{"gene":"LACC1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2016,"finding":"FAMIN (LACC1) forms a complex with fatty acid synthase (FASN) on peroxisomes and promotes flux through de novo lipogenesis to drive fatty-acid oxidation (FAO) and glycolysis, thereby regenerating ATP. FAMIN-dependent FAO controls inflammasome activation, mitochondrial and NADPH-oxidase-dependent ROS production, and bactericidal activity of macrophages. Disease-risk variants p.I254V and p.C284R result in diminished and loss of function, respectively.","method":"Co-immunoprecipitation/complex formation, metabolic flux assays, macrophage knockout/knockdown with functional readouts (ROS, inflammasome activation, bacterial killing, endotoxin shock model)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex formation, multiple orthogonal metabolic assays, genetic loss-of-function with defined cellular and in vivo phenotypes, disease-variant functional characterization","pmids":["27478939"],"is_preprint":false},{"year":2020,"finding":"FAMIN (LACC1) is a multifunctional purine enzyme: it phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate (a eukaryotically unprecedented activity), and additionally has adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activities. In macrophages, FAMIN enables a purine nucleotide cycle (PNC) between adenosine and IMP/adenylosuccinate that consumes aspartate and releases fumarate, synchronizing mitochondrial activity with glycolysis through fatty acid oxidation and ATP-citrate lyase.","method":"Unbiased liquid chromatography-mass spectrometry enzymatic activity screen, in vitro enzymatic assays with purified protein, macrophage metabolic studies","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution with LC-MS activity screen, multiple enzymatic activities characterized, mechanistic pathway validated in macrophages","pmids":["31978345"],"is_preprint":false},{"year":2022,"finding":"LACC1 converts L-citrulline to L-ornithine and isocyanic acid in both mice and humans, acting as a biochemical bridge between proinflammatory NOS2 and polyamine metabolism via ornithine decarboxylase 1 (ODC1). Genetic epistasis in mouse models and bone marrow-derived macrophages infected with Salmonella Typhimurium confirmed that LACC1 phenotypes require upstream NOS2 and downstream ODC1; chemical complementation of Lacc1-/- macrophages with L-ornithine significantly restored wild-type activities.","method":"Biochemical enzyme activity assays, Lacc1-/- mouse models, genetic epistasis (NOS2 and ODC1 double mutants), chemical complementation with L-ornithine, Salmonella infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic activity established biochemically, validated by genetic epistasis in vivo and in vitro with chemical complementation, multiple orthogonal approaches","pmids":["35978195"],"is_preprint":false},{"year":2017,"finding":"Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2-signalling complex and is critical for optimal NOD2-induced signalling, mitochondrial ROS production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A and amplifies pattern recognition receptor-induced SDH activity. Disease-risk variant Val254 and mutations of nearby histidines 249/250 reduce PRR-induced outcomes. LACC1 is expressed in both cytoplasm and mitochondria.","method":"Co-immunoprecipitation (LACC1 with NOD2 complex and SDH subunit A), siRNA knockdown, transfection of disease-risk variants, mitochondrial ROS measurement, bacterial clearance assay, immunofluorescence localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with NOD2 complex and SDH-A, knockdown with defined phenotypic readouts, disease-variant functional comparison, subcellular localization with functional consequence","pmids":["28593945"],"is_preprint":false},{"year":2019,"finding":"Upon NOD2 stimulation, LACC1 localizes to the endoplasmic reticulum and forms a complex with ER-stress sensors. All three ER-stress branches (PERK, IRE1α, ATF6) are required for NOD2-induced signalling, cytokines, and antimicrobial pathways in human macrophages. LACC1 and its localization to the ER are required for these outcomes. Disease-risk variants Val254 and Arg284 show reduced NOD2-induced ER stress-associated outcomes that are restored by rescuing ER stress.","method":"Immunofluorescence localization, co-immunoprecipitation of LACC1 with ER-stress sensors, siRNA knockdown of PERK/IRE1α/ATF6, transfection of disease-risk variants, macrophage functional assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with ER stress sensors, defined ER localization with functional consequence, disease-variant functional rescue experiment, multiple ER stress branch knockdowns","pmids":["31875558"],"is_preprint":false},{"year":2020,"finding":"In Lacc1-/- mice, myeloid-specific deletion of LACC1 (Lacc1Δmye) recapitulates whole-body knockout phenotypes: increased intestinal bacterial burden and altered T-cell cytokine profiles (increased Th2, decreased Th1/Th17). In macrophages, LACC1 is required for TLR-induced bacterial uptake (dependent on PDK1), and for MAPK- and NF-κB-dependent induction of ROS, reactive nitrogen species, and autophagy. In dendritic cells, LACC1 is required for Th1/Th17 cytokine induction during CD4+ T cell co-culture.","method":"Conditional knockout mice (Lacc1Δmye), T-cell transfer colitis model, oral Salmonella Typhimurium infection, DSS colitis, bone marrow-derived macrophage functional assays (ROS, RNS, autophagy, bacterial uptake), cytokine complementation experiments","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in vivo with multiple disease models, defined cellular mechanism (PDK1-dependent uptake, MAPK/NF-κB ROS), myeloid-specific genetic rescue with cytokine complementation","pmids":["32693188"],"is_preprint":false},{"year":2021,"finding":"LACC1 is primarily expressed in macrophages upon mTOR signaling. Autophagy-inducing proteins RACK1 and AMPK interact with LACC1 (shown by bimolecular fluorescence complementation and biochemical assays). Autophagy blockade causes LACC1 cleavage and degradation. LACC1 deficiency reduces autophagy flux in primary macrophages and is associated with defects in lipid droplet accumulation and mitochondrial respiration, suggesting LACC1-dependent autophagy fuels macrophage bioenergetic metabolism.","method":"Bimolecular fluorescence