{"gene":"LGALS8","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2012,"finding":"Galectin-8 (LGALS8) acts as a cytosolic danger receptor that detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles, and recruits the autophagy adaptor NDP52 (CALCOCO2) to activate antibacterial autophagy. Galectin-8-dependent NDP52 recruitment is transient and precedes ubiquitin-dependent NDP52 recruitment.","method":"Loss-of-function experiments in human cells, co-immunoprecipitation, fluorescence microscopy, Salmonella infection assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays in human cells with multiple orthogonal methods (imaging, Co-IP, bacterial infection readout), highly cited, established mechanism replicated in subsequent studies","pmids":["22246322"],"is_preprint":false},{"year":2012,"finding":"Galectin-8 monitors endosomal and lysosomal integrity by sensing luminal glycans that become exposed on the cytosolic face upon vesicle damage (sterile or pathogen-induced), functioning as a general sensor of endomembrane damage regardless of pathogen species (Salmonella, Listeria, Shigella).","method":"Fluorescence microscopy with glycan-binding domain mutants, infection with multiple pathogens, sterile lysosome-damaging agents","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple pathogens and sterile damage tested, functionally validated with domain mutants, replicated in subsequent studies","pmids":["22246322"],"is_preprint":false},{"year":2017,"finding":"Galectin-8 detects picornavirus-permeated endosomes and marks them for autophagic degradation (pore-activated clearance pathway); PLA2G16 counteracts this by facilitating viral genome translocation, placing LGALS8 upstream of autophagic clearance in a competition with viral escape.","method":"Genome-wide haploid genetic screen for suppressors of ΔPLA2G16 phenotype, epistasis analysis, infection assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide suppressor screen with epistasis, multiple orthogonal validations, independent identification of LGALS8 in this pathway","pmids":["28077878"],"is_preprint":false},{"year":2018,"finding":"Galectin-8 (LGALS8), upon lysosomal damage, inhibits MTOR and activates AMPK, thereby inducing autophagy. Intracellular galectins act as active signal transducers controlling master metabolic regulators rather than merely passive 'eat me' tags.","method":"Lysosomal damage assays, MTOR/AMPK activity measurements, galectin knockout/knockdown in cells, APEX2-based proximity proteomics","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (kinase activity assays, genetic KO, proximity proteomics) in single study with clear mechanistic readout","pmids":["30081722"],"is_preprint":false},{"year":2016,"finding":"Galectin-8 promotes pathological lymphangiogenesis through a molecular mechanism involving crosstalk among VEGF-C, podoplanin, and integrin pathways (α1β1 and α5β1). VEGFR-3 knockdown does not affect galectin-8-mediated lymphatic endothelial cell sprouting, placing integrins rather than VEGFR-3 as downstream effectors of galectin-8 in this context.","method":"Lgals8−/− and Pdpn−/− mouse models, corneal allograft transplantation, HSV keratitis model, siRNA knockdown of VEGFR-3 and integrins, LEC sprouting assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO mouse models, epistasis between galectin-8/podoplanin/integrin pathways, in vivo and in vitro orthogonal assays","pmids":["27066737"],"is_preprint":false},{"year":2019,"finding":"CALCOCO2/NDP52 recruits the ULK and TBK1 kinase complexes to LGALS8-marked damaged Salmonella-containing vacuoles to initiate phagophore formation. CALCOCO2 forms a trimer with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1, linking galectin-8 danger sensing to de novo autophagy induction at cargo sites.","method":"Co-immunoprecipitation, dominant-negative and mutant constructs, fluorescence microscopy, autophagy induction assays in Salmonella-infected cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, mutant analysis, clear pathway placement with defined trimeric complex, builds on replicated prior work","pmids":["31258038"],"is_preprint":false},{"year":2022,"finding":"LGALS8/galectin-8 contributes to MTOR inactivation at damaged lysosomes via the Ragulator-RRAGA-RRAGB complex, acting together with NUFIP2; this function is governed by GABARAP and membrane Atg8ylation.","method":"Lysosome immunopurification (LysoIP), proteomics, MTOR activity assays, Atg8ylation-deficient mutants, fluorescence microscopy","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Moderate — LysoIP proteomics combined with MTOR activity assays and genetic mutants, clear molecular pathway placement","pmids":["36394332"],"is_preprint":false},{"year":2024,"finding":"In human osteoclasts, galectin-8 regulates bone resorption, osteoclast nuclearity, and mTORC1 signaling. The short isoform is predominant for bone resorption. LC-MS/MS proteomic analysis identified 22 interacting partners shared by both isoforms; short-isoform-specific interactors include cell adhesion and lysosomal proteins. Interactions of galectin-8 with CLCN3, CLCN7, LAMP1, and LAMP2 (secretory vesicle proteins) were confirmed in human osteoclasts.","method":"Isoform-specific siRNA knockdown, LC-MS/MS proteomics in HEK293T cells, co-immunoprecipitation validation in human osteoclasts, bone resorption assays","journal":"Life Science Alliance","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — isoform-specific KD with functional readout, LC-MS/MS proteomics with Co-IP validation, multiple orthogonal methods in one