{"gene":"LACTB","run_date":"2026-06-10T02:59:49","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 / Strong — direct fractionation and electron microscopy demonstrating localization and filament structure, replicated and built upon by multiple subsequent structural studies","pmids":["19858488"],"is_preprint":false},{"year":2001,"finding":"LACTB is a mammalian active-site serine protein with sequence similarity to bacterial penicillin-binding proteins/beta-lactamases, containing an active site motif related to C-class beta-lactamases and a predicted amino-terminal transmembrane domain.","method":"Sequence analysis, cDNA cloning, Northern blot expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — sequence-based identification replicated and functionally confirmed by subsequent structural and enzymatic studies","pmids":["11707067"],"is_preprint":false},{"year":2017,"finding":"LACTB potently inhibits breast cancer cell proliferation by altering mitochondrial lipid metabolism; mechanistically, it reduces levels of mitochondrial phosphatidylserine decarboxylase (PISD), which is involved in the synthesis of mitochondrial phosphatidylethanolamine, thereby inducing breast cancer cell differentiation.","method":"In vitro overexpression/knockdown, in vivo mouse models, lipidomics, PISD protein level measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo studies with defined molecular mechanism (PISD reduction), replicated across multiple cancer models","pmids":["28329758"],"is_preprint":false},{"year":2018,"finding":"LACTB directly binds the C terminus of p53 and inhibits p53 degradation by preventing MDM2 from interacting with p53, thereby stabilizing p53 and exerting tumor-suppressive effects in colorectal cancer cells with wild-type TP53.","method":"Co-immunoprecipitation, CRISPR/Cas9 knockout, ectopic expression, Western blot, p53-null cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and multiple cell-line experiments from single lab, functional epistasis confirmed by p53-null rescue","pmids":["29899406"],"is_preprint":false},{"year":2020,"finding":"LACTB regulates PIK3R3 activity to influence PI3K levels, thereby promoting autophagy and inhibiting EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer cells.","method":"RNA-seq, immunoprecipitation, Western blot, Transwell invasion assay, xenograft model","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunoprecipitation and RNA-seq with pathway validation, single lab","pmids":["32636680"],"is_preprint":false},{"year":2021,"finding":"LACTB directly binds PP1A (protein phosphatase 1A) and attenuates the interaction between PP1A and YAP, resulting in increased YAP phosphorylation at Ser127, decreased YAP nuclear translocation, and YAP inactivation in a LATS1-independent manner, thereby suppressing melanoma progression.","method":"Co-immunoprecipitation, overexpression, phospho-YAP detection by Western blot, phosphorylation-defective YAP mutant rescue, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutant rescue, and in vivo data from single lab with multiple orthogonal methods","pmids":["33675985"],"is_preprint":false},{"year":2022,"finding":"Cryo-electron microscopy structures of human LACTB filaments at 2.8–3.1 Å resolution revealed that three interfaces are required for filament assembly, formation of higher-order helical structures facilitates cleavage activity, and the middle region is necessary for substrate hydrolysis but not filament formation; LACTB specifically cleaves peptide bonds adjacent to aspartic acid residues.","method":"Cryo-electron microscopy, site-directed mutagenesis, enzymatic activity assays, inhibitor-bound structure (Z-AAD-CMK)","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at near-atomic resolution combined with mutagenesis and activity assays, independently replicated by Bennett et al. 2022","pmids":["35247327"],"is_preprint":false},{"year":2022,"finding":"Human LACTB self-assembles into micron-scale filaments that increase catalytic activity; residues at the filament-forming interface are required for filamentation, and mutations disrupting filamentation reduce enzyme activity; LACTB filaments can bind lipid membranes.","method":"Cryo-EM, site-directed mutagenesis, enzyme activity assays, lipid-binding assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional mutagenesis and lipid-binding assays, independent replication of Zhang et al. 2022 structural findings","pmids":["36534696"],"is_preprint":false},{"year":2022,"finding":"LACTB expression leads to cell cycle arrest in G1 phase and increased mitochondrial reactive oxygen species production, which causes DNA oxidation and activation of an intrinsic caspase-independent cell death pathway in breast cancer cells.","method":"Protein array, flow cytometry, Western blot, immunofluorescence, cell proliferation assays, 2D/3D cell culture, in vivo experiments","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, protein array, in vivo) from single lab defining the cell death pathway","pmids":["36282364"],"is_preprint":false},{"year":2023,"finding":"PCBP1 directly binds LACTB mRNA and promotes its degradation; LACTB upregulation promotes erastin-induced ferroptosis and mitochondrial dysfunction; the ferroptosis-promoting effect of LACTB is mediated through downregulation of PISD (phosphatidylserine decarboxylase), as PISD overexpression reverses LACTB-mediated ferroptosis.","method":"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, flow cytometry, JC-1 staining, xenograft model","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down and RIP confirming direct PCBP1-LACTB mRNA binding, with functional epistasis via PISD rescue, single lab","pmids":["37157950"],"is_preprint":false},{"year":2024,"finding":"OXCT1 functions as a lysine succinyltransferase (with residue G424 essential for this activity) and succinylates LACTB at lysine K284; this succinylation inhibits LACTB proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, promoting hepatocellular carcinoma progression.","method":"In vitro succinyltransferase assay, mass spectrometry, site-directed mutagenesis (G424 in OXCT1; K284 in LACTB), Western blot, enzymatic activity assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, mass spectrometry identification of succinylation site, and mutagenesis validation, single rigorous study with multiple orthogonal methods","pmids":["38176415"],"is_preprint":false},{"year":2024,"finding":"LACTB is a novel mitochondrial protease that cleaves and activates phospholipase A2 group VI (PLA2G6); LACTB and downstream PLA2G6 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 against kidney injury.","method":"Mouse knockout/overexpression models, genetic epistasis (PLA2G6 KO rescue), lipidomics in