{"gene":"LACTB","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2009,"finding":"LACTB is localized in the mitochondrial intermembrane space, where it polymerizes into stable filaments extending more than a hundred nanometers, promoting intramitochondrial membrane organization and micro-compartmentalization.","method":"Subcellular fractionation, electron microscopy, direct localization experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — direct localization with structural characterization, replicated in subsequent structural studies","pmids":["19858488"],"is_preprint":false},{"year":2001,"finding":"LACTB encodes a mammalian serine beta-lactamase-like protein with a conserved active-site serine motif related to C-class beta-lactamases, and contains a predicted amino-terminal transmembrane domain; it is the first reported vertebrate member of this microbial peptidase family.","method":"Sequence cloning, database searching, Northern blot, genomic mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 — original cloning and characterization with multiple methods, foundational study","pmids":["11707067"],"is_preprint":false},{"year":2005,"finding":"Mouse LACTB can be expressed as an N-terminal GST fusion protein in E. coli and adopts a well-defined secondary structure (alpha-helices, beta-sheets, turns) as determined by FTIR spectroscopy, confirming it is a properly folded serine protease.","method":"Recombinant protein expression, glutathione-agarose affinity chromatography, MALDI-TOF mass spectrometry, FTIR spectroscopy","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution of folded protein, single study","pmids":["16202624"],"is_preprint":false},{"year":2017,"finding":"LACTB potently inhibits breast cancer cell proliferation by altering mitochondrial lipid metabolism, at least in part through reduction of mitochondrial phosphatidylserine decarboxylase (PISD) levels, thereby decreasing mitochondrial phosphatidylethanolamine synthesis and promoting cancer cell differentiation.","method":"In vitro and in vivo mouse/human studies, lipidomic analysis, loss-of-function and gain-of-function experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in vitro and in vivo, highly cited foundational study","pmids":["28329758"],"is_preprint":false},{"year":2018,"finding":"LACTB directly binds to the C terminus of p53 and inhibits p53 ubiquitination and degradation by preventing MDM2 from interacting with p53, thereby stabilizing p53 protein; this tumor suppressive activity requires wild-type p53.","method":"Co-immunoprecipitation, CRISPR/Cas9 knockout, ectopic overexpression, in vitro and in vivo assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP with functional validation, single lab","pmids":["29899406"],"is_preprint":false},{"year":2020,"finding":"LACTB regulates PIK3R3 to modulate PI3K levels, promoting autophagy and inhibiting EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer cells.","method":"Immunoprecipitation, RNA-seq, Western blotting, transmission electron microscopy, xenograft model","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with pathway analysis, single lab","pmids":["32636680"],"is_preprint":false},{"year":2021,"finding":"LACTB directly binds to PP1A and attenuates the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation (increased phospho-YAP Ser127), preventing nuclear translocation of YAP in a LATS1-independent manner to suppress melanoma progression.","method":"Co-immunoprecipitation, overexpression, phosphorylation-defective YAP mutants, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct binding shown by Co-IP with mechanistic mutant validation, single lab","pmids":["33675985"],"is_preprint":false},{"year":2022,"finding":"CryoEM structures of human LACTB filaments (wild-type, middle-region deletion mutant, and inhibitor Z-AAD-CMK complex) at 2.8–3.1 Å resolution revealed that three interfaces mediate filament assembly, that higher-order helical structure facilitates cleavage activity, and that LACTB cleaves peptide bonds adjacent to aspartic acid residues.","method":"Cryo-electron microscopy structure determination, activity assays, deletion mutagenesis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution cryo-EM structure with mutagenesis and enzymatic validation","pmids":["35247327"],"is_preprint":false},{"year":2022,"finding":"Human LACTB self-assembles into micron-scale filaments; cryoEM structure defines the assembly mechanism; highly ordered filament bundles stabilize the active state of the enzyme; mutations at filament-forming interfaces reduce enzyme activity; and LACTB filaments can bind lipid membranes.","method":"Cryo-electron microscopy, site-directed mutagenesis, enzyme activity assays, lipid membrane binding assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 — independent cryo-EM structural study with mutagenesis and activity assays, orthogonal confirmation of Zhang et al. 2022","pmids":["36534696"],"is_preprint":false},{"year":2022,"finding":"LACTB expression leads to G1-phase cell cycle arrest and increased mitochondrial reactive oxygen species, which activates an intrinsic caspase-independent cell death pathway in breast cancer cells.","method":"Protein array, flow cytometry, cell proliferation assays, immunofluorescence, in vivo experiments, western blot","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in one study, single lab","pmids":["36282364"],"is_preprint":false},{"year":2022,"finding":"LACTB suppresses epithelial ovarian cancer by downregulating the Snail2/Slug transcription factor, leading to inhibition of the EMT program and promotion of cancer cell differentiation.","method":"In vitro, in vivo, and 3D culture experiments with overexpression and loss-of-function","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple experimental systems, pathway placed downstream of Slug, single lab","pmids":["36375842"],"is_preprint":false},{"year":2023,"finding":"PCBP1 directly binds to LACTB mRNA (validated by RNA pull-down and RNA immunoprecipitation) and promotes its degradation; LACTB upregulation promotes erastin-induced ferroptosis and mitochondrial dysfunction through the LACTB/PISD axis.","method":"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, CCK-8, flow cytometry, JC-1 