complementation, co-immunoprecipitation/biochemical assays, siRNA knockdown, autophagy flux assay, lipid droplet staining, mitochondrial respiration measurement, patient-derived macrophages with loss-of-expression mutations","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bimolecular fluorescence complementation plus biochemical assays for RACK1/AMPK interaction, functional autophagy and metabolic readouts in patient macrophages, single lab","pmids":["33606008"],"is_preprint":false},{"year":2016,"finding":"FAMIN (LACC1) protein localizes exclusively to peroxisomes (with some positivity for organelle endomembrane structures) in macrophage-differentiated THP-1 cells. LACC1 co-expression signatures are enriched for PPAR signaling pathway genes, and PPAR ligands downregulate FAMIN expression in vitro.","method":"Immunofluorescence microscopy (subcellular co-localization), siRNA knockdown, gene-set enrichment analysis, PPAR ligand treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunofluorescence localization to peroxisomes confirmed in multiple cell types, PPAR regulation shown by ligand treatment with expression readout, single lab","pmids":["27959965"],"is_preprint":false},{"year":2023,"finding":"Lupeol activates PPARα to reduce LACC1 expression, thereby inhibiting NF-κB pathway activation and macrophage pyroptosis in experimental autoimmune myocarditis. This places LACC1 downstream of PPARα and upstream of NF-κB in macrophage inflammatory signaling.","method":"Transcriptome sequencing, molecular docking, siRNA knockdown, adenovirus overexpression, western blotting, immunofluorescence in EAM mouse model and BMDMs/THP-1 macrophages","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown and overexpression with NF-κB pathway readouts, in vivo and in vitro corroboration, but single lab and pathway placement is pharmacological","pmids":["37976692"],"is_preprint":false},{"year":2022,"finding":"In an in vitro stroke model, inhibition of LACC1 reduces inflammation and ROS-induced oxidative stress by activating AMPK expression and suppressing NLRP3. AMPK inhibition reverses the effects of LACC1 silencing, placing LACC1 upstream of AMPK/NLRP3 in macrophage inflammatory signaling during ischemic injury.","method":"siRNA knockdown, AMPK inhibitor treatment, ROS measurement, inflammatory cytokine measurement, mouse stroke model","journal":"Acta neurobiologiae experimentalis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with pharmacological rescue, limited mechanistic detail in abstract","pmids":["35833820"],"is_preprint":false},{"year":2025,"finding":"NOD2 promotes sepsis-induced neuroinflammation by enhancing ER stress through LACC1 in microglia; LACC1 downregulation partially mitigates these effects, identifying LACC1 as a downstream mediator of NOD2-driven ER stress in the brain.","method":"NOD2-/- CRISPR/Cas9 mice, siRNA knockdown of NOD2 and LACC1 in microglia, ER stress inhibitor (4-PBA), CLP sepsis model, western blotting, immunofluorescence, transmission electron microscopy of ER","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and siRNA epistasis in vivo and in vitro, ER stress pharmacological rescue, structural ER visualization, single lab","pmids":["40335000"],"is_preprint":false}],"current_model":"LACC1 (FAMIN) is a multifunctional immunometabolic enzyme in macrophages that: (1) phosphorolytically cleaves adenosine and participates in a purine nucleotide cycle linking FAO and glycolysis; (2) converts L-citrulline to L-ornithine, bridging NOS2 and polyamine metabolism; (3) forms complexes with FASN on peroxisomes to drive de novo lipogenesis and FAO; (4) associates with the NOD2 signaling complex and ER stress sensors upon innate immune stimulation to amplify ROS, cytokine, and antimicrobial outputs; and (5) interacts with RACK1 and AMPK to support autophagy flux and macrophage bioenergetics — with disease-risk variants (I254V, C284R) causing diminished or lost function across these activities."},"narrative":{"mechanistic_narrative":"LACC1 (FAMIN) is a multifunctional immunometabolic enzyme that couples central metabolism to innate immune effector functions in macrophages [PMID:27478939, PMID:31978345]. Biochemically, it is a promiscuous purine enzyme that phosphorolytically cleaves adenosine and carries adenosine deaminase, purine nucleoside phosphorylase, and methylthioadenosine phosphorylase activities, enabling a purine nucleotide cycle that consumes aspartate and releases fumarate to synchronize mitochondrial activity with glycolysis through fatty-acid oxidation [PMID:31978345]; it additionally converts L-citrulline to L-ornithine, bridging NOS2-driven inflammation to ODC1-dependent polyamine metabolism [PMID:35978195]. Through complex formation with fatty acid synthase on peroxisomes, LACC1 promotes de novo lipogenesis that fuels FAO and ATP regeneration, thereby controlling inflammasome activation, mitochondrial and NADPH-oxidase ROS, and bactericidal capacity [PMID:27478939, PMID:27959965]. In innate immune signaling, LACC1 is recruited to the NOD2-signalling complex and constitutively associates with succinate dehydrogenase subunit A to amplify PRR-induced SDH activity, mitochondrial ROS, cytokine secretion and bacterial clearance [PMID:28593945], and upon NOD2 stimulation relocalizes to the ER where it engages the PERK/IRE1α/ATF6 stress sensors required for antimicrobial output [PMID:31875558]. LACC1 expression is induced via mTOR and its turnover is autophagy-dependent, with RACK1 and AMPK as interaction partners supporting autophagy flux and macrophage bioenergetics [PMID:33606008]. Myeloid LACC1 is required in vivo for control of intestinal bacterial burden and for balanced Th1/Th17 versus Th2 responses [PMID:32693188]. Disease-risk variants p.I254V and p.C284R cause diminished or lost function across these activities [PMID:27478939, PMID:31875558].","teleology":[{"year":2016,"claim":"Established the first molecular function of LACC1/FAMIN by showing it acts as a metabolic hub on peroxisomes that links lipid metabolism to macrophage antimicrobial effector functions, explaining how a disease-risk locus shapes immunity.","evidence":"Co-IP with FASN, metabolic flux assays, and macrophage knockout/knockdown with ROS, inflammasome, bacterial-killing and endotoxin-shock readouts; immunofluorescence localization to