52, Co-IP, fluorescence microscopy, and bacterial infection assays","pmids":["25998689"],"confidence":"Medium","gaps":["Single-lab study extending earlier findings without independent replication","Structural basis for the LGALS8–NDP52 interaction was not determined","Whether other galectins engage NDP52 through the same domain was not tested"]},{"year":2016,"claim":"The discovery that Lgals8-knockout mice exhibit reduced inflammatory lymphangiogenesis revealed an extracellular, non-autophagic role for galectin-8 in promoting pathological vessel growth through podoplanin–integrin (α1β1, α5β1) crosstalk independently of VEGFR-3.","evidence":"Lgals8−/− and Pdpn−/− mouse models, corneal transplant and HSV keratitis models, integrin inhibition assays","pmids":["27066737"],"confidence":"High","gaps":["Direct molecular mechanism linking galectin-8 to integrin activation was not elucidated","Whether intracellular versus secreted galectin-8 mediates lymphangiogenesis was not resolved"]},{"year":2017,"claim":"Two advances broadened LGALS8's protective scope: a genome-wide screen showed galectin-8-mediated autophagy restricts picornavirus entry (antagonized by PLA2G16), establishing LGALS8 as an antiviral sensor, while Lgals8−/− dendritic cell studies demonstrated an endogenous role in DC maturation and CD4+ T cell priming.","evidence":"Haploid genetic screen and suppressor screen for viral infection; Lgals8−/− bone marrow-derived DC cultures with flow cytometry, ELISA, and in vivo immunization","pmids":["28077878","28811319"],"confidence":"High","gaps":["Mechanism of DC activation by galectin-8 (receptor identity, signaling cascade) was not identified","Whether antiviral autophagy and antibacterial autophagy use identical downstream machinery was unresolved"]},{"year":2018,"claim":"Proximity proteomics and kinase assays demonstrated that galectin-8 is not merely a passive damage tag but actively transduces signals by inhibiting mTOR and activating AMPK upon lysosomal damage, directly connecting endomembrane surveillance to metabolic autophagy regulation.","evidence":"APEX2 proximity labeling proteomics, mTOR/AMPK kinase activity assays, galectin-KO/KD in lysosomal damage models","pmids":["30081722"],"confidence":"High","gaps":["Direct binding partner through which LGALS8 inhibits mTOR was not identified","Relative contributions of LGALS8 versus LGALS9 to mTOR inhibition were unclear"]},{"year":2019,"claim":"Reconstitution of the LGALS8→NDP52→FIP200/TBK1 cascade on damaged Salmonella vacuoles established that galectin-8 functions as the upstream 'eat-me' signal that nucleates the complete autophagy-initiation machinery at the cargo site.","evidence":"Co-IP, mutagenesis of NDP52 binding domains, fluorescence microscopy, knockdown with phenotypic rescue in Salmonella infection","pmids":["31258038"],"confidence":"High","gaps":["Whether ULK1 kinase activity is directly regulated by LGALS8 binding was not tested","Temporal ordering of NDP52 versus TBK1 recruitment was not fully resolved"]},{"year":2020,"claim":"Identification of a cooperative miRNA network (miR-125b, miR-221, miR-579) that post-transcriptionally controls LGALS8 levels in macrophages revealed that Legionella exploits host miRNA regulation to suppress galectin-8-dependent antibacterial defense.","evidence":"miRNA overexpression/knockdown, mass spectrometry proteomics, intracellular Legionella replication assays","pmids":["32209695"],"confidence":"Medium","gaps":["Whether bacteria actively induce these miRNAs or passively benefit from basal regulation was not distinguished","Single-lab finding without independent replication"]},{"year":2022,"claim":"LysoIP proteomics identified the Ragulator–RRAGA/B complex and NUFIP2 as the molecular conduit through which galectin-8 inhibits mTOR at damaged lysosomes, with GABARAP/Atg8ylation coordinating this process.","evidence":"Lysosome immunopurification proteomics, GABARAP interaction assays, Co-IP, mTOR activity assays, knockdown experiments","pmids":["36394332"],"confidence":"High","gaps":["Whether galectin-8 directly binds Ragulator subunits or acts through an intermediary was not resolved","Structural details of the LGALS8–GABARAP interaction on damaged membranes are unknown"]},{"year":2024,"claim":"Isoform-specific studies in osteoclasts revealed that the short LGALS8 isoform preferentially regulates bone resorption, multinucleation, and mTORC1 signaling, interacting with lysosomal proteins (CLCN3, CLCN7, LAMP1, LAMP2) not bound by the long isoform, thereby establishing functional divergence between LGALS8 splice variants.","evidence":"Isoform-specific siRNA, LC-MS/MS interactomics, Co-IP validation, bone resorption assays in human osteoclasts","pmids":["38395460"],"confidence":"High","gaps":["How the short isoform uniquely engages chloride channels and LAMPs structurally is unresolved","In vivo significance of isoform-specific bone resorption has not been tested in animal models"]},{"year":2025,"claim":"Lgals8−/− mice revealed that endogenous galectin-8 is dispensable during acute kidney injury but limits maladaptive fibrotic repair by restricting collagen deposition and Th17 infiltration, extending LGALS8's protective roles to anti-fibrotic tissue homeostasis.","evidence":"Lgals8−/− knockout mice, folic acid-induced AKI model, flow cytometry, histological fibrosis scoring","pmids":["40375122"],"confidence":"Medium","gaps":["Single-lab, single-model study; replication in other fibrosis models needed","Mechanism by which LGALS8 suppresses Th17 infiltration and ECM deposition is not defined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of galectin-8's glycan selectivity for damaged versus intact membranes, the identity of the cell-surface receptor mediating DC activation, and the in vivo consequences of isoform-specific functions in bone and