staining, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-binding validated by multiple orthogonal RNA methods, functional rescue shown, single lab","pmids":["37157950"],"is_preprint":false},{"year":2024,"finding":"OXCT1 functions as a lysine succinyltransferase (requiring residue G424 for this activity) and succinylates LACTB at K284; succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, promoting hepatocellular carcinoma progression.","method":"In vitro succinyltransferase assay, mass spectrometry identification of succinylation sites, mutagenesis, western blotting, functional metabolic assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with site-specific mutagenesis and mass spectrometry validation","pmids":["38176415"],"is_preprint":false},{"year":2023,"finding":"In regulatory dendritic cells, the metabolic enzyme Suclg2 prevents succinylation of Lactb at lysine 288, thereby suppressing Lactb-mediated activation of NF-κB signaling and maintaining tolerogenic DC function.","method":"Metabolomic, transcriptomic, and functional investigations; Suclg2 interference experiments; NF-κB signaling assays","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2–3 — multi-omic approach with functional validation, succinylation site identified, single lab","pmids":["37216870"],"is_preprint":false},{"year":2024,"finding":"LACTB is a mitochondrial protease that cleaves and activates phospholipase A2 group VI (PLA2G6); together they convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine, thereby regulating mitochondrial function and ferroptosis. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished LACTB's protective function.","method":"Mouse knockout and tubule-specific overexpression, genetic epistasis (double-KO), lipidomic studies in mouse and human, in vivo kidney injury models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — genetic epistasis with substrate identification and lipidomics, multiple orthogonal approaches","pmids":["39561766"],"is_preprint":false},{"year":2024,"finding":"LACTB blocks HSPA8 transcription in a p53-dependent manner, resulting in elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signaling, thereby triggering ferroptosis and suppressing liver cancer progression.","method":"LACTB knockout and ectopic overexpression, western blot, in vivo xenograft, p53-binding site mutation experiments","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissected with p53-binding site mutant validation, single lab","pmids":["39047638"],"is_preprint":false},{"year":2025,"finding":"LACTB is required for apoptosis-induced inner mitochondrial membrane remodeling, which promotes cytochrome c release; purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes; LACTB does not affect BAX or Drp1 recruitment and acts independently of OPA1 processing.","method":"LACTB knockdown/overexpression, cytochrome c release assays, purified protein membrane remodeling assay with cardiolipin-enriched nanotubes, apoptosis flow cytometry","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with purified protein and membrane nanotubes combined with cellular loss/gain-of-function and mechanistic controls","pmids":["41223265"],"is_preprint":false},{"year":2025,"finding":"LACTB exhibits D-aspartyl endopeptidase (DAEP) activity — it cleaves proteins at the carboxy-terminus of D-aspartic acid residues, including a peptide derived from amyloid β1-10 containing D-Asp at position 7, making it the first identified mammalian protein with this activity.","method":"In vitro DAEP activity assay with peptide substrates, structural comparison with bacterial paenidase","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic characterization with defined substrates","pmids":["40286848"],"is_preprint":false},{"year":2025,"finding":"LACTB destabilizes OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion; upstream, acetylated KLF5 (at K369) acts as a transcriptional repressor of LACTB.","method":"CRISPR/Cas9 KLF5 knockout, acetylation-mimic and deacetylation-mimic KLF5 mutants, protein-protein and protein-DNA interaction assays, xenograft model, western blot","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic mutant validation, single lab, pathway positioning via epistasis","pmids":["41213373"],"is_preprint":false},{"year":2026,"finding":"LACTB interacts with carnitine palmitoyltransferase 2 (CPT2) and promotes its ubiquitin-mediated degradation, thereby impairing fatty acid oxidation and exacerbating hepatic steatosis in metabolic dysfunction-associated steatotic liver disease.","method":"Co-immunoprecipitation, LACTB overexpression and knockdown in vivo and in vitro, HFD mouse model, western blot","journal":"Diabetes, obesity & metabolism","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with in vivo functional validation, single lab","pmids":["41527692"],"is_preprint":false},{"year":2024,"finding":"LACTB double-mutant (M5L+R469K, from SNPs rs34317102 and rs2729835 found in osteosarcoma) reduces wild-type p53 stability by enhancing PSMB7 catalytic activity while also protecting mutant p53R156P from lysosomal degradation, conferring oncogene-like functions; clavulanate potassium (a beta-lactamase inhibitor) binds and blocks LACTBM5L+R469K.","method":"Mutagenesis, PSMB7 activity assays, protein stability assays, in vitro and in vivo overexpression, drug binding/inhibition assay","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis combined with mechanistic functional assays, single lab","pmids":["39324579"],"is_preprint":false}],"current_model":"LACTB is a mitochondrial intermembrane space serine protease that polymerizes into filaments (with filament assembly enhancing its catalytic activity) and functions as a tumor suppressor by: (1) altering mitochondrial lipid metabolism through reduction of PISD and activation of PLA2G6-mediated phospholipid remodeling; (2) remodeling cardiolipin-enriched inner mitochondrial membranes to promote cytochrome c release and apoptosis independently of OPA1 and BAX/Drp1; (3) cleaving peptides adjacent to D-aspartate residues (D-aspartyl endopeptidase activity); (4) stabilizing p53 by blocking MDM2 binding; (5) inactivating YAP by attenuating PP1A-mediated dephosphorylation; and (6) being post-translationally regulated by OXCT1-mediated succinylation at K284 (which inhibits its proteolytic activity) and by Suclg2-mediated suppression of succinylation."