peroxisomes","pmids":["27478939","27959965"],"confidence":"High","gaps":["The direct enzymatic activity of LACC1 itself was not defined","How the FASN complex is assembled or regulated was not established"]},{"year":2017,"claim":"Connected LACC1 to a defined innate-immune receptor pathway, showing it physically joins the NOD2 signalling complex and boosts mitochondrial respiratory output to amplify antimicrobial responses.","evidence":"Reciprocal Co-IP of LACC1 with the NOD2 complex and SDH subunit A, siRNA knockdown, disease-variant transfection, mitochondrial ROS and bacterial clearance assays in human macrophages","pmids":["28593945"],"confidence":"High","gaps":["Whether LACC1 directly modifies SDH or acts indirectly was not resolved","Mechanism of recruitment to the NOD2 complex unknown"]},{"year":2019,"claim":"Added a subcellular dimension to NOD2 signalling by showing stimulation drives LACC1 to the ER where it cooperates with all three unfolded-protein-response branches to enable antimicrobial output.","evidence":"Immunofluorescence localization, Co-IP of LACC1 with ER-stress sensors, siRNA knockdown of PERK/IRE1α/ATF6, disease-variant rescue by ER-stress restoration in macrophages","pmids":["31875558"],"confidence":"High","gaps":["How LACC1 traffics between peroxisomes, mitochondria and ER was not defined","Direct biochemical link between LACC1 enzymatic activity and ER-stress sensor engagement unestablished"]},{"year":2020,"claim":"Defined the long-sought catalytic identity of LACC1 as a multifunctional purine enzyme, revealing an unprecedented adenosine phosphorolysis activity that powers a purine nucleotide cycle coordinating mitochondrial and glycolytic metabolism.","evidence":"Unbiased LC-MS enzymatic activity screen with purified protein, in vitro reconstitution of multiple activities, and macrophage metabolic studies","pmids":["31978345"],"confidence":"High","gaps":["No structural basis for the multiple activities reported","Relative physiological contribution of each catalytic activity not weighted"]},{"year":2020,"claim":"Demonstrated the cell-autonomous, myeloid requirement for LACC1 in vivo, linking its loss to defective bacterial handling and skewed adaptive T-cell responses through PDK1-dependent uptake and MAPK/NF-κB-driven effector programs.","evidence":"Lacc1Δmye conditional knockout mice, T-cell transfer and DSS colitis, oral Salmonella infection, and BMDM assays for ROS, RNS, autophagy and bacterial uptake with cytokine complementation","pmids":["32693188"],"confidence":"High","gaps":["Whether enzymatic activities identified in vitro drive each in vivo phenotype not directly tested","Molecular link between LACC1 and PDK1 not defined"]},{"year":2021,"claim":"Placed LACC1 in the autophagy network, identifying RACK1 and AMPK as partners and showing autophagy controls LACC1 stability while LACC1-supported autophagy fuels macrophage bioenergetics.","evidence":"Bimolecular fluorescence complementation and biochemical assays for RACK1/AMPK interaction, autophagy-flux, lipid-droplet and mitochondrial-respiration readouts in patient-derived macrophages","pmids":["33606008"],"confidence":"Medium","gaps":["Interactions shown in a single lab without reciprocal validation in independent systems","Directionality between autophagy regulation and LACC1 enzymatic function unresolved"]},{"year":2022,"claim":"Identified a second discrete enzymatic activity, citrulline-to-ornithine conversion, biochemically and genetically positioning LACC1 between NOS2 and polyamine biosynthesis as the basis of its antimicrobial phenotypes.","evidence":"Biochemical enzyme assays, Lacc1-/- mice, NOS2/ODC1 genetic epistasis, L-ornithine chemical complementation, and Salmonella infection","pmids":["35978195"],"confidence":"High","gaps":["How this activity integrates with the purine nucleotide cycle in the same enzyme not addressed","Isocyanic acid fate and downstream signaling not characterized"]},{"year":2022,"claim":"Extended LACC1's inflammatory role to ischemic injury, placing it upstream of AMPK/NLRP3 in macrophage oxidative-stress and inflammatory signaling.","evidence":"siRNA knockdown with AMPK-inhibitor rescue, ROS and cytokine measurement in an in vitro stroke model","pmids":["35833820"],"confidence":"Low","gaps":["Single lab with limited mechanistic detail and no direct interaction data","Apparent pro-inflammatory directionality conflicts with loss-of-function phenotypes elsewhere and is not reconciled"]},{"year":2023,"claim":"Positioned LACC1 transcriptionally downstream of PPARα and upstream of NF-κB in macrophage pyroptosis, indicating nuclear-receptor control of LACC1 expression as an inflammatory rheostat.","evidence":"Transcriptome sequencing, siRNA knockdown, adenoviral overexpression and western blotting in an EAM mouse model and macrophage lines","pmids":["37976692"],"confidence":"Medium","gaps":["Pathway placement is pharmacological rather than direct","Whether PPARα regulates LACC1 promoter directly not shown"]},{"year":2025,"claim":"Generalized the NOD2-LACC1-ER-stress axis beyond macrophages to microglia, showing LACC1 mediates NOD2-driven neuroinflammation via the ER in sepsis.","evidence":"NOD2 CRISPR knockout mice, siRNA epistasis of NOD2 and LACC1, ER-stress inhibition, CLP sepsis model with ER ultrastructure imaging","pmids":["40335000"],"confidence":"Medium","gaps":["Direct biochemical link between LACC1 and ER-stress induction in microglia not established","Single lab; relationship to LACC1 enzymatic activities not tested"]},{"year":null,"claim":"How LACC1's distinct enzymatic activities (purine phosphorolysis, citrulline conversion) are mechanistically unified within one protein and how they map onto its peroxisomal, mitochondrial and ER localizations to produce each immune phenotype remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model integrating the multiple catalytic activities","Mechanism of stimulus-dependent relocalization across organelles unknown","Causal chain from a single catalytic activity to each in vivo immune phenotype not isolated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[4]}],"complexes":["NOD2 signalling complex","LACC1-FASN complex"],"partners":["FASN","NOD2","SDHA","RACK1","AMPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IV20","full_name":"Purine nucleoside phosphorylase LACC1","aliases":["Adenosine deaminase LACC1","Fatty