mouse and human, in vitro protease assay","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protease-substrate identification with genetic epistasis rescue in vivo, lipidomics, multiple orthogonal methods","pmids":["39561766"],"is_preprint":false},{"year":2023,"finding":"Suclg2 suppresses LACTB succinylation at lysine K288 (mouse numbering) in regulatory dendritic cells (diffDCs); Lactb succinylation at this residue activates NF-κB signaling; Suclg2-mediated prevention of Lactb succinylation is required for maintaining the tolerogenic function of diffDCs.","method":"Metabolomics, transcriptomics, functional immune assays, succinylation site identification by mass spectrometry, Suclg2 interference","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — succinylation site identified by MS with functional validation in immune cells, single lab","pmids":["37216870"],"is_preprint":false},{"year":2024,"finding":"LACTB blocks HSPA8 transcription in a p53-dependent manner in liver cancer; this results in elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signaling, thereby triggering ferroptosis and suppressing liver cancer progression.","method":"Overexpression/knockout experiments, Western blot, in vivo xenograft, GPX4/SLC7A11 pathway analysis, p53 binding site mutation","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis with p53 binding site mutation, multiple markers assessed, single lab","pmids":["39047638"],"is_preprint":false},{"year":2025,"finding":"LACTB is required for apoptosis-induced inner mitochondrial membrane (IMM) remodeling, which facilitates cytochrome c release; LACTB knockdown reduces cytochrome c release and apoptosis, while overexpression promotes these effects; LACTB does not affect BAX or Drp1 recruitment to mitochondria; purified LACTB directly binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes; LACTB's role in IMM remodeling is independent of OPA1 processing and apoptosis-specific.","method":"Knockdown/overexpression, cytochrome c release assay, mitochondrial morphology imaging, purified protein lipid-binding and remodeling assay with cardiolipin-enriched membrane nanotubes","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified protein and lipid membranes, multiple orthogonal methods (KD, OE, direct binding assay), peer-reviewed publication","pmids":["41223265"],"is_preprint":false},{"year":2025,"finding":"LACTB has D-aspartyl endopeptidase (DAEP) activity, cleaving proteins at the carboxy terminus of D-aspartic acid residues, including a peptide derived from amyloid β1-10 containing D-Asp at position 7; this activity was identified by structural comparison with bacterial paenidase and confirmed by in vitro assay.","method":"In vitro enzymatic assay with D-Asp-containing peptide substrates, structural comparison with bacterial DAEP (paenidase)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic characterization with defined substrates, structural basis provided, single lab","pmids":["40286848"],"is_preprint":false},{"year":2025,"finding":"Acetylated KLF5 (at lysine 369) acts as a transcriptional repressor of LACTB; LACTB in turn destabilizes OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion, governing colorectal cancer cell stemness and differentiation.","method":"ChIP/protein-DNA interaction assays, Co-IP, CRISPR/Cas9 KO, acetylation mimic/deacetylation mimic KLF5 mutants, Western blot, xenograft model","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein-DNA binding assays and mutagenesis with functional epistasis, single lab","pmids":["41213373"],"is_preprint":false},{"year":2026,"finding":"LACTB is identified as a primary enzyme responsible for succinylcarnitine hydrolysis in myeloid cells; loss of LACTB enzymatic activity (enzymatically-dead mice) elevates succinylcarnitine levels and modulates OXPHOS, lipid profiles, and efferocytosis-related functions in microglia.","method":"Mendelian randomization, LACTB KD macrophages, LACTB KO iPSC-derived microglia, enzymatically-dead mouse model, metabolomics, lipidomics, transcriptomics, xenotransplantation","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatically-dead mouse model with metabolomics confirming LACTB as succinylcarnitine hydrolase, multiple orthogonal methods, preprint not yet peer-reviewed","pmids":["41929023"],"is_preprint":true},{"year":2026,"finding":"LACTB interacts with CPT2 (carnitine palmitoyltransferase 2) and promotes its ubiquitin-mediated degradation; LACTB overexpression exacerbates hepatic steatosis in high-fat diet mice, and the effect on lipid metabolism is dependent on CPT2.","method":"Co-immunoprecipitation, in vivo LACTB KD/overexpression mouse models, Western blot, ubiquitination assay","journal":"Diabetes, obesity & metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vivo genetic epistasis (CPT2-dependent rescue), single lab","pmids":["41527692"],"is_preprint":false},{"year":2010,"finding":"LACTB was expressed as an N-terminal GST fusion protein in E. coli with confirmed secondary structure (alpha-helices, beta-sheets, turns) by FTIR spectrometry, establishing that the protein can be properly folded for biochemical study.","method":"Recombinant protein expression, glutathione-agarose affinity chromatography, MALDI-TOF mass spectrometry, immunoblotting, FTIR spectrometry","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — recombinant protein production and structural characterization by FTIR, but no functional enzymatic assay, single study","pmids":["16202624"],"is_preprint":false},{"year":2024,"finding":"Double missense mutations M5L and R469K in LACTB (present in 92.31% of osteosarcoma patients) confer oncogene-like functions: LACTB(M5L+R469K) reduces wild-type p53 by enhancing PSMB7 catalytic activity and protects mutant p53(R156P) from lysosomal degradation; clavulanate potassium binds and blocks LACTB(M5L+R469K) to suppress osteosarcoma proliferation.","method":"Overexpression of mutant LACTB constructs, PSMB7 activity assays, p53 degradation assays (proteasomal vs lysosomal), drug binding and proliferation assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic assays (proteasome activity, lysosomal degradation pathway) with specific LACTB mutant constructs, single lab","pmids":["39324579"],"is_preprint":false},{"year":2020,"finding":"In nasopharyngeal carcinoma, LACTB promotes metastasis by activating ERBB3/EGFR-ERK signaling, which in turn affects stability and acetylation of histone H3; LACTB does not influence cellular proliferation in this context.","method":"Overexpression/knockdown, in vitro motility assays, in vivo metastasis model, pathway inhibitor studies, histone modification analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional studies with pathway analysis, single