immunity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of LGALS8 bound to damaged membrane glycans exists","The receptor through which extracellular galectin-8 activates dendritic cells is unidentified","In vivo validation of short versus long isoform-specific functions is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,6]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,5,9]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,2,3,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,10]}],"complexes":[],"partners":["CALCOCO2","CLCN7","CLCN3","LAMP1","LAMP2","PDPN","RRAGA","RRAGB"],"other_free_text":[]},"mechanistic_narrative":"LGALS8 (Galectin-8) is a tandem-repeat β-galactoside-binding lectin that functions as a cytosolic danger receptor for endomembrane damage and as an extracellular modulator of immunity and lymphangiogenesis. Upon bacterial invasion or sterile lysosomal damage, LGALS8 detects exposed host glycans on compromised endosomal/lysosomal membranes, recruits the autophagy adaptor NDP52/CALCOCO2 to nucleate phagophore formation via FIP200 and TBK1 complexes, and simultaneously inhibits mTOR through the Ragulator–RRAGA/B complex while activating AMPK and TFEB-dependent lysosomal biogenesis [PMID:22246324, PMID:30081722, PMID:36394332, PMID:31258038]. This surveillance mechanism restricts intracellular replication of both bacteria (Salmonella, Legionella) and viruses (picornaviruses) [PMID:28077878, PMID:32209695]. Extracellularly, LGALS8 promotes pathological lymphangiogenesis via podoplanin–integrin crosstalk independently of VEGFR-3 and activates dendritic cells for adaptive immune priming, while its short isoform specifically regulates osteoclast bone resorption through interactions with lysosomal chloride channels (CLCN3, CLCN7) and LAMP proteins [PMID:27066737, PMID:28811319, PMID:38395460]."},"prefetch_data":{"uniprot":{"accession":"O00214","full_name":"Galectin-8","aliases":["Po66 carbohydrate-binding protein","Po66-CBP","Prostate carcinoma tumor antigen 1","PCTA-1"],"length_aa":317,"mass_kda":35.8,"function":"Beta-galactoside-binding lectin that acts as a sensor of membrane damage caused by infection and restricts the proliferation of infecting pathogens by targeting them for autophagy (PubMed:22246324, PubMed:28077878). Detects membrane rupture by binding beta-galactoside ligands located on the lumenal side of the endosome membrane; these ligands becoming exposed to the cytoplasm following rupture (PubMed:22246324, PubMed:28077878). Restricts infection by initiating autophagy via interaction with CALCOCO2/NDP52 (PubMed:22246324, PubMed:28077878). Required to restrict infection of bacterial invasion such as S.typhimurium (PubMed:22246324). Also required to restrict infection of Picornaviridae viruses (PubMed:28077878). Has a marked preference for 3'-O-sialylated and 3'-O-sulfated glycans (PubMed:21288902)","subcellular_location":"Cytoplasmic vesicle; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O00214/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LGALS8","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/LGALS8","total_profiled":1310},"omim":[{"mim_id":"613867","title":"PHOSPHOLIPASE A AND ACYLTRANSFERASE 3; PLAAT3","url":"https://www.omim.org/entry/613867"},{"mim_id":"606099","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 8; LGALS8","url":"https://www.omim.org/entry/606099"},{"mim_id":"604587","title":"CALCIUM BINDING AND COILED-COIL DOMAIN PROTEIN 2; CALCOCO2","url":"https://www.omim.org/entry/604587"},{"mim_id":"602664","title":"CASPASE 4, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP4","url":"https://www.omim.org/entry/602664"},{"mim_id":"602518","title":"LECTIN, GALACTOSIDE-BINDING, SOLUBLE, 4; LGALS4","url":"https://www.omim.org/entry/602518"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LGALS8"},"hgnc":{"alias_symbol":["PCTA-1"],"prev_symbol":[]},"alphafold":{"accession":"O00214","domains":[{"cath_id":"2.60.120.200","chopping":"10-159","consensus_level":"high","plddt":94.4561,"start":10,"end":159},{"cath_id":"2.60.120.200","chopping":"169-317","consensus_level":"high","plddt":90.3254,"start":169,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00214","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00214-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00214-F1-predicted_aligned_error_v6.png","plddt_mean":90.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LGALS8","jax_strain_url":"https://www.jax.org/strain/search?query=LGALS8"},"sequence":{"accession":"O00214","fasta_url":"https://rest.uniprot.org/uniprotkb/O00214.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00214/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00214"}},"corpus_meta":[{"pmid":"22246324","id":"PMC_22246324","title":"Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22246324","citation_count":836,"is_preprint":false},{"pmid":"28077878","id":"PMC_28077878","title":"PLA2G16 represents a switch between entry and clearance of Picornaviridae.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28077878","citation_count":169,"is_preprint":false},{"pmid":"8692978","id":"PMC_8692978","title":"Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PCTA-1 a member of the galectin gene family.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8692978","citation_count":127,"is_preprint":false},{"pmid":"30081722","id":"PMC_30081722","title":"Galectins control MTOR and AMPK in response to lysosomal damage to induce autophagy.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30081722","citation_count":122,"is_preprint":false},{"pmid":"25649018","id":"PMC_25649018","title":"Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25649018","citation_count":108,"is_preprint":false},{"pmid":"15115907","id":"PMC_15115907","title":"Tumor galectinology: insights into the complex network of a family of endogenous lectins.","date":"2004","source":"Glycoconjugate journal","url":"https://pubmed.ncbi.nlm.nih.gov/15115907","citation_count":106,"is_preprint":false},{"pmid":"27066737","id":"PMC_27066737","title":"Pathological lymphangiogenesis is modulated by galectin-8-dependent crosstalk between podoplanin and integrin-associated VEGFR-3.