acid metabolism-immunity nexus","Guanosine phosphorylase LACC1","Isocyanic acid synthase","Laccase domain-containing protein 1","S-methyl-5'-thioadenosine phosphorylase LACC1"],"length_aa":430,"mass_kda":47.8,"function":"Purine nucleoside enzyme that catalyzes the phosphorolysis of adenosine, guanosine and inosine nucleosides, yielding D-ribose 1-phosphate and the respective free bases, adenine, guanine and hypoxanthine (PubMed:31978345). Also catalyzes the phosphorolysis of S-methyl-5'-thioadenosine into adenine and S-methyl-5-thio-alpha-D-ribose 1-phosphate (PubMed:31978345). Also has adenosine deaminase activity (PubMed:31978345). Acts as a regulator of innate immunity in macrophages by modulating the purine nucleotide metabolism, thereby regulating the metabolic function and bioenergetic state of macrophages (PubMed:31978345). Enables a purine nucleotide cycle between adenosine and inosine monophosphate and adenylosuccinate that prevents cytoplasmic acidification and balances the cytoplasmic-mitochondrial redox interface (PubMed:31978345). The purine nucleotide cycle consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity (PubMed:31978345). Participates in pattern recognition receptor (PRR)-induced cytokines in macrophages: associates with the NOD2-signaling complex and promotes optimal NOD2-induced signaling, cytokine secretion and bacterial clearance (PubMed:28593945, PubMed:31875558). Localizes to the endoplasmic reticulum upon PRR stimulation of macrophages and associates with endoplasmic reticulum-stress sensors, promoting the endoplasmic reticulum unfolded protein response (UPR) (PubMed:31875558). Component of L-arginine metabolism in activated macrophages supporting anti-inflammatory and antibacterial macrophage effector functions. Cleaves L-citrulline, a product of L-arginine metabolized via NOS2, to yield isocyanate, a reactive carbonyl species-like cytotoxin, and L-ornithine, a precursor in polyamine biosynthesis. Through L-ornithine controls cellular polyamine pools likely triggering polyamine-mediated proinflammatory cytokine suppression and autophagy stimulation (PubMed:35978195). Directly interacts with components of autophagy machinery to regulate macrophage metabolism and bacterial phagocytosis. Acts downstream of the energy sensor AMP-activated protein kinase (AMPK) to promote autophagy associated to lipid droplets generation providing fatty acids for mitochondrial respiration (PubMed:33606008). Does not show laccase activity (PubMed:27959965, PubMed:31978345)","subcellular_location":"Cytoplasm; Nucleus; Endoplasmic reticulum; Peroxisome","url":"https://www.uniprot.org/uniprotkb/Q8IV20/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LACC1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LACC1","total_profiled":1310},"omim":[{"mim_id":"618795","title":"JUVENILE ARTHRITIS; JUVAR","url":"https://www.omim.org/entry/618795"},{"mim_id":"613409","title":"LACCASE (MULTICOPPER REDUCTASE) DOMAIN-CONTAINING PROTEIN 1; LACC1","url":"https://www.omim.org/entry/613409"},{"mim_id":"613407","title":"LEPROSY, SUSCEPTIBILITY TO, 6; LPRS6","url":"https://www.omim.org/entry/613407"},{"mim_id":"109650","title":"BEHCET SYNDROME","url":"https://www.omim.org/entry/109650"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LACC1"},"hgnc":{"alias_symbol":["FLJ38725","FAMIN"],"prev_symbol":["C13orf31"]},"alphafold":{"accession":"Q8IV20","domains":[{"cath_id":"3.40.50","chopping":"5-49_66-170","consensus_level":"high","plddt":81.58,"start":5,"end":170},{"cath_id":"3.60.140.10","chopping":"175-429","consensus_level":"high","plddt":96.5219,"start":175,"end":429}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV20","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV20-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV20-F1-predicted_aligned_error_v6.png","plddt_mean":88.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LACC1","jax_strain_url":"https://www.jax.org/strain/search?query=LACC1"},"sequence":{"accession":"Q8IV20","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IV20.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IV20/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV20"}},"corpus_meta":[{"pmid":"27478939","id":"PMC_27478939","title":"C13orf31 (FAMIN) is a central regulator of immunometabolic function.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27478939","citation_count":140,"is_preprint":false},{"pmid":"25220867","id":"PMC_25220867","title":"Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis.","date":"2015","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/25220867","citation_count":101,"is_preprint":false},{"pmid":"31978345","id":"PMC_31978345","title":"FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.","date":"2020","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/31978345","citation_count":65,"is_preprint":false},{"pmid":"28593945","id":"PMC_28593945","title":"Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28593945","citation_count":63,"is_preprint":false},{"pmid":"35978195","id":"PMC_35978195","title":"LACC1 bridges NOS2 and polyamine metabolism in inflammatory macrophages.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35978195","citation_count":56,"is_preprint":false},{"pmid":"25367361","id":"PMC_25367361","title":"NOD2 and CCDC122-LACC1 genes are associated with leprosy susceptibility in Brazilians.","date":"2014","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25367361","citation_count":46,"is_preprint":false},{"pmid":"29706348","id":"PMC_29706348","title":"Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29706348","citation_count":39,"is_preprint":false},{"pmid":"33606008","id":"PMC_33606008","title":"LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33606008","citation_count":35,"is_preprint":false},{"pmid":"37976692","id":"PMC_37976692","title":"Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway.","date":"2023","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37976692","citation_count":30,"is_preprint":false},{"pmid":"27881174","id":"PMC_27881174","title":"Juvenile arthritis caused by a novel FAMIN (LACC1) mutation in two children with systemic and extended oligoarticular course.","date":"2016","source":"Pediatric rheumatology online journal","url":"https://pubmed.ncbi.nlm.nih.gov/27881174","citation_count":30,"is_preprint":false},{"pmid":"27098602","id":"PMC_27098602","title":"LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis.","date":"2016","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/27098602","citation_count":29,"is_preprint":false},{"pmid":"29538758","id":"PMC_29538758","title":"Using genes to triangulate the pathophysiology of granulomatous autoinflammatory disease: NOD2, PLCG2 and LACC1.","date":"2018","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29538758","citation_count":26,"is_preprint":false},{"pmid":"31875558","id":"PMC_31875558","title":"LACC1 Required for NOD2-Induced, ER Stress-Mediated Innate Immune Outcomes in Human Macrophages and LACC1 Risk Variants Modulate These Outcomes.