lab; notable context-specific finding (pro-metastatic role)","pmids":["33152401"],"is_preprint":false},{"year":2022,"finding":"LACTB suppresses migration and invasion of glioblastoma by downregulating RHOC expression and inhibiting the RHOC/Cofilin signaling pathway.","method":"Overexpression in LN229 and U87 cell lines, migration/invasion assays, Western blot for RHOC and Cofilin pathway markers","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic depth (expression-level readout of RHOC/Cofilin), no direct binding or epistasis experiment","pmids":["36088805"],"is_preprint":false}],"current_model":"LACTB is a mitochondrial intermembrane space serine protease that polymerizes into filaments to increase its catalytic activity; it specifically cleaves peptide bonds adjacent to D-aspartic acid residues, activates PLA2G6 to regulate phospholipid metabolism and ferroptosis, remodels cardiolipin-enriched inner mitochondrial membranes to facilitate cytochrome c release and apoptosis, reduces PISD levels to alter mitochondrial phosphatidylethanolamine synthesis, and is post-translationally regulated by OXCT1-mediated succinylation at K284 (which inhibits its proteolytic activity); in cancer contexts it acts predominantly as a tumor suppressor by stabilizing p53 (via MDM2 exclusion), promoting cell differentiation, and inducing ferroptosis, though gain-of-function mutations (M5L+R469K) can convert it to an oncogenic regulator of p53 stability."},"narrative":{"mechanistic_narrative":"LACTB is a mitochondrial intermembrane-space serine protein, sequence-related to bacterial penicillin-binding proteins and beta-lactamases, that polymerizes into stable micron-scale filaments and organizes intramitochondrial micro-compartments [PMID:19858488, PMID:11707067]. Cryo-EM of human LACTB filaments resolved three assembly interfaces and showed that higher-order helical assembly potentiates catalysis, with the filament-forming residues required for full enzymatic activity; LACTB cleaves peptide bonds adjacent to aspartate and exhibits D-aspartyl endopeptidase activity, and its filaments bind lipid membranes [PMID:35247327, PMID:36534696, PMID:40286848]. The enzyme acts on mitochondrial lipid metabolism: it cleaves and activates PLA2G6 to convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine, and lowers phosphatidylserine decarboxylase (PISD) levels, thereby reshaping mitochondrial phospholipid pools, regulating ferroptosis, and driving cancer-cell differentiation [PMID:28329758, PMID:39561766]. LACTB preferentially binds and remodels cardiolipin-enriched inner-membrane nanotubes and is required for apoptosis-associated inner-membrane remodeling that facilitates cytochrome c release, independent of BAX/Drp1 recruitment and OPA1 processing [PMID:41223265]. In cancer it predominantly behaves as a tumor suppressor, stabilizing p53 by excluding MDM2 and triggering p53-dependent ferroptosis programs [PMID:29899406, PMID:39047638]. Its proteolytic activity is restrained by post-translational succinylation: OXCT1 succinylates LACTB at K284 to inhibit catalysis and support tumor mitochondrial respiration [PMID:38176415]. LACTB also functions as a metabolic hydrolase, hydrolyzing succinylcarnitine in myeloid cells and influencing CPT2-dependent hepatic lipid handling [PMID:41929023, PMID:41527692].","teleology":[{"year":2001,"claim":"Established LACTB as a candidate mammalian serine enzyme by recognizing its active-site motif and homology to bacterial beta-lactamases/penicillin-binding proteins, framing it as a potential protease rather than an uncharacterized ORF.","evidence":"Sequence analysis, cDNA cloning, and Northern blot expression profiling","pmids":["11707067"],"confidence":"Medium","gaps":["No enzymatic activity or substrate demonstrated","Subcellular localization not defined"]},{"year":2009,"claim":"Resolved where LACTB acts and how it is organized, showing it localizes to the mitochondrial intermembrane space and self-assembles into stable filaments that compartmentalize the mitochondrion.","evidence":"Subcellular fractionation and electron microscopy","pmids":["19858488"],"confidence":"High","gaps":["Filament assembly determinants unresolved","No catalytic role linked to filamentation yet"]},{"year":2017,"claim":"Connected LACTB to a defined cellular phenotype, demonstrating it suppresses breast cancer proliferation by lowering PISD and rewiring mitochondrial phosphatidylethanolamine synthesis to induce differentiation.","evidence":"Overexpression/knockdown, mouse models, and lipidomics with PISD quantification","pmids":["28329758"],"confidence":"High","gaps":["Mechanism by which LACTB reduces PISD not defined","Direct protease substrate not identified"]},{"year":2018,"claim":"Provided a non-lipid tumor-suppressive mechanism, showing LACTB binds the p53 C terminus and blocks MDM2 to stabilize p53 in wild-type-TP53 colorectal cancer.","evidence":"Reciprocal Co-IP, CRISPR knockout, and p53-null rescue","pmids":["29899406"],"confidence":"Medium","gaps":["Whether protease activity is required for p53 stabilization unclear","Single-lab data"]},{"year":2022,"claim":"Defined the structural basis of LACTB catalysis, showing filament assembly via three interfaces potentiates D-aspartate-adjacent peptide bond cleavage and that filaments bind lipid membranes.","evidence":"Cryo-EM at 2.8–3.1 Å, site-directed mutagenesis, enzyme and lipid-binding assays (two independent studies)","pmids":["35247327","36534696"],"confidence":"High","gaps":["Physiological protein substrates not identified from structure","How membrane binding couples to proteolysis unresolved"]},{"year":2022,"claim":"Linked LACTB to cell death and stress output, showing its expression causes G1 arrest and mitochondrial ROS-driven caspase-independent death in breast cancer.","evidence":"Protein array, flow cytometry, immunofluorescence, and in vivo assays","pmids":["36282364"],"confidence":"Medium","gaps":["Molecular trigger of ROS increase undefined","Relationship to its lipid-metabolic role unclear"]},{"year":2023,"claim":"Revealed upstream regulation and a ferroptosis output, showing PCBP1 degrades LACTB mRNA and that LACTB promotes erastin-induced ferroptosis through PISD downregulation.","evidence":"RNA pull-down, RIP, luciferase reporter, JC-1 staining, and PISD rescue","pmids":["37157950"],"confidence":"Medium","gaps":["Direct enzymatic basis of PISD reduction unresolved","Single-lab epistasis"]},{"year":2024,"claim":"Identified a direct succinylation switch, showing OXCT1 succinylates LACTB at K284 to inhibit its proteolytic activity and enhance tumor mitochondrial respiration.","evidence":"In vitro succinyltransferase reconstitution, mass spectrometry, and mutagenesis of OXCT1 G424 and LACTB