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of LACTB as the first vertebrate member of the bacterial penicillin-binding protein/beta-lactamase superfamily established that a conserved active-site serine protease domain persists in mammalian mitochondria.","evidence":"Sequence cloning, Northern blot, and genomic mapping of the human and mouse LACTB gene","pmids":["11707067"],"confidence":"High","gaps":["No enzymatic activity demonstrated","Subcellular localization not experimentally confirmed","No substrate identified"]},{"year":2009,"claim":"Direct localization of LACTB to the mitochondrial intermembrane space and visualization of its polymerization into extended filaments resolved where the protease operates and revealed an unusual structural organization suggesting a role in intramitochondrial membrane compartmentalization.","evidence":"Subcellular fractionation and electron microscopy in mammalian cells","pmids":["19858488"],"confidence":"High","gaps":["Filament function and relationship to catalysis unknown","No substrates identified","No physiological phenotype from loss-of-function"]},{"year":2017,"claim":"The discovery that LACTB inhibits breast cancer proliferation through reduction of PISD and consequent alteration of mitochondrial phospholipid composition established LACTB as a tumor suppressor acting via lipid metabolism.","evidence":"Gain- and loss-of-function in vitro and in vivo with lipidomic profiling in breast cancer models","pmids":["28329758"],"confidence":"High","gaps":["Whether PISD is a direct proteolytic substrate unknown","Mechanism of cancer cell differentiation downstream of lipid changes unresolved","Generalizability to non-breast cancers not established"]},{"year":2018,"claim":"Demonstration that LACTB stabilizes p53 by physically blocking MDM2 binding revealed a second, non-lipid-mediated tumor suppressive mechanism and showed that LACTB's anti-cancer activity requires wild-type p53.","evidence":"Reciprocal co-immunoprecipitation, ubiquitination assays, CRISPR knockout, and xenograft models","pmids":["29899406"],"confidence":"Medium","gaps":["Single-lab finding awaiting independent replication","Whether p53 stabilization occurs in the mitochondrial compartment or cytosol not defined","Relationship between protease activity and p53 binding unclear"]},{"year":2021,"claim":"Identification of PP1A as a direct LACTB-binding partner whose interaction with YAP is attenuated by LACTB demonstrated a LATS1-independent mechanism for Hippo pathway regulation in melanoma suppression.","evidence":"Co-immunoprecipitation with phospho-YAP mutant analysis and in vivo xenograft","pmids":["33675985"],"confidence":"Medium","gaps":["Single-lab study","Whether LACTB's protease activity is required for PP1A sequestration untested","Compartment where LACTB–PP1A interaction occurs not resolved"]},{"year":2022,"claim":"Two independent cryo-EM structures at near-atomic resolution revealed that three inter-subunit interfaces drive filament assembly, that higher-order filament bundling stabilizes the active conformation, and that LACTB cleaves peptide bonds adjacent to aspartate residues—linking polymer architecture to enzymatic function.","evidence":"Cryo-EM at 2.8–3.1 Å with site-directed mutagenesis and in vitro activity assays from two independent labs","pmids":["35247327","36534696"],"confidence":"High","gaps":["Endogenous protein substrates in mitochondria not identified from structural work alone","Filament dynamics and regulation in vivo unknown","Whether lipid-membrane binding modulates activity not quantitatively characterized"]},{"year":2022,"claim":"LACTB's tumor suppressive functions were extended to epithelial ovarian cancer (via Snail2/Slug downregulation and EMT inhibition) and breast cancer (via ROS-driven caspase-independent cell death and G1 arrest), broadening the range of cancers and pathways involved.","evidence":"Overexpression/loss-of-function in multiple cancer cell lines, 3D culture, protein array, flow cytometry, and in vivo models","pmids":["36375842","36282364"],"confidence":"Medium","gaps":["Direct proteolytic link to Slug downregulation not shown","Caspase-independent death mechanism not fully defined","Each study from a single lab"]},{"year":2023,"claim":"Discovery that succinylation at K288 (mouse)/K284 (human) by OXCT1 inhibits LACTB proteolytic activity, and that Suclg2 opposes this modification, established a post-translational regulatory switch linking TCA cycle metabolism to LACTB function.","evidence":"In vitro succinyltransferase assay with mass spectrometry (OXCT1 study); multi-omic profiling with Suclg2 interference in dendritic cells","pmids":["38176415","37216870"],"confidence":"High","gaps":["How succinylation structurally disrupts the active site or filament assembly not determined","Relative contributions of OXCT1 vs. non-enzymatic succinylation in vivo unknown","Whether other acyl modifications regulate LACTB untested"]},{"year":2024,"claim":"Identification of PLA2G6 as a direct LACTB substrate whose cleavage activates phospholipid remodeling (oxidized PE → lyso-PE) provided the first genetically validated proteolytic substrate and linked LACTB to ferroptosis protection in kidney injury.","evidence":"Genetic epistasis with tubule-specific LACTB overexpression and PLA2G6 knockout mice, lipidomics in mouse and human tissue","pmids":["39561766"],"confidence":"High","gaps":["Cleavage site on PLA2G6 not mapped","Whether PLA2G6 activation accounts for the PISD reduction phenotype unknown","Relevance to non-renal tissues not tested"]},{"year":2025,"claim":"Biochemical demonstration that LACTB possesses D-aspartyl endopeptidase activity—cleaving after D-aspartate residues including in amyloid β peptides—identified LACTB as the first mammalian enzyme with this specificity, suggesting roles in D-amino acid-containing peptide clearance.","evidence":"In vitro DAEP activity assay with synthetic peptide substrates and structural comparison to bacterial paenidase","pmids":["40286848"],"confidence":"High","gaps":["Physiological D-Asp-containing substrates in mitochondria not identified","Whether D-aspartyl endopeptidase activity accounts for PLA2G6 cleavage