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27066737","citation_count":87,"is_preprint":false},{"pmid":"14758080","id":"PMC_14758080","title":"Human galectin-8 isoforms and cancer.","date":"2002","source":"Glycoconjugate journal","url":"https://pubmed.ncbi.nlm.nih.gov/14758080","citation_count":85,"is_preprint":false},{"pmid":"15940270","id":"PMC_15940270","title":"Discrimination between serous low malignant potential and invasive epithelial ovarian tumors using molecular profiling.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15940270","citation_count":72,"is_preprint":false},{"pmid":"27116978","id":"PMC_27116978","title":"Large-scale assessment of the gliomasphere model system.","date":"2016","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27116978","citation_count":72,"is_preprint":false},{"pmid":"28570605","id":"PMC_28570605","title":"Frameshift indels introduced by genome editing can lead to in-frame exon skipping.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28570605","citation_count":70,"is_preprint":false},{"pmid":"32065482","id":"PMC_32065482","title":"A risk signature with four autophagy-related genes for predicting survival of glioblastoma multiforme.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32065482","citation_count":58,"is_preprint":false},{"pmid":"11494049","id":"PMC_11494049","title":"Galectin-8: a complex sub-family of galectins (Review).","date":"2001","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11494049","citation_count":56,"is_preprint":false},{"pmid":"19196461","id":"PMC_19196461","title":"Understanding Haemophilus parasuis infection in porcine spleen through a transcriptomics approach.","date":"2009","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/19196461","citation_count":55,"is_preprint":false},{"pmid":"25437054","id":"PMC_25437054","title":"Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta.","date":"2014","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25437054","citation_count":52,"is_preprint":false},{"pmid":"10980616","id":"PMC_10980616","title":"Molecular characterization of prostate carcinoma tumor antigen-1, PCTA-1, a human galectin-8 related gene.","date":"2000","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/10980616","citation_count":51,"is_preprint":false},{"pmid":"28811319","id":"PMC_28811319","title":"Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation.","date":"2017","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/28811319","citation_count":35,"is_preprint":false},{"pmid":"22493696","id":"PMC_22493696","title":"DNA methylation analysis of bone marrow cells at diagnosis of acute lymphoblastic leukemia and at remission.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22493696","citation_count":35,"is_preprint":false},{"pmid":"38183492","id":"PMC_38183492","title":"PRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy.","date":"2024","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38183492","citation_count":26,"is_preprint":false},{"pmid":"29922168","id":"PMC_29922168","title":"Co-expression Analysis of Sirtuins and Related Metabolic Biomarkers in Juveniles of Gilthead Sea Bream (Sparus aurata) With Differences in Growth Performance.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29922168","citation_count":26,"is_preprint":false},{"pmid":"29258207","id":"PMC_29258207","title":"Role of Galectins in Multiple Myeloma.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29258207","citation_count":25,"is_preprint":false},{"pmid":"25998689","id":"PMC_25998689","title":"Dual function of CALCOCO2/NDP52 during xenophagy.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25998689","citation_count":24,"is_preprint":false},{"pmid":"36343795","id":"PMC_36343795","title":"Coronary artery plaque rupture and erosion: Role of wall shear stress profiling and biological patterns in acute coronary syndromes.","date":"2022","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/36343795","citation_count":23,"is_preprint":false},{"pmid":"34669463","id":"PMC_34669463","title":"Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34669463","citation_count":23,"is_preprint":false},{"pmid":"36394332","id":"PMC_36394332","title":"Membrane Atg8ylation, stress granule formation, and MTOR regulation during lysosomal damage.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/36394332","citation_count":22,"is_preprint":false},{"pmid":"24886063","id":"PMC_24886063","title":"Mining the pre-diagnostic antibody repertoire of TgMMTV-neu mice to identify autoantibodies useful for the early detection of human breast cancer.","date":"2014","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24886063","citation_count":21,"is_preprint":false},{"pmid":"31258038","id":"PMC_31258038","title":"CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31258038","citation_count":20,"is_preprint":false},{"pmid":"23555683","id":"PMC_23555683","title":"Identifying resistance mechanisms against five tyrosine kinase inhibitors targeting the ERBB/RAS pathway in 45 cancer cell lines.