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31875558","citation_count":26,"is_preprint":false},{"pmid":"27959965","id":"PMC_27959965","title":"Functional Analyses of the Crohn's Disease Risk Gene LACC1.","date":"2016","source":"PloS 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dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26235265","citation_count":16,"is_preprint":false},{"pmid":"33718577","id":"PMC_33718577","title":"New or vanishing frontiers: LACC1-associated juvenile arthritis.","date":"2020","source":"International journal of pediatrics & adolescent medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33718577","citation_count":11,"is_preprint":false},{"pmid":"37186377","id":"PMC_37186377","title":"Clinical characteristics and genotype analysis of a Chinese patient with juvenile arthritis due to novel LACC1 frameshift mutation and literature review.","date":"2023","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37186377","citation_count":7,"is_preprint":false},{"pmid":"33493343","id":"PMC_33493343","title":"A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.","date":"2021","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33493343","citation_count":7,"is_preprint":false},{"pmid":"40186254","id":"PMC_40186254","title":"Lacc1-engineered extracellular vesicles reprogram mitochondrial metabolism to alleviate inflammation and cartilage degeneration in TMJ osteoarthritis.","date":"2025","source":"Journal of nanobiotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/40186254","citation_count":5,"is_preprint":false},{"pmid":"25227103","id":"PMC_25227103","title":"Study on the construction of recombined plasmid pMG36e-lacc1 and the electroporation of Lactobacillus buchneri.","date":"2014","source":"Bio-medical materials and engineering","url":"https://pubmed.ncbi.nlm.nih.gov/25227103","citation_count":5,"is_preprint":false},{"pmid":"37366569","id":"PMC_37366569","title":"LACC1: A critical involvement in macrophage immunometabolism.","date":"2023","source":"Cell biology 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Asp220Asn) in familial juvenile arthritis: identification and functional analysis.","date":"2025","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40713900","citation_count":4,"is_preprint":false},{"pmid":"36610229","id":"PMC_36610229","title":"MicroRNA-211-5p in extracellular vesicles derived from BMSCs facilitates the repair of rat frozen shoulder via regulating KDM2B/LACC1 axis.","date":"2022","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/36610229","citation_count":4,"is_preprint":false},{"pmid":"38944365","id":"PMC_38944365","title":"LACC1 deficiency leading to juvenile arthritis and anemia.","date":"2024","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/38944365","citation_count":3,"is_preprint":false},{"pmid":"38064597","id":"PMC_38064597","title":"LACC1 Promoted Nerve Injury in an Anesthesia-Induced Cognitive Disorder Model via RIP2 Expression through ROS-NOD2 Induction.","date":"2024","source":"Alternative therapies in health and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38064597","citation_count":3,"is_preprint":false},{"pmid":"40335000","id":"PMC_40335000","title":"NOD2 promotes sepsis-induced neuroinflammation by increasing brain endoplasmic reticulum stress mediated by LACC1.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40335000","citation_count":2,"is_preprint":false},{"pmid":"37921883","id":"PMC_37921883","title":"[Monogenic variants in Laccase domain-containing 1 (LACC1) as the cause of juvenile arthritis].","date":"2023","source":"Zeitschrift fur Rheumatologie","url":"https://pubmed.ncbi.nlm.nih.gov/37921883","citation_count":1,"is_preprint":false},{"pmid":"41376621","id":"PMC_41376621","title":"The research progress of LACC1.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41376621","citation_count":0,"is_preprint":false},{"pmid":"41430577","id":"PMC_41430577","title":"CCDC122-LACC1 gene polymorphism is associated with protection against leprosy in a population from Northeastern Brazil: a case-control study.","date":"2025","source":"BMC infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41430577","citation_count":0,"is_preprint":false},{"pmid":"41193588","id":"PMC_41193588","title":"Bone marrow mesenchymal stem cell exosome-derived miR-223 regulated cellular pyroptosis of macrophage in osteomyelitis through regulating LACC1.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41193588","citation_count":0,"is_preprint":false},{"pmid":"41736164","id":"PMC_41736164","title":"Challenges in functional validation and mechanistic interpretation of a novel LACC1 variant in familial juvenile arthritis.","date":"2026","source":"Human genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41736164","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19432,"output_tokens":3447,"usd":0.055001,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11109,"output_tokens":4156,"usd":0.079723,"stage2_stop_reason":"end_turn"},"total_usd":0.134724,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"FAMIN (LACC1) forms a complex with fatty acid synthase (FASN) on peroxisomes and promotes flux through de novo lipogenesis to drive fatty-acid oxidation (FAO) and glycolysis, thereby regenerating ATP. FAMIN-dependent FAO controls inflammasome activation, mitochondrial and NADPH-oxidase-dependent ROS production, and bactericidal activity of macrophages. Disease-risk variants p.I254V and p.C284R result in diminished and loss of function, respectively.