untested","In vivo relevance of amyloid β cleavage not established"]},{"year":2025,"claim":"Reconstitution showed that purified LACTB selectively binds and remodels cardiolipin-enriched membrane nanotubes to promote cytochrome c release during apoptosis, independent of BAX, Drp1, and OPA1, establishing a direct membrane-remodeling mechanism in the intrinsic apoptosis pathway.","evidence":"Purified protein with cardiolipin-enriched lipid nanotubes, cytochrome c release assays, knockdown/overexpression with apoptosis quantification","pmids":["41223265"],"confidence":"High","gaps":["Whether proteolytic activity is required for membrane remodeling not dissected","How LACTB filaments interact with cristae junctions in situ unknown","Relationship to LACTB's anti-tumor function via this mechanism not tested"]},{"year":null,"claim":"A unified model integrating LACTB's D-aspartyl endopeptidase activity, filament-dependent membrane remodeling, lipid metabolic control, and diverse signaling outputs (p53, YAP, NF-κB) into a coherent mechanistic framework is still missing—particularly the identity and hierarchy of its endogenous mitochondrial substrates.","evidence":"","pmids":[],"confidence":"Low","gaps":["Comprehensive substrate profiling (degradomics) of LACTB has not been performed","Structural basis for how succinylation inhibits activity not determined","Whether the tumor-suppressive and apoptotic functions are separable from protease activity remains unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,8,12,14,17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,16]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,7,8]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,3,9,16]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,12,14,19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,6,10,15,20]}],"complexes":[],"partners":["PISD","PLA2G6","TP53","MDM2","PPP1CA","OXCT1","CPT2","OMA1"],"other_free_text":[]},"mechanistic_narrative":"LACTB is a mitochondrial intermembrane space serine protease of the penicillin-binding protein family that self-assembles into filaments whose higher-order structure stabilizes the catalytically active state and enables membrane binding, with D-aspartyl endopeptidase specificity representing the first such activity identified in mammals [PMID:19858488, PMID:35247327, PMID:36534696, PMID:40286848]. LACTB functions as a tumor suppressor across multiple cancer types by altering mitochondrial lipid metabolism—reducing PISD to lower phosphatidylethanolamine levels and cleaving/activating PLA2G6 to remodel oxidized phospholipids—and by stabilizing p53 through blocking MDM2 interaction, thereby promoting differentiation, ferroptosis, and apoptosis [PMID:28329758, PMID:39561766, PMID:29899406, PMID:36282364]. During apoptosis, LACTB binds and remodels cardiolipin-enriched inner mitochondrial membranes to facilitate cytochrome c release independently of BAX, Drp1, and OPA1, and it destabilizes OMA1 to modulate OPA1-mediated fusion [PMID:41223265, PMID:41213373]. Its proteolytic activity is negatively regulated by OXCT1-mediated succinylation at K284, linking metabolic signaling to LACTB function [PMID:38176415]."},"prefetch_data":{"uniprot":{"accession":"P83111","full_name":"Serine beta-lactamase-like protein LACTB, mitochondrial","aliases":[],"length_aa":547,"mass_kda":60.7,"function":"Mitochondrial serine protease that acts as a regulator of mitochondrial lipid metabolism (PubMed:28329758). Acts by decreasing protein levels of PISD, a mitochondrial enzyme that converts phosphatidylserine (PtdSer) to phosphatidylethanolamine (PtdEtn), thereby affecting mitochondrial lipid metabolism (PubMed:28329758). It is unclear whether it acts directly by mediating proteolysis of PISD or by mediating proteolysis of another lipid metabolism protein (PubMed:28329758). Acts as a tumor suppressor that has the ability to inhibit proliferation of multiple types of breast cancer cells: probably by promoting decreased levels of PISD, thereby affecting mitochondrial lipid metabolism (PubMed:28329758)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P83111/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LACTB","classification":"Not Classified","n_dependent_lines":54,"n_total_lines":1208,"dependency_fraction":0.04470198675496689},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LACTB","total_profiled":1310},"omim":[{"mim_id":"615623","title":"CYTOCHROME C OXIDASE ASSEMBLY FACTOR 7; COA7","url":"https://www.omim.org/entry/615623"},{"mim_id":"612770","title":"PHOSPHATIDYLSERINE DECARBOXYLASE; PISD","url":"https://www.omim.org/entry/612770"},{"mim_id":"611354","title":"INTEGRATOR COMPLEX SUBUNIT 11; INTS11","url":"https://www.omim.org/entry/611354"},{"mim_id":"611352","title":"INTEGRATOR COMPLEX SUBUNIT 9; INTS9","url":"https://www.omim.org/entry/611352"},{"mim_id":"609708","title":"LIPOPROTEIN LIPASE; LPL","url":"https://www.omim.org/entry/609708"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Mitotic chromosome","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LACTB"},"hgnc":{"alias_symbol":["FLJ14902"],"prev_symbol":["MRPL56"]},"alphafold":{"accession":"P83111","domains":[{"cath_id":"3.40.710.10","chopping":"102-160_376-471_478-547","consensus_level":"medium","plddt":93.9802,"start":102,"end":547},{"cath_id":"3.40.710.10","chopping":"169-231_289-357","consensus_level":"medium","plddt":95.7482,"start":169,"end":357}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P83111","model_url":"https://alphafold.ebi.ac.uk/files/AF-P83111-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P83111-F1-predicted_aligned_error_v6.png","plddt_mean":78.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LACTB","jax_strain_url":"https://www.jax.org/strain/search?query=LACTB"},"sequence":{"accession":"P83111","fasta_url":"https://rest.uniprot.org/uniprotkb/P83111.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P83111/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P83111"}},"corpus_meta":[{"pmid":"28329758","id":"PMC_28329758","title":"LACTB is a tumour suppressor that modulates lipid metabolism and cell state.