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23555683","citation_count":20,"is_preprint":false},{"pmid":"25115182","id":"PMC_25115182","title":"Alternative splicing in osteoclasts and Paget's disease of bone.","date":"2014","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25115182","citation_count":19,"is_preprint":false},{"pmid":"15679620","id":"PMC_15679620","title":"Secretion of prostatic specific antigen, proliferative activity and androgen response in epithelial-stromal co-cultures from human prostate carcinoma.","date":"2005","source":"International journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/15679620","citation_count":19,"is_preprint":false},{"pmid":"38613488","id":"PMC_38613488","title":"Galectin-8 inhibition and functions in immune response and tumor biology.","date":"2024","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/38613488","citation_count":16,"is_preprint":false},{"pmid":"31837777","id":"PMC_31837777","title":"Short communication: Inflammation, migration, and cell-cell interaction-related gene network expression in leukocytes is enhanced in Simmental compared with Holstein dairy cows after calving.","date":"2019","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/31837777","citation_count":15,"is_preprint":false},{"pmid":"34745940","id":"PMC_34745940","title":"LncRNA LGALS8-AS1 Promotes Breast Cancer Metastasis Through miR-125b-5p/SOX12 Feedback Regulatory Network.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34745940","citation_count":13,"is_preprint":false},{"pmid":"11795826","id":"PMC_11795826","title":"Immunohistochemical expression of the intracellular component of galectin-8 in squamous cell metaplasia of the bronchial epithelium in neoplastic and benign processes.","date":"2001","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/11795826","citation_count":13,"is_preprint":false},{"pmid":"28018170","id":"PMC_28018170","title":"mRNA Transcriptomics of Galectins Unveils Heterogeneous Organization in Mouse and Human Brain.","date":"2016","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28018170","citation_count":13,"is_preprint":false},{"pmid":"32209695","id":"PMC_32209695","title":"A MicroRNA Network Controls Legionella pneumophila Replication in Human Macrophages via LGALS8 and MX1.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32209695","citation_count":12,"is_preprint":false},{"pmid":"31602302","id":"PMC_31602302","title":"Natural and synthetic pathogen associated molecular patterns modulate galectin expression in cow blood.","date":"2019","source":"Journal of animal science and technology","url":"https://pubmed.ncbi.nlm.nih.gov/31602302","citation_count":11,"is_preprint":false},{"pmid":"38824843","id":"PMC_38824843","title":"Epigenetic footprints: Investigating placental DNA methylation in the context of prenatal exposure to phenols and phthalates.","date":"2024","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/38824843","citation_count":11,"is_preprint":false},{"pmid":"38544823","id":"PMC_38544823","title":"Exploring the Role of Non-synonymous and Deleterious Variants Identified in Colorectal Cancer: A Multi-dimensional Computational Scrutiny of Exomes.","date":"2024","source":"Current genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38544823","citation_count":10,"is_preprint":false},{"pmid":"37424827","id":"PMC_37424827","title":"Galectin-8 alters immune microenvironment and promotes tumor progression.","date":"2023","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/37424827","citation_count":9,"is_preprint":false},{"pmid":"38579899","id":"PMC_38579899","title":"Inflammation-induced sialin mediates nitrate efflux in dysfunctional endothelium affecting NO bioavailability.","date":"2024","source":"Nitric oxide : biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38579899","citation_count":9,"is_preprint":false},{"pmid":"38395460","id":"PMC_38395460","title":"Galectin-8 modulates human osteoclast activity partly through isoform-specific interactions.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/38395460","citation_count":9,"is_preprint":false},{"pmid":"12234517","id":"PMC_12234517","title":"A candidate gene approach within the susceptibility region PCaP on 1q42.2-43 excludes deleterious mutations of the PCTA-1 gene to be responsible for hereditary prostate cancer.","date":"2002","source":"European urology","url":"https://pubmed.ncbi.nlm.nih.gov/12234517","citation_count":8,"is_preprint":false},{"pmid":"38642052","id":"PMC_38642052","title":"Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.","date":"2024","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38642052","citation_count":8,"is_preprint":false},{"pmid":"36050693","id":"PMC_36050693","title":"Assessment of galectins -1, -3, -4, -8, and -9 expression in ovarian carcinoma patients with clinical implications.","date":"2022","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36050693","citation_count":7,"is_preprint":false},{"pmid":"34334204","id":"PMC_34334204","title":"Effect of source and amount of vitamin D on function and mRNA expression in immune cells in dairy cows.","date":"2021","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/34334204","citation_count":7,"is_preprint":false},{"pmid":"36807469","id":"PMC_36807469","title":"Long non-coding RNA LGALS8-AS1 facilitates PLAGL2-mediated malignant phenotypes in gastric cancer.","date":"2023","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36807469","citation_count":5,"is_preprint":false},{"pmid":"37716002","id":"PMC_37716002","title":"Long noncoding RNA LGALS8-AS1 promotes angiogenesis and brain metastases in non-small cell lung cancer.","date":"2023","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/37716002","citation_count":4,"is_preprint":false},{"pmid":"38470107","id":"PMC_38470107","title":"Activation of the lysosomal damage response and selective autophagy: the coordinated actions of galectins, TRIM proteins, and CGAS-STING1 in providing immunity against Mycobacterium tuberculosis.","date":"2024","source":"Critical reviews in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/38470107","citation_count":4,"is_preprint":false},{"pmid":"32157440","id":"PMC_32157440","title":"The association between increasing levels of O-GlcNAc and galectins in the liver tissue of hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus).","date":"2020","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/32157440","citation_count":4,"is_preprint":false},{"pmid":"40119673","id":"PMC_40119673","title":"Galectin-3 regulates erythropoiesis and enhances the immunoregulatory properties of CD71+ erythroid cells across developmental stages.","date":"2025","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/40119673","citation_count":3,"is_preprint":false},{"pmid":"34439592","id":"PMC_34439592","title":"Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus.","date":"2021","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34439592","citation_count":3,"is_preprint":false},{"pmid":"36014414","id":"PMC_36014414","title":"Quantitative Proteomics Explore the Potential Targets and Action Mechanisms of Hydroxychloroquine.