\",\n      \"method\": \"Co-immunoprecipitation/complex formation, metabolic flux assays, macrophage knockout/knockdown with functional readouts (ROS, inflammasome activation, bacterial killing, endotoxin shock model)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex formation, multiple orthogonal metabolic assays, genetic loss-of-function with defined cellular and in vivo phenotypes, disease-variant functional characterization\",\n      \"pmids\": [\"27478939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FAMIN (LACC1) is a multifunctional purine enzyme: it phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate (a eukaryotically unprecedented activity), and additionally has adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activities. In macrophages, FAMIN enables a purine nucleotide cycle (PNC) between adenosine and IMP/adenylosuccinate that consumes aspartate and releases fumarate, synchronizing mitochondrial activity with glycolysis through fatty acid oxidation and ATP-citrate lyase.\",\n      \"method\": \"Unbiased liquid chromatography-mass spectrometry enzymatic activity screen, in vitro enzymatic assays with purified protein, macrophage metabolic studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution with LC-MS activity screen, multiple enzymatic activities characterized, mechanistic pathway validated in macrophages\",\n      \"pmids\": [\"31978345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LACC1 converts L-citrulline to L-ornithine and isocyanic acid in both mice and humans, acting as a biochemical bridge between proinflammatory NOS2 and polyamine metabolism via ornithine decarboxylase 1 (ODC1). Genetic epistasis in mouse models and bone marrow-derived macrophages infected with Salmonella Typhimurium confirmed that LACC1 phenotypes require upstream NOS2 and downstream ODC1; chemical complementation of Lacc1-/- macrophages with L-ornithine significantly restored wild-type activities.\",\n      \"method\": \"Biochemical enzyme activity assays, Lacc1-/- mouse models, genetic epistasis (NOS2 and ODC1 double mutants), chemical complementation with L-ornithine, Salmonella infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic activity established biochemically, validated by genetic epistasis in vivo and in vitro with chemical complementation, multiple orthogonal approaches\",\n      \"pmids\": [\"35978195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2-signalling complex and is critical for optimal NOD2-induced signalling, mitochondrial ROS production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A and amplifies pattern recognition receptor-induced SDH activity. Disease-risk variant Val254 and mutations of nearby histidines 249/250 reduce PRR-induced outcomes. LACC1 is expressed in both cytoplasm and mitochondria.\",\n      \"method\": \"Co-immunoprecipitation (LACC1 with NOD2 complex and SDH subunit A), siRNA knockdown, transfection of disease-risk variants, mitochondrial ROS measurement, bacterial clearance assay, immunofluorescence localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with NOD2 complex and SDH-A, knockdown with defined phenotypic readouts, disease-variant functional comparison, subcellular localization with functional consequence\",\n      \"pmids\": [\"28593945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Upon NOD2 stimulation, LACC1 localizes to the endoplasmic reticulum and forms a complex with ER-stress sensors. All three ER-stress branches (PERK, IRE1α, ATF6) are required for NOD2-induced signalling, cytokines, and antimicrobial pathways in human macrophages. LACC1 and its localization to the ER are required for these outcomes. Disease-risk variants Val254 and Arg284 show reduced NOD2-induced ER stress-associated outcomes that are restored by rescuing ER stress.\",\n      \"method\": \"Immunofluorescence localization, co-immunoprecipitation of LACC1 with ER-stress sensors, siRNA knockdown of PERK/IRE1α/ATF6, transfection of disease-risk variants, macrophage functional assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with ER stress sensors, defined ER localization with functional consequence, disease-variant functional rescue experiment, multiple ER stress branch knockdowns\",\n      \"pmids\": [\"31875558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Lacc1-/- mice, myeloid-specific deletion of LACC1 (Lacc1Δmye) recapitulates whole-body knockout phenotypes: increased intestinal bacterial burden and altered T-cell cytokine profiles (increased Th2, decreased Th1/Th17). In macrophages, LACC1 is required for TLR-induced bacterial uptake (dependent on PDK1), and for MAPK- and NF-κB-dependent induction of ROS, reactive nitrogen species, and autophagy. In dendritic cells, LACC1 is required for Th1/Th17 cytokine induction during CD4+ T cell co-culture.\",\n      \"method\": \"Conditional knockout mice (Lacc1Δmye), T-cell transfer colitis model, oral Salmonella Typhimurium infection, DSS colitis, bone marrow-derived macrophage functional assays (ROS, RNS, autophagy, bacterial uptake), cytokine complementation experiments\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in vivo with multiple disease models, defined cellular mechanism (PDK1-dependent uptake, MAPK/NF-κB ROS), myeloid-specific genetic rescue with cytokine complementation\",\n      \"pmids\": [\"32693188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LACC1 is primarily expressed in macrophages upon mTOR signaling. Autophagy-inducing proteins RACK1 and AMPK interact with LACC1 (shown by bimolecular fluorescence complementation and biochemical assays). Autophagy blockade causes LACC1 cleavage and degradation. LACC1 deficiency reduces autophagy flux in primary macrophages and is associated with defects in lipid droplet accumulation and mitochondrial respiration, suggesting LACC1-dependent autophagy fuels macrophage bioenergetic metabolism.\",\n      \"method\": \"Bimolecular fluorescence complementation, co-immunoprecipitation/biochemical assays, siRNA knockdown, autophagy flux assay, lipid droplet staining, mitochondrial respiration measurement, patient-derived macrophages with loss-of-expression mutations\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bimolecular fluorescence complementation plus biochemical assays for RACK1/AMPK interaction, functional autophagy and metabolic readouts in patient macrophages, single lab\",\n      \"pmids\": [\"33606008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAMIN (LACC1) protein localizes exclusively to peroxisomes (with some positivity for organelle endomembrane structures) in macrophage-differentiated THP-1 cells. LACC1 co-expression signatures are enriched for PPAR signaling pathway genes, and PPAR ligands downregulate FAMIN expression in vitro.