K284","pmids":["38176415"],"confidence":"High","gaps":["Desuccinylase for K284 not identified","Effect on filament assembly not tested"]},{"year":2024,"claim":"Pinpointed a bona fide LACTB protease substrate, showing it cleaves and activates PLA2G6 to convert oxidized PE to lyso-PE, with PLA2G6 deletion abolishing LACTB's protective effect against kidney injury.","evidence":"Mouse knockout/overexpression, in vivo genetic epistasis (PLA2G6 KO rescue), lipidomics, and in vitro protease assay","pmids":["39561766"],"confidence":"High","gaps":["Whether PLA2G6 activation explains the cancer phenotypes untested","Filament dependence of PLA2G6 cleavage unknown"]},{"year":2024,"claim":"Extended the p53 axis to ferroptosis, showing LACTB represses HSPA8 transcription in a p53-dependent manner to elevate ferritinophagy and inhibit SLC7A11/GPX4 signaling in liver cancer.","evidence":"Overexpression/knockout, pathway marker analysis, and p53 binding-site mutation","pmids":["39047638"],"confidence":"Medium","gaps":["Direct vs indirect transcriptional control of HSPA8 unresolved","How a mitochondrial protease controls nuclear transcription unclear"]},{"year":2024,"claim":"Demonstrated context-dependent oncogenic conversion, showing osteosarcoma-prevalent M5L+R469K mutations make LACTB reduce wild-type p53 and protect mutant p53, with clavulanate blocking this activity.","evidence":"Mutant LACTB constructs, PSMB7 activity and proteasomal/lysosomal degradation assays, and drug-binding assays","pmids":["39324579"],"confidence":"Medium","gaps":["Structural impact of mutations on catalysis untested","Single-lab mechanistic model"]},{"year":2025,"claim":"Established a direct membrane-remodeling role in apoptosis, showing LACTB binds and remodels cardiolipin-enriched inner-membrane nanotubes to facilitate cytochrome c release independent of BAX/Drp1 and OPA1 processing.","evidence":"Knockdown/overexpression, cytochrome c release assays, and purified-protein lipid remodeling on cardiolipin nanotubes","pmids":["41223265"],"confidence":"High","gaps":["Whether proteolytic activity is needed for membrane remodeling unresolved","Upstream apoptotic signal that engages LACTB undefined"]},{"year":2025,"claim":"Defined LACTB's catalytic specificity at the chemical level, establishing it as a D-aspartyl endopeptidase that cleaves at the C terminus of D-aspartate residues.","evidence":"In vitro enzymatic assays with D-Asp-containing peptide substrates and structural comparison with bacterial paenidase","pmids":["40286848"],"confidence":"High","gaps":["Endogenous D-Asp-containing substrates in vivo not identified","Physiological role of DAEP activity unknown"]},{"year":2025,"claim":"Added a transcriptional-regulatory circuit and a fusion-machinery target, showing acetylated KLF5 represses LACTB while LACTB destabilizes OMA1 to modulate OPA1-mediated fusion and colorectal stemness.","evidence":"ChIP/protein-DNA assays, Co-IP, CRISPR knockout, and KLF5 acetylation-mimic mutants","pmids":["41213373"],"confidence":"Medium","gaps":["Direct vs indirect OMA1 destabilization unresolved","Single-lab data"]},{"year":2026,"claim":"Broadened LACTB's biochemistry to small-molecule metabolism, identifying it as the primary succinylcarnitine hydrolase in myeloid cells and as a regulator of CPT2 stability in hepatic lipid handling.","evidence":"Enzymatically-dead mouse model, KO microglia, metabolomics/lipidomics (preprint) and Co-IP with CPT2-dependent in vivo rescue","pmids":["41929023","41527692"],"confidence":"Medium","gaps":["Succinylcarnitine hydrolysis result is from a preprint","Whether one active site supports both peptidase and ester-hydrolase activities untested"]},{"year":null,"claim":"How LACTB's single catalytic activity and filament state are switched among its many outputs — phospholipid remodeling, ferroptosis, p53 stabilization, membrane remodeling, and metabolite hydrolysis — and which functions are direct protease-dependent versus indirect remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking filament assembly, substrate choice, and tissue-specific phenotypes","Most cancer mechanisms lack a defined direct protease substrate"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[6,11,15]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[15,17,18]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,14]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6,7]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,11,18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8,14]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,14,16]}],"complexes":["LACTB filament"],"partners":["PLA2G6","TP53","OXCT1","CPT2","PP1A","PIK3R3"],"other_free_text":[]}},"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":153,"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":73,"is_preprint":false},{"pmid":"38176415","id":"PMC_38176415","title":"OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating 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Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39324579","citation_count":6,"is_preprint":false},{"pmid":"39941048","id":"PMC_39941048","title":"The Pivotal Role of 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":4,"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":"41223265","id":"PMC_41223265","title":"The tumor suppressor LACTB remodels 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macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41213373","citation_count":0,"is_preprint":false},{"pmid":"38787728","id":"PMC_38787728","title":"Protocol for identifying OXCT1-mediated LACTB succinylation sites in vitro.","date":"2024","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/38787728","citation_count":0,"is_preprint":false},{"pmid":"41775345","id":"PMC_41775345","title":"LINC00852 inhibits colorectal cancer progression by regulating cell apoptosis, epithelial‒mesenchymal transition, invasion, and cuproptosis through miR-1276/LACTB.","date":"2026","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/41775345","citation_count":0,"is_preprint":false},{"pmid":"41929023","id":"PMC_41929023","title":"Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine levels and reduced Alzheimers disease risk.