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36014414","citation_count":3,"is_preprint":false},{"pmid":"40375122","id":"PMC_40375122","title":"Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury.","date":"2025","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/40375122","citation_count":1,"is_preprint":false},{"pmid":"41734713","id":"PMC_41734713","title":"Hypoxia-induced LGALS8-AS1 sustains oxidative phosphorylation to drive breast cancer progression.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41734713","citation_count":0,"is_preprint":false},{"pmid":"41020869","id":"PMC_41020869","title":"Integration of eQTL and GEO Datasets to Identify Genes Associated with Breast Ductal Carcinoma In Situ.","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41020869","citation_count":0,"is_preprint":false},{"pmid":"40181221","id":"PMC_40181221","title":"Mediators of the causal associations between protein ratios and ischemic stroke: a two-step Mendelian randomization study.","date":"2025","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/40181221","citation_count":0,"is_preprint":false},{"pmid":"39722688","id":"PMC_39722688","title":"Insulin like growth factor 2 mRNA binding protein 2 regulates vascular development in cerebral arteriovenous malformations.","date":"2024","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39722688","citation_count":0,"is_preprint":false},{"pmid":"38752371","id":"PMC_38752371","title":"CALCOCO2/NDP52 associates with RAB9 to initiate an antiviral response to hepatitis B virus infection through a lysosomal degradation pathway.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/38752371","citation_count":0,"is_preprint":false},{"pmid":"40489038","id":"PMC_40489038","title":"Shared hub genes in membranous nephropathy and kidney renal clear cell carcinoma: investigating molecular overlap and tumor progression.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40489038","citation_count":0,"is_preprint":false},{"pmid":"39288719","id":"PMC_39288719","title":"Citrus pectin modulates chicken peripheral blood mononuclear cell proteome in vitro.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/39288719","citation_count":0,"is_preprint":false},{"pmid":"41882123","id":"PMC_41882123","title":"Multimerin1 and not Galectin-8 tempers WNT signaling to promote gastric chief cell differentiation.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41882123","citation_count":0,"is_preprint":false},{"pmid":"41278970","id":"PMC_41278970","title":"Multimerin1, not Galectin-8, Promotes Gastric Chief Cell Differentiation by Tempering WNT Signaling.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41278970","citation_count":0,"is_preprint":false},{"pmid":"38011643","id":"PMC_38011643","title":"Screening and Identifying Reference Genes for Erythrocyte Production from Cord Blood CD34+ Cells Exposed to Hypoxia.","date":"2023","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38011643","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.13.25329572","title":"Plasma Proteomic Signature of Frailty in 50,506 Adults","date":"2025-06-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.13.25329572","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35861,"output_tokens":3319,"usd":0.078684},"stage2":{"model":"claude-opus-4-6","input_tokens":6698,"output_tokens":3255,"usd":0.172297},"total_usd":0.250981,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"Galectin-8 (LGALS8) acts as a cytosolic danger receptor that detects host glycans exposed on damaged Salmonella-containing vacuoles, then recruits the autophagy adaptor NDP52 (CALCOCO2) to activate antibacterial selective autophagy, restricting Salmonella proliferation in human cells.\",\n      \"method\": \"Co-immunoprecipitation, live-cell fluorescence imaging, siRNA knockdown with bacterial proliferation assay, endosomal damage assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, live imaging, KD with defined phenotype; foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"22246324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During picornavirus entry, galectin-8 detects permeated endosomes and marks them for autophagic degradation (pore-activated clearance pathway); PLA2G16 competes with this clearance by facilitating viral genome translocation, placing LGALS8-mediated autophagy as an antiviral defense mechanism suppressible by PLA2G16.\",\n      \"method\": \"Genome-wide haploid genetic screen, suppressor screen, siRNA knockdown, viral infection assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide screen plus epistasis suppressor screen; strong mechanistic placement of LGALS8 in antiviral pathway\",\n      \"pmids\": [\"28077878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon lysosomal membrane damage, cytosolic galectin-8 (LGALS8) inhibits MTOR and activates AMPK, functioning as an active signal transducer (not merely a passive damage tag) that controls master regulators of autophagy in response to endomembrane damage.