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28329758","citation_count":152,"is_preprint":false},{"pmid":"29899406","id":"PMC_29899406","title":"LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29899406","citation_count":76,"is_preprint":false},{"pmid":"19858488","id":"PMC_19858488","title":"LACTB is a filament-forming protein localized in mitochondria.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19858488","citation_count":72,"is_preprint":false},{"pmid":"38176415","id":"PMC_38176415","title":"OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38176415","citation_count":65,"is_preprint":false},{"pmid":"32636680","id":"PMC_32636680","title":"LACTB Regulates PIK3R3 to Promote Autophagy and Inhibit EMT and Proliferation Through the PI3K/AKT/mTOR Signaling Pathway in Colorectal Cancer.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32636680","citation_count":49,"is_preprint":false},{"pmid":"11707067","id":"PMC_11707067","title":"Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11707067","citation_count":38,"is_preprint":false},{"pmid":"26603571","id":"PMC_26603571","title":"MicroRNA-125b-5p attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production by targeting inhibiting LACTB in THP-1 macrophages.","date":"2015","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/26603571","citation_count":32,"is_preprint":false},{"pmid":"33675985","id":"PMC_33675985","title":"LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33675985","citation_count":31,"is_preprint":false},{"pmid":"28835318","id":"PMC_28835318","title":"Overexpression of LACTB, a Mitochondrial Protein That Inhibits Proliferation and Invasion in Glioma Cells.","date":"2017","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28835318","citation_count":30,"is_preprint":false},{"pmid":"33152401","id":"PMC_33152401","title":"LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival.","date":"2020","source":"Cancer 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LACTB in the Process of Cancer Development.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39941048","citation_count":3,"is_preprint":false},{"pmid":"38149985","id":"PMC_38149985","title":"A potential therapeutic approach for gastric cancer: inhibition of LACTB transcript 1.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/38149985","citation_count":3,"is_preprint":false},{"pmid":"40603395","id":"PMC_40603395","title":"Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40603395","citation_count":2,"is_preprint":false},{"pmid":"40711831","id":"PMC_40711831","title":"A Near-Infrared Fluorescent Probe for Monitoring of LACTB Activity in NSCLC Diagnosis and Therapy.","date":"2025","source":"Analytical 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it is the first reported vertebrate member of this microbial peptidase family.\",\n      \"method\": \"Sequence cloning, database searching, Northern blot, genomic mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original cloning and characterization with multiple methods, foundational study\",\n      \"pmids\": [\"11707067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse LACTB can be expressed as an N-terminal GST fusion protein in E. coli and adopts a well-defined secondary structure (alpha-helices, beta-sheets, turns) as determined by FTIR spectroscopy, confirming it is a properly folded serine protease.\",\n      \"method\": \"Recombinant protein expression, glutathione-agarose affinity chromatography, MALDI-TOF mass spectrometry, FTIR spectroscopy\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of folded protein, single study\",\n      \"pmids\": [\"16202624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LACTB potently inhibits breast cancer cell proliferation by altering mitochondrial lipid metabolism, at least in part through reduction of mitochondrial phosphatidylserine decarboxylase (PISD) levels, thereby decreasing mitochondrial phosphatidylethanolamine synthesis and promoting cancer cell differentiation.\",\n      \"method\": \"In vitro and in vivo mouse/human studies, lipidomic analysis, loss-of-function and gain-of-function experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in vitro and in vivo, highly cited foundational study\",\n      \"pmids\": [\"28329758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LACTB directly binds to the C terminus of p53 and inhibits p53 ubiquitination and degradation by preventing MDM2 from interacting with p53, thereby stabilizing p53 protein; this tumor suppressive activity requires wild-type p53.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR/Cas9 knockout, ectopic overexpression, in vitro and in vivo assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP with functional validation, single lab\",\n      \"pmids\": [\"29899406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LACTB regulates PIK3R3 to modulate PI3K levels, promoting autophagy and inhibiting EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer cells.\",\n      \"method\": \"Immunoprecipitation, RNA-seq, Western blotting, transmission electron microscopy, xenograft model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with pathway analysis, single lab\",\n      \"pmids\": [\"32636680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LACTB directly binds to PP1A and attenuates the interaction between PP1A and YAP, resulting in decreased YAP dephosphorylation (increased phospho-YAP Ser127), preventing nuclear translocation of YAP in a LATS1-independent manner to suppress melanoma progression.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, phosphorylation-defective YAP mutants, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct binding shown by Co-IP with mechanistic mutant validation, single lab\",\n      \"pmids\": [\"33675985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CryoEM structures of human LACTB filaments (wild-type, middle-region deletion mutant, and inhibitor Z-AAD-CMK complex) at 2.8–3.1 Å resolution revealed that three interfaces mediate filament assembly, that higher-order helical structure facilitates cleavage activity, and that LACTB cleaves peptide bonds adjacent to aspartic acid residues.