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41929023","citation_count":0,"is_preprint":false},{"pmid":"42000972","id":"PMC_42000972","title":"Fiber type-specific expression of LACTB leverages a function in oxidative metabolism.","date":"2026","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/42000972","citation_count":0,"is_preprint":false},{"pmid":"41527692","id":"PMC_41527692","title":"The depletion of serine beta-lactamase-like protein (LACTB) ameliorates metabolic dysfunction-associated steatotic liver disease by reducing ubiquitin-mediated degradation of carnitine palmitoyltransferase 2.","date":"2026","source":"Diabetes, obesity & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/41527692","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.12.648505","title":"The tumour suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis","date":"2025-04-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.12.648505","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22855,"output_tokens":5468,"usd":0.075292,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13982,"output_tokens":4637,"usd":0.092918,"stage2_stop_reason":"end_turn"},"total_usd":0.16821,"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\": 2009,\n      \"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.\",\n      \"method\": \"Subcellular fractionation, electron microscopy, direct localization experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct fractionation and electron microscopy demonstrating localization and filament structure, replicated and built upon by multiple subsequent structural studies\",\n      \"pmids\": [\"19858488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LACTB is a mammalian active-site serine protein with sequence similarity to bacterial penicillin-binding proteins/beta-lactamases, containing an active site motif related to C-class beta-lactamases and a predicted amino-terminal transmembrane domain.\",\n      \"method\": \"Sequence analysis, cDNA cloning, Northern blot expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — sequence-based identification replicated and functionally confirmed by subsequent structural and enzymatic studies\",\n      \"pmids\": [\"11707067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LACTB potently inhibits breast cancer cell proliferation by altering mitochondrial lipid metabolism; mechanistically, it reduces levels of mitochondrial phosphatidylserine decarboxylase (PISD), which is involved in the synthesis of mitochondrial phosphatidylethanolamine, thereby inducing breast cancer cell differentiation.\",\n      \"method\": \"In vitro overexpression/knockdown, in vivo mouse models, lipidomics, PISD protein level measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo studies with defined molecular mechanism (PISD reduction), replicated across multiple cancer models\",\n      \"pmids\": [\"28329758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LACTB directly binds the C terminus of p53 and inhibits p53 degradation by preventing MDM2 from interacting with p53, thereby stabilizing p53 and exerting tumor-suppressive effects in colorectal cancer cells with wild-type TP53.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR/Cas9 knockout, ectopic expression, Western blot, p53-null cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and multiple cell-line experiments from single lab, functional epistasis confirmed by p53-null rescue\",\n      \"pmids\": [\"29899406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LACTB regulates PIK3R3 activity to influence PI3K levels, thereby promoting autophagy and inhibiting EMT and proliferation through the PI3K/AKT/mTOR signaling pathway in colorectal cancer cells.\",\n      \"method\": \"RNA-seq, immunoprecipitation, Western blot, Transwell invasion assay, xenograft model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunoprecipitation and RNA-seq with pathway validation, single lab\",\n      \"pmids\": [\"32636680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LACTB directly binds PP1A (protein phosphatase 1A) and attenuates the interaction between PP1A and YAP, resulting in increased YAP phosphorylation at Ser127, decreased YAP nuclear translocation, and YAP inactivation in a LATS1-independent manner, thereby suppressing melanoma progression.\",\n      \"method\": \"Co-immunoprecipitation, overexpression, phospho-YAP detection by Western blot, phosphorylation-defective YAP mutant rescue, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutant rescue, and in vivo data from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33675985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-electron microscopy structures of human LACTB filaments at 2.8–3.1 Å resolution revealed that three interfaces are required for filament assembly, formation of higher-order helical structures facilitates cleavage activity, and the middle region is necessary for substrate hydrolysis but not filament formation; LACTB specifically cleaves peptide bonds adjacent to aspartic acid residues.\",\n      \"method\": \"Cryo-electron microscopy, site-directed mutagenesis, enzymatic activity assays, inhibitor-bound structure (Z-AAD-CMK)\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at near-atomic resolution combined with mutagenesis and activity assays, independently replicated by Bennett et al. 2022\",\n      \"pmids\": [\"35247327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human LACTB self-assembles into micron-scale filaments that increase catalytic activity; residues at the filament-forming interface are required for filamentation, and mutations disrupting filamentation reduce enzyme activity; LACTB filaments can bind lipid membranes.\",\n      \"method\": \"Cryo-EM, site-directed mutagenesis, enzyme activity assays, lipid-binding assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional mutagenesis and lipid-binding assays, independent replication of Zhang et al. 2022 structural findings\",\n      \"pmids\": [\"36534696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LACTB expression leads to cell cycle arrest in G1 phase and increased mitochondrial reactive oxygen species production, which causes DNA oxidation and activation of an intrinsic caspase-independent cell death pathway in breast cancer cells.\",\n      \"method\": \"Protein array, flow cytometry, Western blot, immunofluorescence, cell proliferation assays, 2D/3D cell culture, in vivo experiments\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, protein array, in vivo) from single lab defining the cell death pathway\",\n      \"pmids\": [\"36282364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PCBP1 directly binds LACTB mRNA and promotes its degradation; LACTB upregulation promotes erastin-induced ferroptosis and mitochondrial dysfunction; the ferroptosis-promoting effect of LACTB is mediated through downregulation of PISD (phosphatidylserine decarboxylase), as PISD overexpression reverses LACTB-mediated ferroptosis.