\",\n      \"method\": \"APEX2 proximity labeling proteomics, kinase activity assays (MTOR, AMPK), lysosomal damage assays with galectin KO/KD\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proximity proteomics, kinase assays, KO); mechanistic link between LGALS8 and MTOR/AMPK established\",\n      \"pmids\": [\"30081722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Galectin-8-marked damaged Salmonella-containing vacuoles recruit CALCOCO2/NDP52, which then assembles a trimeric complex with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1 (components of ULK and TBK1 kinase complexes) to initiate phagophore formation at the cargo site, establishing LGALS8 as the upstream 'eat-me' signal that nucleates the autophagy-initiation machinery.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, mutagenesis of CALCOCO2 binding domains, KD with phenotypic rescue\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis, and defined phenotypic readout; mechanistic pathway placement of LGALS8→NDP52→ULK/TBK1\",\n      \"pmids\": [\"31258038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Galectin-8 promotes pathological lymphangiogenesis through a mechanism involving crosstalk among VEGF-C, podoplanin, and integrin pathways (α1β1 and α5β1), independently of VEGFR-3; Lgals8-/- mice show reduced inflammatory lymphangiogenesis and improved corneal graft survival.\",\n      \"method\": \"Lgals8-/- mouse model, Pdpn-/- mouse model, VEGFR-3 knockdown, integrin inhibition assays, corneal transplant model, herpes simplex keratitis model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO models with multiple orthogonal pathway dissection experiments; replicated across disease models\",\n      \"pmids\": [\"27066737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Upon lysosomal damage, galectin-8 contributes to MTOR inactivation via the Ragulator-RRAGA-RRAGB complex together with NUFIP2, and this function is coordinated by GABARAPs/Atg8ylation at the damaged lysosome membrane, linking membrane Atg8ylation to MTOR regulation.\",\n      \"method\": \"Lysosome immunopurification (LysoIP), proteomics, GABARAP interaction assays, Co-IP, MTOR activity assays, KD experiments\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — LysoIP proteomics plus Co-IP and MTOR activity assays; mechanistic placement of LGALS8 in Ragulator-RRAGA-RRAGB complex regulation\",\n      \"pmids\": [\"36394332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CALCOCO2/NDP52 binds galectin-8 (LGALS8) adsorbed on damaged Salmonella-containing vacuoles via one domain to mediate bacterial targeting to phagophores, while a distinct domain mediates LC3A/B/GABARAPL2 and MYO6 binding for autophagosome maturation, demonstrating dual separable functions of the LGALS8-NDP52 interaction.\",\n      \"method\": \"Domain mutagenesis of NDP52, Co-IP, fluorescence microscopy, bacterial infection assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with Co-IP; single lab reviewing own findings with partial new data\",\n      \"pmids\": [\"25998689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Exogenous galectin-8 activates dendritic cells to express MHCII, CD80, CD86, and secrete pro-inflammatory cytokines (particularly IL-6); Lgals8-/- bone marrow-derived DCs display reduced CD86 and IL-6 expression and impaired antigen-specific CD4+ T cell activation, demonstrating an endogenous role of LGALS8 in DC maturation and adaptive immune priming.\",\n      \"method\": \"Flow cytometry, cytokine ELISA, Lgals8-/- mouse DC cultures, antigen-specific T cell proliferation assay, in vivo FMDV immunization model\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with multiple readouts (flow cytometry, cytokines, T cell assays, in vivo protection); mechanistic role in DC activation established\",\n      \"pmids\": [\"28811319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A network of three miRNAs (miR-125b, miR-221, miR-579) cooperatively downregulates LGALS8 in human macrophages to restrict Legionella pneumophila replication; LGALS8 protein functions as an antibacterial effector whose level is controlled post-transcriptionally by this miRNA network.\",\n      \"method\": \"miRNA overexpression/knockdown, proteome analysis (mass spectrometry), intracellular bacterial replication assays, ChIP-seq for chromatin changes\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics plus functional bacterial replication assay; single lab but orthogonal methods\",\n      \"pmids\": [\"32209695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In human osteoclasts, galectin-8 regulates bone resorption, osteoclast nuclearity, and mTORC1 signaling; the short isoform predominantly mediates bone resorption. LC-MS/MS proteomic analysis identified 22 shared interacting partners for both isoforms and 9 partners unique to the short isoform, including cell adhesion and lysosomal proteins (CLCN3, CLCN7, LAMP1, LAMP2), with interactions confirmed by Co-IP in human osteoclasts.\",\n      \"method\": \"Isoform-specific siRNA knockdown, LC-MS/MS proteomics, Co-immunoprecipitation, bone resorption assays, mTORC1 activity assays\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — proteomics plus Co-IP validation plus functional KD assays with multiple readouts; mechanistic isoform distinction established\",\n      \"pmids\": [\"38395460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 regulates LGALS8 mRNA stability through m6A modification; IGF2BP2 knockdown reduces LGALS8 expression and impairs angiogenesis in endothelial cells and zebrafish, establishing LGALS8 as a downstream effector of m6A-dependent mRNA regulation in vascular development.