study","pmids":["38395460"],"is_preprint":false},{"year":2020,"finding":"A network of three miRNAs (miR-125b, miR-221, miR-579) concertedly downregulates LGALS8 expression in human macrophages upon Legionella pneumophila infection, thereby suppressing antibacterial immunity. LGALS8 downregulation facilitates Legionella replication, establishing LGALS8 as a component of the miRNA-controlled cell-autonomous immune network.","method":"miRNA profiling, ChIP-seq for histone acetylation, proteome analysis, miRNA overexpression/inhibition with intracellular bacterial replication readout in human macrophages","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional miRNA manipulation with bacterial growth readout, single lab study","pmids":["32209695"],"is_preprint":false},{"year":2024,"finding":"IGF2BP2 regulates LGALS8 mRNA stability through m6A modification; LGALS8 deficiency severely impairs angiogenesis in vitro and leads to cerebrovascular dysplasia in vivo (zebrafish model).","method":"RNA-seq and MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular development assays, LGALS8 rescue experiments","journal":"Frontiers in Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics (RNA-seq + MeRIP-seq), in vitro and in vivo (zebrafish) orthogonal validation, single lab","pmids":["39722688"],"is_preprint":false},{"year":2017,"finding":"Galectin-8 activates dendritic cells by promoting mature phenotype (increased MHCII, CD80, CD86 surface expression) and proinflammatory cytokine secretion (prominently IL-6). BMDCs from Lgals8-deficient mice show reduced CD86 and IL-6 and impaired ability to stimulate antigen-specific CD4 T cell activation, demonstrating an endogenous role of galectin-8 in DC activation.","method":"Bone marrow-derived DC cultures from Lgals8 knockout mice, flow cytometry, cytokine ELISA, antigen-specific T cell co-culture assays, in vivo FMDV challenge model","journal":"Journal of Leukocyte Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple functional readouts (phenotypic markers, cytokines, T cell activation), in vivo validation, single lab","pmids":["28811319"],"is_preprint":false},{"year":2025,"finding":"Endogenous galectin-8 in the kidney does not protect against the acute phase of AKI but prevents maladaptive repair by regulating extracellular matrix homeostasis, limiting fibrosis (reduced collagen I/III deposition), and mitigating Th17 cell infiltration during the fibrotic phase.","method":"Lgals8−/− mouse model, folic acid-induced AKI, flow cytometry for immune cell profiling, histological assessment of fibrosis, RT-qPCR","journal":"Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with multiple phenotypic readouts at two time points, single lab","pmids":["40375122"],"is_preprint":false},{"year":2015,"finding":"CALCOCO2/NDP52 binds LGALS8/galectin-8 on damaged Salmonella-containing vacuoles via a distinct domain from that used for LC3C binding; this targeting function is separable from the maturation function of CALCOCO2 (which requires LC3A/B/GABARAPL2 and MYO6 binding).","method":"Domain mapping with deletion mutants, co-immunoprecipitation, fluorescence microscopy in Salmonella-infected cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutant analysis with Co-IP and imaging, single lab but mechanistically precise","pmids":["25998689"],"is_preprint":false},{"year":1996,"finding":"PCTA-1 (LGALS8) encodes a secreted ~35 kDa protein sharing ~40% sequence homology with the N-terminal region of galectin family members; identified by surface-epitope masking and expression cloning from human LNCaP prostate cancer cells.","method":"Surface-epitope masking immunological subtraction, cDNA expression library screening, protein size determination","journal":"Proceedings of the National Academy of Sciences USA","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — original cloning and characterization study; protein expression and secretion confirmed biochemically, but limited mechanistic follow-up in this paper","pmids":["8692978"],"is_preprint":false},{"year":2000,"finding":"PCTA-1/LGALS8 maps to chromosomal locus 1q42-43 and is expressed as multiple isoforms at the mRNA level due to alternative splicing. Over-expression studies in cells were conducted to examine effects on cellular phenotype.","method":"Genomic mapping, RT-PCR isoform analysis, overexpression in cell lines","journal":"Oncogene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genomic/mRNA characterization with limited functional follow-up; phenotypic effects of overexpression not precisely defined in abstract","pmids":["10980616"],"is_preprint":false},{"year":2024,"finding":"LGALS8 (galectin-8) inhibits MTOR and activates TFEB, driving ATG and lysosomal gene transcription in response to endomembrane damage. LGALS8-mediated ubiquitination recruits autophagy receptors (CALCOCO2, TRIM16, SQSTM1) upon lysosomal damage when ESCRT repair fails.","method":"Review/synthesis of mechanistic studies including MTOR activity assays, TFEB nuclear translocation assays, autophagy receptor recruitment experiments (cited from primary literature)","journal":"Journal of Molecular Medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review article synthesizing previously published findings; no new primary experiments described in this abstract","pmids":["38183492"],"is_preprint":false},{"year":2024,"finding":"In the context of hepatitis B virus infection, CALCOCO2/NDP52-mediated lysosomal degradation does NOT require LGALS8 (negative result), distinguishing anti-HBV autophagy from anti-bacterial xenophagy which depends on