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, flow cytometry, JC-1 staining, xenograft model\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down and RIP confirming direct PCBP1-LACTB mRNA binding, with functional epistasis via PISD rescue, single lab\",\n      \"pmids\": [\"37157950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OXCT1 functions as a lysine succinyltransferase (with residue G424 essential for this activity) and succinylates LACTB at lysine K284; this succinylation inhibits LACTB proteolytic activity, resulting in increased mitochondrial membrane potential and respiration, promoting hepatocellular carcinoma progression.\",\n      \"method\": \"In vitro succinyltransferase assay, mass spectrometry, site-directed mutagenesis (G424 in OXCT1; K284 in LACTB), Western blot, enzymatic activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activity, mass spectrometry identification of succinylation site, and mutagenesis validation, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"38176415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LACTB is a novel mitochondrial protease that cleaves and activates phospholipase A2 group VI (PLA2G6); LACTB and downstream PLA2G6 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 against kidney injury.\",\n      \"method\": \"Mouse knockout/overexpression models, genetic epistasis (PLA2G6 KO rescue), lipidomics in mouse and human, in vitro protease assay\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protease-substrate identification with genetic epistasis rescue in vivo, lipidomics, multiple orthogonal methods\",\n      \"pmids\": [\"39561766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Suclg2 suppresses LACTB succinylation at lysine K288 (mouse numbering) in regulatory dendritic cells (diffDCs); Lactb succinylation at this residue activates NF-κB signaling; Suclg2-mediated prevention of Lactb succinylation is required for maintaining the tolerogenic function of diffDCs.\",\n      \"method\": \"Metabolomics, transcriptomics, functional immune assays, succinylation site identification by mass spectrometry, Suclg2 interference\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — succinylation site identified by MS with functional validation in immune cells, single lab\",\n      \"pmids\": [\"37216870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LACTB blocks HSPA8 transcription in a p53-dependent manner in liver cancer; this results in elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signaling, thereby triggering ferroptosis and suppressing liver cancer progression.\",\n      \"method\": \"Overexpression/knockout experiments, Western blot, in vivo xenograft, GPX4/SLC7A11 pathway analysis, p53 binding site mutation\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis with p53 binding site mutation, multiple markers assessed, 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 (IMM) remodeling, which facilitates cytochrome c release; LACTB knockdown reduces cytochrome c release and apoptosis, while overexpression promotes these effects; LACTB does not affect BAX or Drp1 recruitment to mitochondria; purified LACTB directly binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes; LACTB's role in IMM remodeling is independent of OPA1 processing and apoptosis-specific.\",\n      \"method\": \"Knockdown/overexpression, cytochrome c release assay, mitochondrial morphology imaging, purified protein lipid-binding and remodeling assay with cardiolipin-enriched membrane nanotubes\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified protein and lipid membranes, multiple orthogonal methods (KD, OE, direct binding assay), peer-reviewed publication\",\n      \"pmids\": [\"41223265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LACTB has D-aspartyl endopeptidase (DAEP) activity, cleaving proteins at the carboxy terminus of D-aspartic acid residues, including a peptide derived from amyloid β1-10 containing D-Asp at position 7; this activity was identified by structural comparison with bacterial paenidase and confirmed by in vitro assay.\",\n      \"method\": \"In vitro enzymatic assay with D-Asp-containing peptide substrates, structural comparison with bacterial DAEP (paenidase)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic characterization with defined substrates, structural basis provided, single lab\",\n      \"pmids\": [\"40286848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Acetylated KLF5 (at lysine 369) acts as a transcriptional repressor of LACTB; LACTB in turn destabilizes OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion, governing colorectal cancer cell stemness and differentiation.\",\n      \"method\": \"ChIP/protein-DNA interaction assays, Co-IP, CRISPR/Cas9 KO, acetylation mimic/deacetylation mimic KLF5 mutants, Western blot, xenograft model\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein-DNA binding assays and mutagenesis with functional epistasis, single lab\",\n      \"pmids\": [\"41213373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LACTB is identified as a primary enzyme responsible for succinylcarnitine hydrolysis in myeloid cells; loss of LACTB enzymatic activity (enzymatically-dead mice) elevates succinylcarnitine levels and modulates OXPHOS, lipid profiles, and efferocytosis-related functions in microglia.\",\n      \"method\": \"Mendelian randomization, LACTB KD macrophages, LACTB KO iPSC-derived microglia, enzymatically-dead mouse model, metabolomics, lipidomics, transcriptomics, xenotransplantation\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatically-dead mouse model with metabolomics confirming LACTB as succinylcarnitine hydrolase, multiple orthogonal methods, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41929023\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LACTB interacts with CPT2 (carnitine palmitoyltransferase 2) and promotes its ubiquitin-mediated degradation; LACTB overexpression exacerbates hepatic steatosis in high-fat diet mice, and the effect on lipid metabolism is dependent on CPT2.\",\n      \"method\": \"Co-immunoprecipitation, in vivo LACTB KD/overexpression mouse models, Western blot, ubiquitination assay\",\n      \"journal\": \"Diabetes, obesity & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vivo genetic epistasis (CPT2-dependent rescue), single lab\",\n      \"pmids\": [\"41527692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LACTB was expressed as an N-terminal GST fusion protein in E. coli with confirmed secondary structure (alpha-helices, beta-sheets, turns) by FTIR spectrometry, establishing that the protein can be properly folded for biochemical study.