\",\n      \"method\": \"RNA-seq, MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular development assay, rescue experiments with LGALS8\",\n      \"journal\": \"Frontiers in Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics plus in vivo zebrafish rescue; single lab but orthogonal methods establishing m6A-LGALS8 axis\",\n      \"pmids\": [\"39722688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS8 inhibits MTOR and activates TFEB to promote ATG and lysosomal gene transcription in response to lysosomal membrane damage, functioning as part of the endomembrane damage response alongside LGALS3 and LGALS9.\",\n      \"method\": \"Review integrating published experimental data including MTOR assays, TFEB nuclear translocation assays, lysosomal damage models\",\n      \"journal\": \"Journal of Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesis of prior experimental work; mechanistic model supported by primary papers (PMID 30081722, 36394332)\",\n      \"pmids\": [\"38183492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endogenous galectin-8 in mouse kidney is dispensable during the acute phase of AKI but protects against maladaptive repair by limiting extracellular matrix deposition (collagen I and III), fibrosis, and Th17 cell infiltration during the fibrotic phase, as demonstrated in Lgals8-/- mice.\",\n      \"method\": \"Lgals8-/- knockout mice, folic acid-induced AKI model, flow cytometry for immune cell characterization, histological fibrosis scoring, RT-qPCR\",\n      \"journal\": \"Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined phenotypic readouts at two phases; single lab, single study\",\n      \"pmids\": [\"40375122\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS8/Galectin-8 is a cytosolic lectin that functions as a danger receptor: it detects host glycans exposed on damaged endosomal/lysosomal membranes caused by bacterial invasion or sterile damage, recruits the autophagy adaptor NDP52/CALCOCO2 to initiate selective autophagy, and simultaneously inhibits MTOR while activating AMPK and TFEB via the Ragulator-RRAGA/B complex to drive lysosomal biogenesis; extracellularly, it promotes lymphangiogenesis through podoplanin-integrin crosstalk and activates dendritic cells to enhance adaptive immune responses, while its short isoform specifically regulates osteoclast bone resorption through interactions with lysosomal chloride channels and LAMP proteins.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LGALS8 (Galectin-8) is a tandem-repeat β-galactoside-binding lectin that functions as a cytosolic danger receptor for endomembrane damage and as an extracellular modulator of immunity and lymphangiogenesis. Upon bacterial invasion or sterile lysosomal damage, LGALS8 detects exposed host glycans on compromised endosomal/lysosomal membranes, recruits the autophagy adaptor NDP52/CALCOCO2 to nucleate phagophore formation via FIP200 and TBK1 complexes, and simultaneously inhibits mTOR through the Ragulator–RRAGA/B complex while activating AMPK and TFEB-dependent lysosomal biogenesis [PMID:22246324, PMID:30081722, PMID:36394332, PMID:31258038]. This surveillance mechanism restricts intracellular replication of both bacteria (Salmonella, Legionella) and viruses (picornaviruses) [PMID:28077878, PMID:32209695]. Extracellularly, LGALS8 promotes pathological lymphangiogenesis via podoplanin–integrin crosstalk independently of VEGFR-3 and activates dendritic cells for adaptive immune priming, while its short isoform specifically regulates osteoclast bone resorption through interactions with lysosomal chloride channels (CLCN3, CLCN7) and LAMP proteins [PMID:27066737, PMID:28811319, PMID:38395460].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying LGALS8 as a cytosolic danger receptor solved the question of how cells detect bacteria-damaged vacuoles: galectin-8 recognizes exposed host glycans on Salmonella-containing vacuoles and recruits NDP52 to initiate selective autophagy, establishing the foundational 'eat-me' signaling axis for xenophagy.\",\n      \"evidence\": \"Co-immunoprecipitation, live-cell imaging, siRNA knockdown with Salmonella proliferation assays in human cells\",\n      \"pmids\": [\"22246324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which galectin-8 specifically distinguishes damaged from intact endosomes was not resolved\",\n        \"Whether the same pathway operates against non-bacterial pathogens was unknown\",\n        \"Downstream signaling consequences beyond NDP52 recruitment were unexplored\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Domain dissection of NDP52 revealed that LGALS8 binding and LC3/MYO6 engagement are structurally separable functions, establishing that NDP52 acts as a bifunctional bridge—one domain senses LGALS8-marked damage, and a distinct domain couples to autophagosome maturation machinery.\",\n      \"evidence\": \"Domain mutagenesis of NDP52, Co-IP, fluorescence microscopy, and bacterial infection assays\",\n      \"pmids\": [\"25998689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study extending earlier findings without independent replication\",\n        \"Structural basis for the LGALS8–NDP52 interaction was not determined\",\n        \"Whether other galectins engage NDP52 through the same domain was not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that Lgals8-knockout mice exhibit reduced inflammatory lymphangiogenesis revealed an extracellular, non-autophagic role for galectin-8 in promoting pathological vessel growth through podoplanin–integrin (α1β1, α5β1) crosstalk independently of VEGFR-3.\",\n      \"evidence\": \"Lgals8−/− and Pdpn−/− mouse models, corneal transplant and HSV keratitis models, integrin inhibition assays\",\n      \"pmids\": [\"27066737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular mechanism linking galectin-8 to integrin activation was not elucidated\",\n        \"Whether intracellular versus secreted galectin-8 mediates lymphangiogenesis was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two advances broadened LGALS8's protective scope: a genome-wide screen showed galectin-8-mediated autophagy restricts picornavirus entry (antagonized by PLA2G16), establishing LGALS8 as an antiviral sensor, while Lgals8−/− dendritic cell studies demonstrated an endogenous role in DC maturation and CD4+ T cell priming.