\",\n      \"method\": \"Immunofluorescence microscopy (subcellular co-localization), siRNA knockdown, gene-set enrichment analysis, PPAR ligand treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunofluorescence localization to peroxisomes confirmed in multiple cell types, PPAR regulation shown by ligand treatment with expression readout, single lab\",\n      \"pmids\": [\"27959965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Lupeol activates PPARα to reduce LACC1 expression, thereby inhibiting NF-κB pathway activation and macrophage pyroptosis in experimental autoimmune myocarditis. This places LACC1 downstream of PPARα and upstream of NF-κB in macrophage inflammatory signaling.\",\n      \"method\": \"Transcriptome sequencing, molecular docking, siRNA knockdown, adenovirus overexpression, western blotting, immunofluorescence in EAM mouse model and BMDMs/THP-1 macrophages\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown and overexpression with NF-κB pathway readouts, in vivo and in vitro corroboration, but single lab and pathway placement is pharmacological\",\n      \"pmids\": [\"37976692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In an in vitro stroke model, inhibition of LACC1 reduces inflammation and ROS-induced oxidative stress by activating AMPK expression and suppressing NLRP3. AMPK inhibition reverses the effects of LACC1 silencing, placing LACC1 upstream of AMPK/NLRP3 in macrophage inflammatory signaling during ischemic injury.\",\n      \"method\": \"siRNA knockdown, AMPK inhibitor treatment, ROS measurement, inflammatory cytokine measurement, mouse stroke model\",\n      \"journal\": \"Acta neurobiologiae experimentalis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with pharmacological rescue, limited mechanistic detail in abstract\",\n      \"pmids\": [\"35833820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NOD2 promotes sepsis-induced neuroinflammation by enhancing ER stress through LACC1 in microglia; LACC1 downregulation partially mitigates these effects, identifying LACC1 as a downstream mediator of NOD2-driven ER stress in the brain.\",\n      \"method\": \"NOD2-/- CRISPR/Cas9 mice, siRNA knockdown of NOD2 and LACC1 in microglia, ER stress inhibitor (4-PBA), CLP sepsis model, western blotting, immunofluorescence, transmission electron microscopy of ER\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and siRNA epistasis in vivo and in vitro, ER stress pharmacological rescue, structural ER visualization, single lab\",\n      \"pmids\": [\"40335000\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LACC1 (FAMIN) is a multifunctional immunometabolic enzyme in macrophages that: (1) phosphorolytically cleaves adenosine and participates in a purine nucleotide cycle linking FAO and glycolysis; (2) converts L-citrulline to L-ornithine, bridging NOS2 and polyamine metabolism; (3) forms complexes with FASN on peroxisomes to drive de novo lipogenesis and FAO; (4) associates with the NOD2 signaling complex and ER stress sensors upon innate immune stimulation to amplify ROS, cytokine, and antimicrobial outputs; and (5) interacts with RACK1 and AMPK to support autophagy flux and macrophage bioenergetics — with disease-risk variants (I254V, C284R) causing diminished or lost function across these activities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LACC1 (FAMIN) is a multifunctional immunometabolic enzyme that couples central metabolism to innate immune effector functions in macrophages [#0, #1]. Biochemically, it is a promiscuous purine enzyme that phosphorolytically cleaves adenosine and carries adenosine deaminase, purine nucleoside phosphorylase, and methylthioadenosine phosphorylase activities, enabling a purine nucleotide cycle that consumes aspartate and releases fumarate to synchronize mitochondrial activity with glycolysis through fatty-acid oxidation [#1]; it additionally converts L-citrulline to L-ornithine, bridging NOS2-driven inflammation to ODC1-dependent polyamine metabolism [#2]. Through complex formation with fatty acid synthase on peroxisomes, LACC1 promotes de novo lipogenesis that fuels FAO and ATP regeneration, thereby controlling inflammasome activation, mitochondrial and NADPH-oxidase ROS, and bactericidal capacity [#0, #7]. In innate immune signaling, LACC1 is recruited to the NOD2-signalling complex and constitutively associates with succinate dehydrogenase subunit A to amplify PRR-induced SDH activity, mitochondrial ROS, cytokine secretion and bacterial clearance [#3], and upon NOD2 stimulation relocalizes to the ER where it engages the PERK/IRE1\\u03b1/ATF6 stress sensors required for antimicrobial output [#4]. LACC1 expression is induced via mTOR and its turnover is autophagy-dependent, with RACK1 and AMPK as interaction partners supporting autophagy flux and macrophage bioenergetics [#6]. Myeloid LACC1 is required in vivo for control of intestinal bacterial burden and for balanced Th1/Th17 versus Th2 responses [#5]. Disease-risk variants p.I254V and p.C284R cause diminished or lost function across these activities [#0, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the first molecular function of LACC1/FAMIN by showing it acts as a metabolic hub on peroxisomes that links lipid metabolism to macrophage antimicrobial effector functions, explaining how a disease-risk locus shapes immunity.\",\n      \"evidence\": \"Co-IP with FASN, metabolic flux assays, and macrophage knockout/knockdown with ROS, inflammasome, bacterial-killing and endotoxin-shock readouts; immunofluorescence localization to peroxisomes\",\n      \"pmids\": [\"27478939\", \"27959965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct enzymatic activity of LACC1 itself was not defined\", \"How the FASN complex is assembled or regulated was not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected LACC1 to a defined innate-immune receptor pathway, showing it physically joins the NOD2 signalling complex and boosts mitochondrial respiratory output to amplify antimicrobial responses.