\",\n      \"method\": \"Cryo-electron microscopy structure determination, activity assays, deletion mutagenesis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution cryo-EM structure with mutagenesis and enzymatic validation\",\n      \"pmids\": [\"35247327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human LACTB self-assembles into micron-scale filaments; cryoEM structure defines the assembly mechanism; highly ordered filament bundles stabilize the active state of the enzyme; mutations at filament-forming interfaces reduce enzyme activity; and LACTB filaments can bind lipid membranes.\",\n      \"method\": \"Cryo-electron microscopy, site-directed mutagenesis, enzyme activity assays, lipid membrane binding assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent cryo-EM structural study with mutagenesis and activity assays, orthogonal confirmation of Zhang et al. 2022\",\n      \"pmids\": [\"36534696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LACTB expression leads to G1-phase cell cycle arrest and increased mitochondrial reactive oxygen species, which activates an intrinsic caspase-independent cell death pathway in breast cancer cells.\",\n      \"method\": \"Protein array, flow cytometry, cell proliferation assays, immunofluorescence, in vivo experiments, western blot\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in one study, single lab\",\n      \"pmids\": [\"36282364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LACTB suppresses epithelial ovarian cancer by downregulating the Snail2/Slug transcription factor, leading to inhibition of the EMT program and promotion of cancer cell differentiation.\",\n      \"method\": \"In vitro, in vivo, and 3D culture experiments with overexpression and loss-of-function\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple experimental systems, pathway placed downstream of Slug, single lab\",\n      \"pmids\": [\"36375842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 directly binds to LACTB mRNA (validated by RNA pull-down and RNA immunoprecipitation) and promotes its degradation; LACTB upregulation promotes erastin-induced ferroptosis and mitochondrial dysfunction through the LACTB/PISD axis.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, CCK-8, flow cytometry, JC-1 staining, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-binding validated by multiple orthogonal RNA methods, functional rescue shown, single lab\",\n      \"pmids\": [\"37157950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OXCT1 functions as a lysine succinyltransferase (requiring residue G424 for this activity) and succinylates LACTB at K284; succinylation of LACTB K284 inhibits its proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, promoting hepatocellular carcinoma progression.\",\n      \"method\": \"In vitro succinyltransferase assay, mass spectrometry identification of succinylation sites, mutagenesis, western blotting, functional metabolic assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with site-specific mutagenesis and mass spectrometry validation\",\n      \"pmids\": [\"38176415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In regulatory dendritic cells, the metabolic enzyme Suclg2 prevents succinylation of Lactb at lysine 288, thereby suppressing Lactb-mediated activation of NF-κB signaling and maintaining tolerogenic DC function.\",\n      \"method\": \"Metabolomic, transcriptomic, and functional investigations; Suclg2 interference experiments; NF-κB signaling assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multi-omic approach with functional validation, succinylation site identified, single lab\",\n      \"pmids\": [\"37216870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LACTB is a mitochondrial protease that cleaves and activates phospholipase A2 group VI (PLA2G6); together they convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine, thereby regulating mitochondrial function and ferroptosis. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished LACTB's protective function.\",\n      \"method\": \"Mouse knockout and tubule-specific overexpression, genetic epistasis (double-KO), lipidomic studies in mouse and human, in vivo kidney injury models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic epistasis with substrate identification and lipidomics, multiple orthogonal approaches\",\n      \"pmids\": [\"39561766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LACTB blocks HSPA8 transcription in a p53-dependent manner, resulting in elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signaling, thereby triggering ferroptosis and suppressing liver cancer progression.\",\n      \"method\": \"LACTB knockout and ectopic overexpression, western blot, in vivo xenograft, p53-binding site mutation experiments\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissected with p53-binding site mutant validation, single lab\",\n      \"pmids\": [\"39047638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LACTB is required for apoptosis-induced inner mitochondrial membrane remodeling, which promotes cytochrome c release; purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes; LACTB does not affect BAX or Drp1 recruitment and acts independently of OPA1 processing.\",\n      \"method\": \"LACTB knockdown/overexpression, cytochrome c release assays, purified protein membrane remodeling assay with cardiolipin-enriched nanotubes, apoptosis flow cytometry\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with purified protein and membrane nanotubes combined with cellular loss/gain-of-function and mechanistic controls\",\n      \"pmids\": [\"41223265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LACTB exhibits D-aspartyl endopeptidase (DAEP) activity — it cleaves proteins at the carboxy-terminus of D-aspartic acid residues, including a peptide derived from amyloid β1-10 containing D-Asp at position 7, making it the first identified mammalian protein with this activity.\",\n      \"method\": \"In vitro DAEP activity assay with peptide substrates, structural comparison with bacterial paenidase\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic characterization with defined substrates\",\n      \"pmids\": [\"40286848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LACTB destabilizes OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion; upstream, acetylated KLF5 (at K369) acts as a transcriptional repressor of LACTB.