LGALS8.","method":"LGALS8-independent CALCOCO2 mutant analysis, ATG5 KO, RAB9-dependent pathway assays in HBV-infected cells","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistically informative negative result from genetic and biochemical experiments distinguishing two CALCOCO2-dependent pathways","pmids":["38752371"],"is_preprint":false}],"current_model":"LGALS8/galectin-8 is a cytosolic β-galactoside-binding lectin that functions as a danger receptor monitoring endomembrane integrity: upon lysosomal or endosomal damage (by bacteria, viruses, or sterile agents), it binds exposed host glycans on damaged vesicles, recruits NDP52/CALCOCO2 to initiate antibacterial selective autophagy via ULK/TBK1 complex assembly, and simultaneously acts as an active signaling node that inhibits MTOR (through the Ragulator-RRAGA/B complex) and activates AMPK/TFEB to drive autophagy and lysosomal biogenesis; extracellularly, galectin-8 promotes pathological lymphangiogenesis through podoplanin–integrin (α1β1/α5β1) crosstalk, activates dendritic cells to enhance adaptive immunity, and in osteoclasts (primarily via its short isoform) regulates bone resorption and mTORC1 signaling through interactions with lysosomal/secretory vesicle proteins including CLCN3, CLCN7, LAMP1, and LAMP2."},"narrative":{"mechanistic_narrative":"LGALS8/galectin-8 is a cytosolic β-galactoside-binding lectin that serves as a danger receptor surveying endomembrane integrity: upon lysosomal, endosomal, or pathogen-containing vacuole damage, luminal host glycans become exposed on the cytosolic face and are bound by galectin-8, which marks the damaged compartment for selective autophagy across bacterial (Salmonella, Listeria, Shigella), viral (picornavirus), and sterile injuries [PMID:22246322, PMID:28077878]. Glycan-bound galectin-8 recruits the autophagy adaptor CALCOCO2/NDP52 through a binding interface distinct from its LC3C/maturation interface, providing transient cargo targeting that precedes ubiquitin-dependent recruitment [PMID:22246322, PMID:25998689]; NDP52 in turn assembles the ULK and TBK1 kinase complexes as a trimer with RB1CC1/FIP200 and TBKBP1-AZI2/NAP1 to nucleate phagophore formation directly at the cargo [PMID:31258038]. Beyond a passive 'eat-me' tag, galectin-8 acts as an active signaling node, inhibiting MTOR and activating AMPK upon lysosomal damage [PMID:30081722], with MTOR inactivation occurring at the damaged lysosome through the Ragulator-RRAGA/RRAGB complex together with NUFIP2 under the control of GABARAP-dependent membrane Atg8ylation [PMID:36394332]. Extracellularly, galectin-8 promotes pathological lymphangiogenesis through VEGF-C/podoplanin/integrin (α1β1, α5β1) crosstalk independent of VEGFR-3 [PMID:27066737] and activates dendritic cells to mature and secrete proinflammatory cytokines, enhancing antigen-specific CD4 T-cell responses [PMID:28811319]. An isoform-specific role exists in human osteoclasts, where the short isoform predominantly drives bone resorption and mTORC1 signaling via interactions with lysosomal/secretory vesicle proteins CLCN3, CLCN7, LAMP1, and LAMP2 [PMID:38395460].","teleology":[{"year":1996,"claim":"Established the existence and basic biochemistry of the gene product, defining it as a secreted galectin-family-related protein before any cellular function was known.","evidence":"Surface-epitope masking immunological subtraction and cDNA expression cloning from human LNCaP prostate cancer cells","pmids":["8692978"],"confidence":"Medium","gaps":["No functional or mechanistic role assigned","Glycan-binding specificity not characterized","Relationship to autophagy/immunity unknown"]},{"year":2012,"claim":"Resolved how the cell detects damaged intracellular vesicles, showing galectin-8 is a cytosolic danger receptor that senses exposed luminal glycans and links membrane damage to selective autophagy.","evidence":"Loss-of-function, Co-IP, fluorescence microscopy and infection with multiple pathogens plus sterile lysosome-damaging agents in human cells","pmids":["22246322"],"confidence":"High","gaps":["Did not define the downstream kinase machinery recruited","Did not separate cargo-targeting from autophagosome maturation functions"]},{"year":2015,"claim":"Defined the molecular logic of adaptor recruitment by mapping that NDP52 engages galectin-8 through a domain separate from its LC3C-binding interface, separating cargo targeting from maturation.","evidence":"Domain-mapping deletion mutants, Co-IP and imaging in Salmonella-infected cells","pmids":["25998689"],"confidence":"Medium","gaps":["Single-lab structural detail without crystallographic interface","How glycan-bound galectin-8 hands off to ubiquitin-dependent recruitment not resolved"]},{"year":2016,"claim":"Extended galectin-8 function beyond intracellular surveillance, establishing an extracellular role in pathological lymphangiogenesis acting through integrins rather than VEGFR-3.","evidence":"Lgals8−/− and Pdpn−/− mouse models, corneal allograft and HSV keratitis models, VEGFR-3/integrin knockdown and LEC sprouting assays","pmids":["27066737"],"confidence":"High","gaps":["Direct receptor for secreted galectin-8 on LECs not defined","Connection between intracellular and extracellular roles unaddressed"]},{"year":2017,"claim":"Generalized galectin-8 sensing to non-bacterial breach by showing it detects picornavirus-permeated endosomes and routes them for autophagic clearance, in competition with viral escape factor PLA2G16.","evidence":"Genome-wide haploid suppressor screen with epistasis and infection assays","pmids":["28077878"],"confidence":"High","gaps":["Whether