\",\n      \"evidence\": \"Reciprocal Co-IP of LACC1 with the NOD2 complex and SDH subunit A, siRNA knockdown, disease-variant transfection, mitochondrial ROS and bacterial clearance assays in human macrophages\",\n      \"pmids\": [\"28593945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LACC1 directly modifies SDH or acts indirectly was not resolved\", \"Mechanism of recruitment to the NOD2 complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added a subcellular dimension to NOD2 signalling by showing stimulation drives LACC1 to the ER where it cooperates with all three unfolded-protein-response branches to enable antimicrobial output.\",\n      \"evidence\": \"Immunofluorescence localization, Co-IP of LACC1 with ER-stress sensors, siRNA knockdown of PERK/IRE1\\u03b1/ATF6, disease-variant rescue by ER-stress restoration in macrophages\",\n      \"pmids\": [\"31875558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LACC1 traffics between peroxisomes, mitochondria and ER was not defined\", \"Direct biochemical link between LACC1 enzymatic activity and ER-stress sensor engagement unestablished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the long-sought catalytic identity of LACC1 as a multifunctional purine enzyme, revealing an unprecedented adenosine phosphorolysis activity that powers a purine nucleotide cycle coordinating mitochondrial and glycolytic metabolism.\",\n      \"evidence\": \"Unbiased LC-MS enzymatic activity screen with purified protein, in vitro reconstitution of multiple activities, and macrophage metabolic studies\",\n      \"pmids\": [\"31978345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for the multiple activities reported\", \"Relative physiological contribution of each catalytic activity not weighted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated the cell-autonomous, myeloid requirement for LACC1 in vivo, linking its loss to defective bacterial handling and skewed adaptive T-cell responses through PDK1-dependent uptake and MAPK/NF-\\u03baB-driven effector programs.\",\n      \"evidence\": \"Lacc1\\u0394mye conditional knockout mice, T-cell transfer and DSS colitis, oral Salmonella infection, and BMDM assays for ROS, RNS, autophagy and bacterial uptake with cytokine complementation\",\n      \"pmids\": [\"32693188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enzymatic activities identified in vitro drive each in vivo phenotype not directly tested\", \"Molecular link between LACC1 and PDK1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed LACC1 in the autophagy network, identifying RACK1 and AMPK as partners and showing autophagy controls LACC1 stability while LACC1-supported autophagy fuels macrophage bioenergetics.\",\n      \"evidence\": \"Bimolecular fluorescence complementation and biochemical assays for RACK1/AMPK interaction, autophagy-flux, lipid-droplet and mitochondrial-respiration readouts in patient-derived macrophages\",\n      \"pmids\": [\"33606008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactions shown in a single lab without reciprocal validation in independent systems\", \"Directionality between autophagy regulation and LACC1 enzymatic function unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a second discrete enzymatic activity, citrulline-to-ornithine conversion, biochemically and genetically positioning LACC1 between NOS2 and polyamine biosynthesis as the basis of its antimicrobial phenotypes.\",\n      \"evidence\": \"Biochemical enzyme assays, Lacc1-/- mice, NOS2/ODC1 genetic epistasis, L-ornithine chemical complementation, and Salmonella infection\",\n      \"pmids\": [\"35978195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this activity integrates with the purine nucleotide cycle in the same enzyme not addressed\", \"Isocyanic acid fate and downstream signaling not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended LACC1's inflammatory role to ischemic injury, placing it upstream of AMPK/NLRP3 in macrophage oxidative-stress and inflammatory signaling.\",\n      \"evidence\": \"siRNA knockdown with AMPK-inhibitor rescue, ROS and cytokine measurement in an in vitro stroke model\",\n      \"pmids\": [\"35833820\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab with limited mechanistic detail and no direct interaction data\", \"Apparent pro-inflammatory directionality conflicts with loss-of-function phenotypes elsewhere and is not reconciled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Positioned LACC1 transcriptionally downstream of PPAR\\u03b1 and upstream of NF-\\u03baB in macrophage pyroptosis, indicating nuclear-receptor control of LACC1 expression as an inflammatory rheostat.\",\n      \"evidence\": \"Transcriptome sequencing, siRNA knockdown, adenoviral overexpression and western blotting in an EAM mouse model and macrophage lines\",\n      \"pmids\": [\"37976692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway placement is pharmacological rather than direct\", \"Whether PPAR\\u03b1 regulates LACC1 promoter directly not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the NOD2-LACC1-ER-stress axis beyond macrophages to microglia, showing LACC1 mediates NOD2-driven neuroinflammation via the ER in sepsis.\",\n      \"evidence\": \"NOD2 CRISPR knockout mice, siRNA epistasis of NOD2 and LACC1, ER-stress inhibition, CLP sepsis model with ER ultrastructure imaging\",\n      \"pmids\": [\"40335000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between LACC1 and ER-stress induction in microglia not established\", \"Single lab; relationship to LACC1 enzymatic activities not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LACC1's distinct enzymatic activities (purine phosphorolysis, citrulline conversion) are mechanistically unified within one protein and how they map onto its peroxisomal, mitochondrial and ER localizations to produce each immune phenotype remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model integrating the multiple catalytic activities\", \"Mechanism of stimulus-dependent relocalization across organelles unknown\", \"Causal chain from a single catalytic activity to each in vivo immune phenotype not isolated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"NOD2 signalling complex\", \"LACC1-FASN complex\"],\n    \"partners\": [\"FASN\", \"NOD2\", \"SDHA\", \"RACK1\", \"AMPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}