\",\n      \"method\": \"Recombinant protein expression, glutathione-agarose affinity chromatography, MALDI-TOF mass spectrometry, immunoblotting, FTIR spectrometry\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — recombinant protein production and structural characterization by FTIR, but no functional enzymatic assay, single study\",\n      \"pmids\": [\"16202624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Double missense mutations M5L and R469K in LACTB (present in 92.31% of osteosarcoma patients) confer oncogene-like functions: LACTB(M5L+R469K) reduces wild-type p53 by enhancing PSMB7 catalytic activity and protects mutant p53(R156P) from lysosomal degradation; clavulanate potassium binds and blocks LACTB(M5L+R469K) to suppress osteosarcoma proliferation.\",\n      \"method\": \"Overexpression of mutant LACTB constructs, PSMB7 activity assays, p53 degradation assays (proteasomal vs lysosomal), drug binding and proliferation assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic assays (proteasome activity, lysosomal degradation pathway) with specific LACTB mutant constructs, single lab\",\n      \"pmids\": [\"39324579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In nasopharyngeal carcinoma, LACTB promotes metastasis by activating ERBB3/EGFR-ERK signaling, which in turn affects stability and acetylation of histone H3; LACTB does not influence cellular proliferation in this context.\",\n      \"method\": \"Overexpression/knockdown, in vitro motility assays, in vivo metastasis model, pathway inhibitor studies, histone modification analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional studies with pathway analysis, single lab; notable context-specific finding (pro-metastatic role)\",\n      \"pmids\": [\"33152401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LACTB suppresses migration and invasion of glioblastoma by downregulating RHOC expression and inhibiting the RHOC/Cofilin signaling pathway.\",\n      \"method\": \"Overexpression in LN229 and U87 cell lines, migration/invasion assays, Western blot for RHOC and Cofilin pathway markers\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic depth (expression-level readout of RHOC/Cofilin), no direct binding or epistasis experiment\",\n      \"pmids\": [\"36088805\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LACTB is a mitochondrial intermembrane space serine protease that polymerizes into filaments to increase its catalytic activity; it specifically cleaves peptide bonds adjacent to D-aspartic acid residues, activates PLA2G6 to regulate phospholipid metabolism and ferroptosis, remodels cardiolipin-enriched inner mitochondrial membranes to facilitate cytochrome c release and apoptosis, reduces PISD levels to alter mitochondrial phosphatidylethanolamine synthesis, and is post-translationally regulated by OXCT1-mediated succinylation at K284 (which inhibits its proteolytic activity); in cancer contexts it acts predominantly as a tumor suppressor by stabilizing p53 (via MDM2 exclusion), promoting cell differentiation, and inducing ferroptosis, though gain-of-function mutations (M5L+R469K) can convert it to an oncogenic regulator of p53 stability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LACTB is a mitochondrial intermembrane-space serine protein, sequence-related to bacterial penicillin-binding proteins and beta-lactamases, that polymerizes into stable micron-scale filaments and organizes intramitochondrial micro-compartments [#0, #1]. Cryo-EM of human LACTB filaments resolved three assembly interfaces and showed that higher-order helical assembly potentiates catalysis, with the filament-forming residues required for full enzymatic activity; LACTB cleaves peptide bonds adjacent to aspartate and exhibits D-aspartyl endopeptidase activity, and its filaments bind lipid membranes [#6, #7, #15]. The enzyme acts on mitochondrial lipid metabolism: it cleaves and activates PLA2G6 to convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine, and lowers phosphatidylserine decarboxylase (PISD) levels, thereby reshaping mitochondrial phospholipid pools, regulating ferroptosis, and driving cancer-cell differentiation [#2, #11]. LACTB preferentially binds and remodels cardiolipin-enriched inner-membrane nanotubes and is required for apoptosis-associated inner-membrane remodeling that facilitates cytochrome c release, independent of BAX/Drp1 recruitment and OPA1 processing [#14]. In cancer it predominantly behaves as a tumor suppressor, stabilizing p53 by excluding MDM2 and triggering p53-dependent ferroptosis programs [#3, #13]. Its proteolytic activity is restrained by post-translational succinylation: OXCT1 succinylates LACTB at K284 to inhibit catalysis and support tumor mitochondrial respiration [#10]. LACTB also functions as a metabolic hydrolase, hydrolyzing succinylcarnitine in myeloid cells and influencing CPT2-dependent hepatic lipid handling [#17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established LACTB as a candidate mammalian serine enzyme by recognizing its active-site motif and homology to bacterial beta-lactamases/penicillin-binding proteins, framing it as a potential protease rather than an uncharacterized ORF.\",\n      \"evidence\": \"Sequence analysis, cDNA cloning, and Northern blot expression profiling\",\n      \"pmids\": [\"11707067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity or substrate demonstrated\", \"Subcellular localization not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved where LACTB acts and how it is organized, showing it localizes to the mitochondrial intermembrane space and self-assembles into stable filaments that compartmentalize the mitochondrion.\",\n      \"evidence\": \"Subcellular fractionation and electron microscopy\",\n      \"pmids\": [\"19858488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Filament assembly determinants unresolved\", \"No catalytic role linked to filamentation yet\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected LACTB to a defined cellular phenotype, demonstrating it suppresses breast cancer proliferation by lowering PISD and rewiring mitochondrial phosphatidylethanolamine synthesis to induce differentiation.\",\n      \"evidence\": \"Overexpression/knockdown, mouse models, and lipidomics with PISD quantification\",\n      \"pmids\": [\"28329758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which LACTB reduces PISD not defined\", \"Direct protease substrate not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided a non-lipid tumor-suppressive mechanism, showing LACTB binds the p53 C terminus and blocks MDM2 to stabilize p53 in wild-type-TP53 colorectal cancer.\",\n      \"evidence\": \"Reciprocal Co-IP, CRISPR knockout, and p53-null rescue\",\n      \"pmids\": [\"29899406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protease activity is required for p53 stabilization unclear\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the structural basis of LACTB catalysis, showing filament assembly via three interfaces potentiates D-aspartate-adjacent peptide bond cleavage and that filaments bind lipid membranes.