\",\n      \"method\": \"CRISPR/Cas9 KLF5 knockout, acetylation-mimic and deacetylation-mimic KLF5 mutants, protein-protein and protein-DNA interaction assays, xenograft model, western blot\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic mutant validation, single lab, pathway positioning via epistasis\",\n      \"pmids\": [\"41213373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LACTB interacts with carnitine palmitoyltransferase 2 (CPT2) and promotes its ubiquitin-mediated degradation, thereby impairing fatty acid oxidation and exacerbating hepatic steatosis in metabolic dysfunction-associated steatotic liver disease.\",\n      \"method\": \"Co-immunoprecipitation, LACTB overexpression and knockdown in vivo and in vitro, HFD mouse model, western blot\",\n      \"journal\": \"Diabetes, obesity & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with in vivo functional validation, single lab\",\n      \"pmids\": [\"41527692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LACTB double-mutant (M5L+R469K, from SNPs rs34317102 and rs2729835 found in osteosarcoma) reduces wild-type p53 stability by enhancing PSMB7 catalytic activity while also protecting mutant p53R156P from lysosomal degradation, conferring oncogene-like functions; clavulanate potassium (a beta-lactamase inhibitor) binds and blocks LACTBM5L+R469K.\",\n      \"method\": \"Mutagenesis, PSMB7 activity assays, protein stability assays, in vitro and in vivo overexpression, drug binding/inhibition assay\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis combined with mechanistic functional assays, single lab\",\n      \"pmids\": [\"39324579\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LACTB is a mitochondrial intermembrane space serine protease that polymerizes into filaments (with filament assembly enhancing its catalytic activity) and functions as a tumor suppressor by: (1) altering mitochondrial lipid metabolism through reduction of PISD and activation of PLA2G6-mediated phospholipid remodeling; (2) remodeling cardiolipin-enriched inner mitochondrial membranes to promote cytochrome c release and apoptosis independently of OPA1 and BAX/Drp1; (3) cleaving peptides adjacent to D-aspartate residues (D-aspartyl endopeptidase activity); (4) stabilizing p53 by blocking MDM2 binding; (5) inactivating YAP by attenuating PP1A-mediated dephosphorylation; and (6) being post-translationally regulated by OXCT1-mediated succinylation at K284 (which inhibits its proteolytic activity) and by Suclg2-mediated suppression of succinylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LACTB is a mitochondrial intermembrane space serine protease of the penicillin-binding protein family that self-assembles into filaments whose higher-order structure stabilizes the catalytically active state and enables membrane binding, with D-aspartyl endopeptidase specificity representing the first such activity identified in mammals [PMID:19858488, PMID:35247327, PMID:36534696, PMID:40286848]. LACTB functions as a tumor suppressor across multiple cancer types by altering mitochondrial lipid metabolism—reducing PISD to lower phosphatidylethanolamine levels and cleaving/activating PLA2G6 to remodel oxidized phospholipids—and by stabilizing p53 through blocking MDM2 interaction, thereby promoting differentiation, ferroptosis, and apoptosis [PMID:28329758, PMID:39561766, PMID:29899406, PMID:36282364]. During apoptosis, LACTB binds and remodels cardiolipin-enriched inner mitochondrial membranes to facilitate cytochrome c release independently of BAX, Drp1, and OPA1, and it destabilizes OMA1 to modulate OPA1-mediated fusion [PMID:41223265, PMID:41213373]. Its proteolytic activity is negatively regulated by OXCT1-mediated succinylation at K284, linking metabolic signaling to LACTB function [PMID:38176415].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of LACTB as the first vertebrate member of the bacterial penicillin-binding protein/beta-lactamase superfamily established that a conserved active-site serine protease domain persists in mammalian mitochondria.\",\n      \"evidence\": \"Sequence cloning, Northern blot, and genomic mapping of the human and mouse LACTB gene\",\n      \"pmids\": [\"11707067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity demonstrated\", \"Subcellular localization not experimentally confirmed\", \"No substrate identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Direct localization of LACTB to the mitochondrial intermembrane space and visualization of its polymerization into extended filaments resolved where the protease operates and revealed an unusual structural organization suggesting a role in intramitochondrial membrane compartmentalization.\",\n      \"evidence\": \"Subcellular fractionation and electron microscopy in mammalian cells\",\n      \"pmids\": [\"19858488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Filament function and relationship to catalysis unknown\", \"No substrates identified\", \"No physiological phenotype from loss-of-function\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The discovery that LACTB inhibits breast cancer proliferation through reduction of PISD and consequent alteration of mitochondrial phospholipid composition established LACTB as a tumor suppressor acting via lipid metabolism.\",\n      \"evidence\": \"Gain- and loss-of-function in vitro and in vivo with lipidomic profiling in breast cancer models\",\n      \"pmids\": [\"28329758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PISD is a direct proteolytic substrate unknown\", \"Mechanism of cancer cell differentiation downstream of lipid changes unresolved\", \"Generalizability to non-breast cancers not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that LACTB stabilizes p53 by physically blocking MDM2 binding revealed a second, non-lipid-mediated tumor suppressive mechanism and showed that LACTB's anti-cancer activity requires wild-type p53.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ubiquitination assays, CRISPR knockout, and xenograft models\",\n      \"pmids\": [\"29899406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding awaiting independent replication\", \"Whether p53 stabilization occurs in the mitochondrial compartment or cytosol not defined\", \"Relationship between protease activity and p53 binding unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of PP1A as a direct LACTB-binding partner whose interaction with YAP is attenuated by LACTB demonstrated a LATS1-independent mechanism for Hippo pathway regulation in melanoma suppression.