the same adaptor cascade operates for viral cargo not shown","Glycan source on virus-permeated endosomes not detailed"]},{"year":2017,"claim":"Demonstrated an immunostimulatory role linking galectin-8 to adaptive immunity through dendritic cell maturation.","evidence":"BMDCs from Lgals8 knockout mice, flow cytometry, cytokine ELISA, T-cell co-culture and in vivo FMDV challenge","pmids":["28811319"],"confidence":"Medium","gaps":["Receptor mediating DC activation not identified","Single-lab study","Intracellular vs secreted galectin-8 contribution not separated"]},{"year":2018,"claim":"Reframed galectin-8 from a passive autophagy tag into an active signal transducer that reprograms metabolic master regulators MTOR and AMPK upon lysosomal damage.","evidence":"Lysosomal damage assays, MTOR/AMPK activity measurements, galectin KO/KD and APEX2 proximity proteomics","pmids":["30081722"],"confidence":"High","gaps":["Molecular link between glycan binding and kinase modulation not yet defined","Did not place MTOR control on the Ragulator axis"]},{"year":2019,"claim":"Connected galectin-8 danger sensing to de novo autophagosome nucleation by defining the NDP52-recruited ULK/TBK1 trimeric complex at cargo sites.","evidence":"Reciprocal Co-IP, dominant-negative/mutant constructs, microscopy and autophagy induction in Salmonella-infected cells","pmids":["31258038"],"confidence":"High","gaps":["Kinetics of complex assembly relative to galectin-8 binding not resolved","Stoichiometry in vivo not determined"]},{"year":2020,"claim":"Identified an upstream regulatory layer showing pathogens suppress galectin-8 to evade cell-autonomous immunity.","evidence":"miRNA profiling, ChIP-seq, proteomics, and miRNA overexpression/inhibition with bacterial replication readout in human macrophages during Legionella infection","pmids":["32209695"],"confidence":"Medium","gaps":["Direct miRNA-target validation on LGALS8 3'UTR not detailed","Single-lab study"]},{"year":2022,"claim":"Placed galectin-8-driven MTOR inactivation precisely at the damaged lysosome on the Ragulator-RRAGA/B axis, controlled by Atg8ylation.","evidence":"LysoIP proteomics, MTOR activity assays, Atg8ylation-deficient mutants and microscopy","pmids":["36394332"],"confidence":"High","gaps":["Direct biochemical contact of galectin-8 with Ragulator components not shown","How NUFIP2 cooperation is regulated unclear"]},{"year":2024,"claim":"Revealed isoform-specialized function, with the short galectin-8 isoform driving osteoclast bone resorption and mTORC1 signaling via defined lysosomal/secretory vesicle protein interactions.","evidence":"Isoform-specific siRNA knockdown, LC-MS/MS proteomics in HEK293T, Co-IP validation in human osteoclasts and bone resorption assays","pmids":["38395460"],"confidence":"High","gaps":["Whether CLCN3/CLCN7/LAMP1/LAMP2 binding is glycan-dependent not shown","Mechanistic link to mTORC1 in osteoclasts not fully resolved"]},{"year":2024,"claim":"Identified post-transcriptional control of LGALS8 by m6A and connected its expression to vascular development.","evidence":"RNA-seq, MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular assays and LGALS8 rescue","pmids":["39722688"],"confidence":"Medium","gaps":["Direct m6A sites on LGALS8 not mapped to function","Single-lab study","Mechanism of angiogenesis defect downstream of LGALS8 unclear"]},{"year":2024,"claim":"Delimited pathway specificity by showing CALCOCO2-dependent anti-HBV lysosomal degradation does not require galectin-8, distinguishing it from galectin-8-dependent antibacterial xenophagy.","evidence":"LGALS8-independent CALCOCO2 mutant analysis, ATG5 KO and RAB9-dependent pathway assays in HBV-infected cells","pmids":["38752371"],"confidence":"Medium","gaps":["Why HBV clearance bypasses galectin-8 not mechanistically explained","Generality across other viruses untested in this study"]},{"year":2025,"claim":"Defined an organ-protective role for endogenous galectin-8 in limiting maladaptive fibrotic repair after kidney injury.","evidence":"Lgals8−/− mouse folic acid-induced AKI model with immune profiling, fibrosis histology and RT-qPCR","pmids":["40375122"],"confidence":"Medium","gaps":["Cell-intrinsic vs systemic source of galectin-8 not resolved","Mechanistic link between galectin-8 and ECM/Th17 regulation not defined","Single-lab study"]},{"year":null,"claim":"It remains unresolved how glycan binding by galectin-8 is mechanistically transduced into MTOR/AMPK/TFEB signaling and adaptor recruitment, and how its intracellular surveillance and extracellular lectin functions are coordinated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of galectin-8 engaging signaling complexes","Direct biochemical bridge from glycan sensing to kinase regulation unknown","Coordination of secreted vs cytosolic pools uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[13,4]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,1,3,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,8,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9]}],"complexes":[],"partners":["CALCOCO2","RRAGA","RRAGB","NUFIP2","GABARAP","CLCN3","CLCN7","LAMP1"],"other_free_text":[]}},"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 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Galectin-8-dependent NDP52 recruitment is transient and precedes ubiquitin-dependent NDP52 recruitment.