\",\n      \"evidence\": \"Haploid genetic screen and suppressor screen for viral infection; Lgals8−/− bone marrow-derived DC cultures with flow cytometry, ELISA, and in vivo immunization\",\n      \"pmids\": [\"28077878\", \"28811319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of DC activation by galectin-8 (receptor identity, signaling cascade) was not identified\",\n        \"Whether antiviral autophagy and antibacterial autophagy use identical downstream machinery was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Proximity proteomics and kinase assays demonstrated that galectin-8 is not merely a passive damage tag but actively transduces signals by inhibiting mTOR and activating AMPK upon lysosomal damage, directly connecting endomembrane surveillance to metabolic autophagy regulation.\",\n      \"evidence\": \"APEX2 proximity labeling proteomics, mTOR/AMPK kinase activity assays, galectin-KO/KD in lysosomal damage models\",\n      \"pmids\": [\"30081722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partner through which LGALS8 inhibits mTOR was not identified\",\n        \"Relative contributions of LGALS8 versus LGALS9 to mTOR inhibition were unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconstitution of the LGALS8→NDP52→FIP200/TBK1 cascade on damaged Salmonella vacuoles established that galectin-8 functions as the upstream 'eat-me' signal that nucleates the complete autophagy-initiation machinery at the cargo site.\",\n      \"evidence\": \"Co-IP, mutagenesis of NDP52 binding domains, fluorescence microscopy, knockdown with phenotypic rescue in Salmonella infection\",\n      \"pmids\": [\"31258038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ULK1 kinase activity is directly regulated by LGALS8 binding was not tested\",\n        \"Temporal ordering of NDP52 versus TBK1 recruitment was not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of a cooperative miRNA network (miR-125b, miR-221, miR-579) that post-transcriptionally controls LGALS8 levels in macrophages revealed that Legionella exploits host miRNA regulation to suppress galectin-8-dependent antibacterial defense.\",\n      \"evidence\": \"miRNA overexpression/knockdown, mass spectrometry proteomics, intracellular Legionella replication assays\",\n      \"pmids\": [\"32209695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether bacteria actively induce these miRNAs or passively benefit from basal regulation was not distinguished\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"LysoIP proteomics identified the Ragulator–RRAGA/B complex and NUFIP2 as the molecular conduit through which galectin-8 inhibits mTOR at damaged lysosomes, with GABARAP/Atg8ylation coordinating this process.\",\n      \"evidence\": \"Lysosome immunopurification proteomics, GABARAP interaction assays, Co-IP, mTOR activity assays, knockdown experiments\",\n      \"pmids\": [\"36394332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether galectin-8 directly binds Ragulator subunits or acts through an intermediary was not resolved\",\n        \"Structural details of the LGALS8–GABARAP interaction on damaged membranes are unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Isoform-specific studies in osteoclasts revealed that the short LGALS8 isoform preferentially regulates bone resorption, multinucleation, and mTORC1 signaling, interacting with lysosomal proteins (CLCN3, CLCN7, LAMP1, LAMP2) not bound by the long isoform, thereby establishing functional divergence between LGALS8 splice variants.\",\n      \"evidence\": \"Isoform-specific siRNA, LC-MS/MS interactomics, Co-IP validation, bone resorption assays in human osteoclasts\",\n      \"pmids\": [\"38395460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the short isoform uniquely engages chloride channels and LAMPs structurally is unresolved\",\n        \"In vivo significance of isoform-specific bone resorption has not been tested in animal models\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Lgals8−/− mice revealed that endogenous galectin-8 is dispensable during acute kidney injury but limits maladaptive fibrotic repair by restricting collagen deposition and Th17 infiltration, extending LGALS8's protective roles to anti-fibrotic tissue homeostasis.\",\n      \"evidence\": \"Lgals8−/− knockout mice, folic acid-induced AKI model, flow cytometry, histological fibrosis scoring\",\n      \"pmids\": [\"40375122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab, single-model study; replication in other fibrosis models needed\",\n        \"Mechanism by which LGALS8 suppresses Th17 infiltration and ECM deposition is not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of galectin-8's glycan selectivity for damaged versus intact membranes, the identity of the cell-surface receptor mediating DC activation, and the in vivo consequences of isoform-specific functions in bone and immunity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of LGALS8 bound to damaged membrane glycans exists\",\n        \"The receptor through which extracellular galectin-8 activates dendritic cells is unidentified\",\n        \"In vivo validation of short versus long isoform-specific functions is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 5, 9]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALCOCO2\",\n      \"CLCN7\",\n      \"CLCN3\",\n      \"LAMP1\",\n      \"LAMP2\",\n      \"PDPN\",\n      \"RRAGA\",\n      \"RRAGB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}