\",\n      \"evidence\": \"Co-immunoprecipitation with phospho-YAP mutant analysis and in vivo xenograft\",\n      \"pmids\": [\"33675985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether LACTB's protease activity is required for PP1A sequestration untested\", \"Compartment where LACTB–PP1A interaction occurs not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Two independent cryo-EM structures at near-atomic resolution revealed that three inter-subunit interfaces drive filament assembly, that higher-order filament bundling stabilizes the active conformation, and that LACTB cleaves peptide bonds adjacent to aspartate residues—linking polymer architecture to enzymatic function.\",\n      \"evidence\": \"Cryo-EM at 2.8–3.1 Å with site-directed mutagenesis and in vitro activity assays from two independent labs\",\n      \"pmids\": [\"35247327\", \"36534696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous protein substrates in mitochondria not identified from structural work alone\", \"Filament dynamics and regulation in vivo unknown\", \"Whether lipid-membrane binding modulates activity not quantitatively characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"LACTB's tumor suppressive functions were extended to epithelial ovarian cancer (via Snail2/Slug downregulation and EMT inhibition) and breast cancer (via ROS-driven caspase-independent cell death and G1 arrest), broadening the range of cancers and pathways involved.\",\n      \"evidence\": \"Overexpression/loss-of-function in multiple cancer cell lines, 3D culture, protein array, flow cytometry, and in vivo models\",\n      \"pmids\": [\"36375842\", \"36282364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolytic link to Slug downregulation not shown\", \"Caspase-independent death mechanism not fully defined\", \"Each study from a single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that succinylation at K288 (mouse)/K284 (human) by OXCT1 inhibits LACTB proteolytic activity, and that Suclg2 opposes this modification, established a post-translational regulatory switch linking TCA cycle metabolism to LACTB function.\",\n      \"evidence\": \"In vitro succinyltransferase assay with mass spectrometry (OXCT1 study); multi-omic profiling with Suclg2 interference in dendritic cells\",\n      \"pmids\": [\"38176415\", \"37216870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How succinylation structurally disrupts the active site or filament assembly not determined\", \"Relative contributions of OXCT1 vs. non-enzymatic succinylation in vivo unknown\", \"Whether other acyl modifications regulate LACTB untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of PLA2G6 as a direct LACTB substrate whose cleavage activates phospholipid remodeling (oxidized PE → lyso-PE) provided the first genetically validated proteolytic substrate and linked LACTB to ferroptosis protection in kidney injury.\",\n      \"evidence\": \"Genetic epistasis with tubule-specific LACTB overexpression and PLA2G6 knockout mice, lipidomics in mouse and human tissue\",\n      \"pmids\": [\"39561766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site on PLA2G6 not mapped\", \"Whether PLA2G6 activation accounts for the PISD reduction phenotype unknown\", \"Relevance to non-renal tissues not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Biochemical demonstration that LACTB possesses D-aspartyl endopeptidase activity—cleaving after D-aspartate residues including in amyloid β peptides—identified LACTB as the first mammalian enzyme with this specificity, suggesting roles in D-amino acid-containing peptide clearance.\",\n      \"evidence\": \"In vitro DAEP activity assay with synthetic peptide substrates and structural comparison to bacterial paenidase\",\n      \"pmids\": [\"40286848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological D-Asp-containing substrates in mitochondria not identified\", \"Whether D-aspartyl endopeptidase activity accounts for PLA2G6 cleavage untested\", \"In vivo relevance of amyloid β cleavage not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reconstitution showed that purified LACTB selectively binds and remodels cardiolipin-enriched membrane nanotubes to promote cytochrome c release during apoptosis, independent of BAX, Drp1, and OPA1, establishing a direct membrane-remodeling mechanism in the intrinsic apoptosis pathway.\",\n      \"evidence\": \"Purified protein with cardiolipin-enriched lipid nanotubes, cytochrome c release assays, knockdown/overexpression with apoptosis quantification\",\n      \"pmids\": [\"41223265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether proteolytic activity is required for membrane remodeling not dissected\", \"How LACTB filaments interact with cristae junctions in situ unknown\", \"Relationship to LACTB's anti-tumor function via this mechanism not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified model integrating LACTB's D-aspartyl endopeptidase activity, filament-dependent membrane remodeling, lipid metabolic control, and diverse signaling outputs (p53, YAP, NF-κB) into a coherent mechanistic framework is still missing—particularly the identity and hierarchy of its endogenous mitochondrial substrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Comprehensive substrate profiling (degradomics) of LACTB has not been performed\", \"Structural basis for how succinylation inhibits activity not determined\", \"Whether the tumor-suppressive and apoptotic functions are separable from protease activity remains unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 8, 12, 14, 17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 3, 9, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005357801\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 12, 14, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 6, 10, 15, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PISD\",\n      \"PLA2G6\",\n      \"TP53\",\n      \"MDM2\",\n      \"PPP1CA\",\n      \"OXCT1\",\n      \"CPT2\",\n      \"OMA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}