\",\n      \"method\": \"Loss-of-function experiments in human cells, co-immunoprecipitation, fluorescence microscopy, Salmonella infection assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays in human cells with multiple orthogonal methods (imaging, Co-IP, bacterial infection readout), highly cited, established mechanism replicated in subsequent studies\",\n      \"pmids\": [\"22246322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Galectin-8 monitors endosomal and lysosomal integrity by sensing luminal glycans that become exposed on the cytosolic face upon vesicle damage (sterile or pathogen-induced), functioning as a general sensor of endomembrane damage regardless of pathogen species (Salmonella, Listeria, Shigella).\",\n      \"method\": \"Fluorescence microscopy with glycan-binding domain mutants, infection with multiple pathogens, sterile lysosome-damaging agents\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple pathogens and sterile damage tested, functionally validated with domain mutants, replicated in subsequent studies\",\n      \"pmids\": [\"22246322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Galectin-8 detects picornavirus-permeated endosomes and marks them for autophagic degradation (pore-activated clearance pathway); PLA2G16 counteracts this by facilitating viral genome translocation, placing LGALS8 upstream of autophagic clearance in a competition with viral escape.\",\n      \"method\": \"Genome-wide haploid genetic screen for suppressors of ΔPLA2G16 phenotype, epistasis analysis, infection assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide suppressor screen with epistasis, multiple orthogonal validations, independent identification of LGALS8 in this pathway\",\n      \"pmids\": [\"28077878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Galectin-8 (LGALS8), upon lysosomal damage, inhibits MTOR and activates AMPK, thereby inducing autophagy. Intracellular galectins act as active signal transducers controlling master metabolic regulators rather than merely passive 'eat me' tags.\",\n      \"method\": \"Lysosomal damage assays, MTOR/AMPK activity measurements, galectin knockout/knockdown in cells, APEX2-based proximity proteomics\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (kinase activity assays, genetic KO, proximity proteomics) in single study with clear mechanistic readout\",\n      \"pmids\": [\"30081722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Galectin-8 promotes pathological lymphangiogenesis through a molecular mechanism involving crosstalk among VEGF-C, podoplanin, and integrin pathways (α1β1 and α5β1). VEGFR-3 knockdown does not affect galectin-8-mediated lymphatic endothelial cell sprouting, placing integrins rather than VEGFR-3 as downstream effectors of galectin-8 in this context.\",\n      \"method\": \"Lgals8−/− and Pdpn−/− mouse models, corneal allograft transplantation, HSV keratitis model, siRNA knockdown of VEGFR-3 and integrins, LEC sprouting assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO mouse models, epistasis between galectin-8/podoplanin/integrin pathways, in vivo and in vitro orthogonal assays\",\n      \"pmids\": [\"27066737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CALCOCO2/NDP52 recruits the ULK and TBK1 kinase complexes to LGALS8-marked damaged Salmonella-containing vacuoles to initiate phagophore formation. CALCOCO2 forms a trimer with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1, linking galectin-8 danger sensing to de novo autophagy induction at cargo sites.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative and mutant constructs, fluorescence microscopy, autophagy induction assays in Salmonella-infected cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, mutant analysis, clear pathway placement with defined trimeric complex, builds on replicated prior work\",\n      \"pmids\": [\"31258038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LGALS8/galectin-8 contributes to MTOR inactivation at damaged lysosomes via the Ragulator-RRAGA-RRAGB complex, acting together with NUFIP2; this function is governed by GABARAP and membrane Atg8ylation.\",\n      \"method\": \"Lysosome immunopurification (LysoIP), proteomics, MTOR activity assays, Atg8ylation-deficient mutants, fluorescence microscopy\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LysoIP proteomics combined with MTOR activity assays and genetic mutants, clear molecular pathway placement\",\n      \"pmids\": [\"36394332\"],\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 is predominant for bone resorption. LC-MS/MS proteomic analysis identified 22 interacting partners shared by both isoforms; short-isoform-specific interactors include cell adhesion and lysosomal proteins. Interactions of galectin-8 with CLCN3, CLCN7, LAMP1, and LAMP2 (secretory vesicle proteins) were confirmed in human osteoclasts.\",\n      \"method\": \"Isoform-specific siRNA knockdown, LC-MS/MS proteomics in HEK293T cells, co-immunoprecipitation validation in human osteoclasts, bone resorption assays\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — isoform-specific KD with functional readout, LC-MS/MS proteomics with Co-IP validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38395460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A network of three miRNAs (miR-125b, miR-221, miR-579) concertedly downregulates LGALS8 expression in human macrophages upon Legionella pneumophila infection, thereby suppressing antibacterial immunity. LGALS8 downregulation facilitates Legionella replication, establishing LGALS8 as a component of the miRNA-controlled cell-autonomous immune network.