\",\n      \"evidence\": \"Cryo-EM at 2.8–3.1 Å, site-directed mutagenesis, enzyme and lipid-binding assays (two independent studies)\",\n      \"pmids\": [\"35247327\", \"36534696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological protein substrates not identified from structure\", \"How membrane binding couples to proteolysis unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked LACTB to cell death and stress output, showing its expression causes G1 arrest and mitochondrial ROS-driven caspase-independent death in breast cancer.\",\n      \"evidence\": \"Protein array, flow cytometry, immunofluorescence, and in vivo assays\",\n      \"pmids\": [\"36282364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger of ROS increase undefined\", \"Relationship to its lipid-metabolic role unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed upstream regulation and a ferroptosis output, showing PCBP1 degrades LACTB mRNA and that LACTB promotes erastin-induced ferroptosis through PISD downregulation.\",\n      \"evidence\": \"RNA pull-down, RIP, luciferase reporter, JC-1 staining, and PISD rescue\",\n      \"pmids\": [\"37157950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic basis of PISD reduction unresolved\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a direct succinylation switch, showing OXCT1 succinylates LACTB at K284 to inhibit its proteolytic activity and enhance tumor mitochondrial respiration.\",\n      \"evidence\": \"In vitro succinyltransferase reconstitution, mass spectrometry, and mutagenesis of OXCT1 G424 and LACTB K284\",\n      \"pmids\": [\"38176415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Desuccinylase for K284 not identified\", \"Effect on filament assembly not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointed a bona fide LACTB protease substrate, showing it cleaves and activates PLA2G6 to convert oxidized PE to lyso-PE, with PLA2G6 deletion abolishing LACTB's protective effect against kidney injury.\",\n      \"evidence\": \"Mouse knockout/overexpression, in vivo genetic epistasis (PLA2G6 KO rescue), lipidomics, and in vitro protease assay\",\n      \"pmids\": [\"39561766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PLA2G6 activation explains the cancer phenotypes untested\", \"Filament dependence of PLA2G6 cleavage unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the p53 axis to ferroptosis, showing LACTB represses HSPA8 transcription in a p53-dependent manner to elevate ferritinophagy and inhibit SLC7A11/GPX4 signaling in liver cancer.\",\n      \"evidence\": \"Overexpression/knockout, pathway marker analysis, and p53 binding-site mutation\",\n      \"pmids\": [\"39047638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect transcriptional control of HSPA8 unresolved\", \"How a mitochondrial protease controls nuclear transcription unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated context-dependent oncogenic conversion, showing osteosarcoma-prevalent M5L+R469K mutations make LACTB reduce wild-type p53 and protect mutant p53, with clavulanate blocking this activity.\",\n      \"evidence\": \"Mutant LACTB constructs, PSMB7 activity and proteasomal/lysosomal degradation assays, and drug-binding assays\",\n      \"pmids\": [\"39324579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural impact of mutations on catalysis untested\", \"Single-lab mechanistic model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a direct membrane-remodeling role in apoptosis, showing LACTB binds and remodels cardiolipin-enriched inner-membrane nanotubes to facilitate cytochrome c release independent of BAX/Drp1 and OPA1 processing.\",\n      \"evidence\": \"Knockdown/overexpression, cytochrome c release assays, and purified-protein lipid remodeling on cardiolipin nanotubes\",\n      \"pmids\": [\"41223265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether proteolytic activity is needed for membrane remodeling unresolved\", \"Upstream apoptotic signal that engages LACTB undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined LACTB's catalytic specificity at the chemical level, establishing it as a D-aspartyl endopeptidase that cleaves at the C terminus of D-aspartate residues.\",\n      \"evidence\": \"In vitro enzymatic assays with D-Asp-containing peptide substrates and structural comparison with bacterial paenidase\",\n      \"pmids\": [\"40286848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous D-Asp-containing substrates in vivo not identified\", \"Physiological role of DAEP activity unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a transcriptional-regulatory circuit and a fusion-machinery target, showing acetylated KLF5 represses LACTB while LACTB destabilizes OMA1 to modulate OPA1-mediated fusion and colorectal stemness.\",\n      \"evidence\": \"ChIP/protein-DNA assays, Co-IP, CRISPR knockout, and KLF5 acetylation-mimic mutants\",\n      \"pmids\": [\"41213373\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect OMA1 destabilization unresolved\", \"Single-lab data\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Broadened LACTB's biochemistry to small-molecule metabolism, identifying it as the primary succinylcarnitine hydrolase in myeloid cells and as a regulator of CPT2 stability in hepatic lipid handling.\",\n      \"evidence\": \"Enzymatically-dead mouse model, KO microglia, metabolomics/lipidomics (preprint) and Co-IP with CPT2-dependent in vivo rescue\",\n      \"pmids\": [\"41929023\", \"41527692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Succinylcarnitine hydrolysis result is from a preprint\", \"Whether one active site supports both peptidase and ester-hydrolase activities untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LACTB's single catalytic activity and filament state are switched among its many outputs — phospholipid remodeling, ferroptosis, p53 stabilization, membrane remodeling, and metabolite hydrolysis — and which functions are direct protease-dependent versus indirect remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking filament assembly, substrate choice, and tissue-specific phenotypes\", \"Most cancer mechanisms lack a defined direct protease substrate\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [6, 11, 15]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [15, 17, 18]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 11, 18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8, 14]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 14, 16]}\n    ],\n    \"complexes\": [\"LACTB filament\"],\n    \"partners\": [\"PLA2G6\", \"TP53\", \"OXCT1\", \"CPT2\", \"PP1A\", \"PIK3R3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}