\",\n      \"method\": \"miRNA profiling, ChIP-seq for histone acetylation, proteome analysis, miRNA overexpression/inhibition with intracellular bacterial replication readout in human macrophages\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional miRNA manipulation with bacterial growth readout, single lab study\",\n      \"pmids\": [\"32209695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP2 regulates LGALS8 mRNA stability through m6A modification; LGALS8 deficiency severely impairs angiogenesis in vitro and leads to cerebrovascular dysplasia in vivo (zebrafish model).\",\n      \"method\": \"RNA-seq and MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular development assays, LGALS8 rescue experiments\",\n      \"journal\": \"Frontiers in Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics (RNA-seq + MeRIP-seq), in vitro and in vivo (zebrafish) orthogonal validation, single lab\",\n      \"pmids\": [\"39722688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Galectin-8 activates dendritic cells by promoting mature phenotype (increased MHCII, CD80, CD86 surface expression) and proinflammatory cytokine secretion (prominently IL-6). BMDCs from Lgals8-deficient mice show reduced CD86 and IL-6 and impaired ability to stimulate antigen-specific CD4 T cell activation, demonstrating an endogenous role of galectin-8 in DC activation.\",\n      \"method\": \"Bone marrow-derived DC cultures from Lgals8 knockout mice, flow cytometry, cytokine ELISA, antigen-specific T cell co-culture assays, in vivo FMDV challenge model\",\n      \"journal\": \"Journal of Leukocyte Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple functional readouts (phenotypic markers, cytokines, T cell activation), in vivo validation, single lab\",\n      \"pmids\": [\"28811319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endogenous galectin-8 in the kidney does not protect against the acute phase of AKI but prevents maladaptive repair by regulating extracellular matrix homeostasis, limiting fibrosis (reduced collagen I/III deposition), and mitigating Th17 cell infiltration during the fibrotic phase.\",\n      \"method\": \"Lgals8−/− mouse model, folic acid-induced AKI, flow cytometry for immune cell profiling, histological assessment of fibrosis, RT-qPCR\",\n      \"journal\": \"Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with multiple phenotypic readouts at two time points, single lab\",\n      \"pmids\": [\"40375122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CALCOCO2/NDP52 binds LGALS8/galectin-8 on damaged Salmonella-containing vacuoles via a distinct domain from that used for LC3C binding; this targeting function is separable from the maturation function of CALCOCO2 (which requires LC3A/B/GABARAPL2 and MYO6 binding).\",\n      \"method\": \"Domain mapping with deletion mutants, co-immunoprecipitation, fluorescence microscopy in Salmonella-infected cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutant analysis with Co-IP and imaging, single lab but mechanistically precise\",\n      \"pmids\": [\"25998689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"PCTA-1 (LGALS8) encodes a secreted ~35 kDa protein sharing ~40% sequence homology with the N-terminal region of galectin family members; identified by surface-epitope masking and expression cloning from human LNCaP prostate cancer cells.\",\n      \"method\": \"Surface-epitope masking immunological subtraction, cDNA expression library screening, protein size determination\",\n      \"journal\": \"Proceedings of the National Academy of Sciences USA\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — original cloning and characterization study; protein expression and secretion confirmed biochemically, but limited mechanistic follow-up in this paper\",\n      \"pmids\": [\"8692978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PCTA-1/LGALS8 maps to chromosomal locus 1q42-43 and is expressed as multiple isoforms at the mRNA level due to alternative splicing. Over-expression studies in cells were conducted to examine effects on cellular phenotype.\",\n      \"method\": \"Genomic mapping, RT-PCR isoform analysis, overexpression in cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genomic/mRNA characterization with limited functional follow-up; phenotypic effects of overexpression not precisely defined in abstract\",\n      \"pmids\": [\"10980616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGALS8 (galectin-8) inhibits MTOR and activates TFEB, driving ATG and lysosomal gene transcription in response to endomembrane damage. LGALS8-mediated ubiquitination recruits autophagy receptors (CALCOCO2, TRIM16, SQSTM1) upon lysosomal damage when ESCRT repair fails.\",\n      \"method\": \"Review/synthesis of mechanistic studies including MTOR activity assays, TFEB nuclear translocation assays, autophagy receptor recruitment experiments (cited from primary literature)\",\n      \"journal\": \"Journal of Molecular Medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review article synthesizing previously published findings; no new primary experiments described in this abstract\",\n      \"pmids\": [\"38183492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the context of hepatitis B virus infection, CALCOCO2/NDP52-mediated lysosomal degradation does NOT require LGALS8 (negative result), distinguishing anti-HBV autophagy from anti-bacterial xenophagy which depends on LGALS8.\",\n      \"method\": \"LGALS8-independent CALCOCO2 mutant analysis, ATG5 KO, RAB9-dependent pathway assays in HBV-infected cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistically informative negative result from genetic and biochemical experiments distinguishing two CALCOCO2-dependent pathways\",\n      \"pmids\": [\"38752371\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LGALS8/galectin-8 is a cytosolic β-galactoside-binding lectin that functions as a danger receptor monitoring endomembrane integrity: upon lysosomal or endosomal damage (by bacteria, viruses, or sterile agents), it binds exposed host glycans on damaged vesicles, recruits NDP52/CALCOCO2 to initiate antibacterial selective autophagy via ULK/TBK1 complex assembly, and simultaneously acts as an active signaling node that inhibits MTOR (through the Ragulator-RRAGA/B complex) and activates AMPK/TFEB to drive autophagy and lysosomal biogenesis; extracellularly, galectin-8 promotes pathological lymphangiogenesis through podoplanin–integrin (α1β1/α5β1) crosstalk, activates dendritic cells to enhance adaptive immunity, and in osteoclasts (primarily via its short isoform) regulates bone resorption and mTORC1 signaling through interactions with lysosomal/secretory vesicle proteins including CLCN3, CLCN7, LAMP1, and LAMP2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LGALS8/galectin-8 is a cytosolic β-galactoside-binding lectin that serves as a danger receptor surveying endomembrane integrity: upon lysosomal, endosomal, or pathogen-containing vacuole damage, luminal host glycans become exposed on the cytosolic face and are bound by galectin-8, which marks the damaged compartment for selective autophagy across bacterial (Salmonella, Listeria, Shigella), viral (picornavirus), and sterile injuries [#1, #0, #2]. Glycan-bound galectin-8 recruits the autophagy adaptor CALCOCO2/NDP52 through a binding interface distinct from its LC3C/maturation interface, providing transient cargo targeting that precedes ubiquitin-dependent recruitment [#0, #12]; NDP52 in turn assembles the ULK and TBK1 kinase complexes as a trimer with RB1CC1/FIP200 and TBKBP1-AZI2/NAP1 to nucleate phagophore formation directly at the cargo [#5]. Beyond a passive 'eat-me' tag, galectin-8 acts as an active signaling node, inhibiting MTOR and activating AMPK upon lysosomal damage [#3], with MTOR inactivation occurring at the damaged lysosome through the Ragulator-RRAGA/RRAGB complex together with NUFIP2 under the control of GABARAP-dependent membrane Atg8ylation [#6]. Extracellularly, galectin-8 promotes pathological lymphangiogenesis through VEGF-C/podoplanin/integrin (α1β1, α5β1) crosstalk independent of VEGFR-3 [#4] and activates dendritic cells to mature and secrete proinflammatory cytokines, enhancing antigen-specific CD4 T-cell responses [#10]. An isoform-specific role exists in human osteoclasts, where the short isoform predominantly drives bone resorption and mTORC1 signaling via interactions with lysosomal/secretory vesicle proteins CLCN3, CLCN7, LAMP1, and LAMP2 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the existence and basic biochemistry of the gene product, defining it as a secreted galectin-family-related protein before any cellular function was known.\",\n      \"evidence\": \"Surface-epitope masking immunological subtraction and cDNA expression cloning from human LNCaP prostate cancer cells\",\n      \"pmids\": [\"8692978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or mechanistic role assigned\", \"Glycan-binding specificity not characterized\", \"Relationship to autophagy/immunity unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved how the cell detects damaged intracellular vesicles, showing galectin-8 is a cytosolic danger receptor that senses exposed luminal glycans and links membrane damage to selective autophagy.\",\n      \"evidence\": \"Loss-of-function, Co-IP, fluorescence microscopy and infection with multiple pathogens plus sterile lysosome-damaging agents in human cells\",\n      \"pmids\": [\"22246322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the downstream kinase machinery recruited\", \"Did not separate cargo-targeting from autophagosome maturation functions\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular logic of adaptor recruitment by mapping that NDP52 engages galectin-8 through a domain separate from its LC3C-binding interface, separating cargo targeting from maturation.\",\n      \"evidence\": \"Domain-mapping deletion mutants, Co-IP and imaging in Salmonella-infected cells\",\n      \"pmids\": [\"25998689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab structural detail without crystallographic interface\", \"How glycan-bound galectin-8 hands off to ubiquitin-dependent recruitment not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended galectin-8 function beyond intracellular surveillance, establishing an extracellular role in pathological lymphangiogenesis acting through integrins rather than VEGFR-3.\",\n      \"evidence\": \"Lgals8−/− and Pdpn−/− mouse models, corneal allograft and HSV keratitis models, VEGFR-3/integrin knockdown and LEC sprouting assays\",\n      \"pmids\": [\"27066737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor for secreted galectin-8 on LECs not defined\", \"Connection between intracellular and extracellular roles unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized galectin-8 sensing to non-bacterial breach by showing it detects picornavirus-permeated endosomes and routes them for autophagic clearance, in competition with viral escape factor PLA2G16.\",\n      \"evidence\": \"Genome-wide haploid suppressor screen with epistasis and infection assays\",\n      \"pmids\": [\"28077878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same adaptor cascade operates for viral cargo not shown\", \"Glycan source on virus-permeated endosomes not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an immunostimulatory role linking galectin-8 to adaptive immunity through dendritic cell maturation.\",\n      \"evidence\": \"BMDCs from Lgals8 knockout mice, flow cytometry, cytokine ELISA, T-cell co-culture and in vivo FMDV challenge\",\n      \"pmids\": [\"28811319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating DC activation not identified\", \"Single-lab study\", \"Intracellular vs secreted galectin-8 contribution not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reframed galectin-8 from a passive autophagy tag into an active signal transducer that reprograms metabolic master regulators MTOR and AMPK upon lysosomal damage.\",\n      \"evidence\": \"Lysosomal damage assays, MTOR/AMPK activity measurements, galectin KO/KD and APEX2 proximity proteomics\",\n      \"pmids\": [\"30081722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between glycan binding and kinase modulation not yet defined\", \"Did not place MTOR control on the Ragulator axis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected galectin-8 danger sensing to de novo autophagosome nucleation by defining the NDP52-recruited ULK/TBK1 trimeric complex at cargo sites.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative/mutant constructs, microscopy and autophagy induction in Salmonella-infected cells\",\n      \"pmids\": [\"31258038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics of complex assembly relative to galectin-8 binding not resolved\", \"Stoichiometry in vivo not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified an upstream regulatory layer showing pathogens suppress galectin-8 to evade cell-autonomous immunity.\",\n      \"evidence\": \"miRNA profiling, ChIP-seq, proteomics, and miRNA overexpression/inhibition with bacterial replication readout in human macrophages during Legionella infection\",\n      \"pmids\": [\"32209695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miRNA-target validation on LGALS8 3'UTR not detailed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed galectin-8-driven MTOR inactivation precisely at the damaged lysosome on the Ragulator-RRAGA/B axis, controlled by Atg8ylation.\",\n      \"evidence\": \"LysoIP proteomics, MTOR activity assays, Atg8ylation-deficient mutants and microscopy\",\n      \"pmids\": [\"36394332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical contact of galectin-8 with Ragulator components not shown\", \"How NUFIP2 cooperation is regulated unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed isoform-specialized function, with the short galectin-8 isoform driving osteoclast bone resorption and mTORC1 signaling via defined lysosomal/secretory vesicle protein interactions.\",\n      \"evidence\": \"Isoform-specific siRNA knockdown, LC-MS/MS proteomics in HEK293T, Co-IP validation in human osteoclasts and bone resorption assays\",\n      \"pmids\": [\"38395460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CLCN3/CLCN7/LAMP1/LAMP2 binding is glycan-dependent not shown\", \"Mechanistic link to mTORC1 in osteoclasts not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-transcriptional control of LGALS8 by m6A and connected its expression to vascular development.\",\n      \"evidence\": \"RNA-seq, MeRIP-seq, IGF2BP2 knockdown in endothelial cells, zebrafish vascular assays and LGALS8 rescue\",\n      \"pmids\": [\"39722688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A sites on LGALS8 not mapped to function\", \"Single-lab study\", \"Mechanism of angiogenesis defect downstream of LGALS8 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delimited pathway specificity by showing CALCOCO2-dependent anti-HBV lysosomal degradation does not require galectin-8, distinguishing it from galectin-8-dependent antibacterial xenophagy.\",\n      \"evidence\": \"LGALS8-independent CALCOCO2 mutant analysis, ATG5 KO and RAB9-dependent pathway assays in HBV-infected cells\",\n      \"pmids\": [\"38752371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why HBV clearance bypasses galectin-8 not mechanistically explained\", \"Generality across other viruses untested in this study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an organ-protective role for endogenous galectin-8 in limiting maladaptive fibrotic repair after kidney injury.\",\n      \"evidence\": \"Lgals8−/− mouse folic acid-induced AKI model with immune profiling, fibrosis histology and RT-qPCR\",\n      \"pmids\": [\"40375122\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-intrinsic vs systemic source of galectin-8 not resolved\", \"Mechanistic link between galectin-8 and ECM/Th17 regulation not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how glycan binding by galectin-8 is mechanistically transduced into MTOR/AMPK/TFEB signaling and adaptor recruitment, and how its intracellular surveillance and extracellular lectin functions are coordinated.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of galectin-8 engaging signaling complexes\", \"Direct biochemical bridge from glycan sensing to kinase regulation unknown\", \"Coordination of secreted vs cytosolic pools uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [13, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 8, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CALCOCO2\", \"RRAGA\", \"RRAGB\", \"NUFIP2\", \"GABARAP\", \"CLCN3\", \"CLCN7\", \"LAMP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"LGALS8","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 22246322"},"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}