Affinage

LACTB

Serine beta-lactamase-like protein LACTB, mitochondrial · UniProt P83111

Length
547 aa
Mass
60.7 kDa
Annotated
2026-04-28
44 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    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

    PMID:11707067

    Open questions at the time
    • No enzymatic activity demonstrated
    • Subcellular localization not experimentally confirmed
    • No substrate identified
  2. 2009 High

    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

    PMID:19858488

    Open questions at the time
    • Filament function and relationship to catalysis unknown
    • No substrates identified
    • No physiological phenotype from loss-of-function
  3. 2017 High

    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

    PMID:28329758

    Open questions at the time
    • 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
  4. 2018 Medium

    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

    PMID:29899406

    Open questions at the time
    • 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
  5. 2021 Medium

    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

    PMID:33675985

    Open questions at the time
    • Single-lab study
    • Whether LACTB's protease activity is required for PP1A sequestration untested
    • Compartment where LACTB–PP1A interaction occurs not resolved
  6. 2022 High

    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

    PMID:35247327 PMID:36534696

    Open questions at the time
    • 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
  7. 2022 Medium

    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

    PMID:36282364 PMID:36375842

    Open questions at the time
    • Direct proteolytic link to Slug downregulation not shown
    • Caspase-independent death mechanism not fully defined
    • Each study from a single lab
  8. 2023 High

    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

    PMID:37216870 PMID:38176415

    Open questions at the time
    • 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
  9. 2024 High

    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

    PMID:39561766

    Open questions at the time
    • Cleavage site on PLA2G6 not mapped
    • Whether PLA2G6 activation accounts for the PISD reduction phenotype unknown
    • Relevance to non-renal tissues not tested
  10. 2025 High

    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

    PMID:40286848

    Open questions at the time
    • 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
  11. 2025 High

    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

    PMID:41223265

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0005198 structural molecule activity 3 GO:0008289 lipid binding 2
Localization
GO:0005739 mitochondrion 5
Pathway
R-HSA-1643685 Disease 6 R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 2
Partners
CPT2MDM2OMA1OXCT1PISDPLA2G6PPP1CATP53

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. Subcellular fractionation, electron microscopy, direct localization experiment Proceedings of the National Academy of Sciences of the United States of America High 19858488
2001 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. Sequence cloning, database searching, Northern blot, genomic mapping Genomics High 11707067
2005 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. Recombinant protein expression, glutathione-agarose affinity chromatography, MALDI-TOF mass spectrometry, FTIR spectroscopy Protein expression and purification Medium 16202624
2017 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. In vitro and in vivo mouse/human studies, lipidomic analysis, loss-of-function and gain-of-function experiments Nature High 28329758
2018 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. Co-immunoprecipitation, CRISPR/Cas9 knockout, ectopic overexpression, in vitro and in vivo assays Oncogene Medium 29899406
2020 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. Immunoprecipitation, RNA-seq, Western blotting, transmission electron microscopy, xenograft model Cancer management and research Medium 32636680
2021 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. Co-immunoprecipitation, overexpression, phosphorylation-defective YAP mutants, in vivo xenograft Cancer letters Medium 33675985
2022 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. Cryo-electron microscopy structure determination, activity assays, deletion mutagenesis Structure (London, England : 1993) High 35247327
2022 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. Cryo-electron microscopy, site-directed mutagenesis, enzyme activity assays, lipid membrane binding assays PLoS biology High 36534696
2022 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. Protein array, flow cytometry, cell proliferation assays, immunofluorescence, in vivo experiments, western blot Apoptosis : an international journal on programmed cell death Medium 36282364
2022 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. In vitro, in vivo, and 3D culture experiments with overexpression and loss-of-function Life science alliance Medium 36375842
2023 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. RNA pull-down, RNA immunoprecipitation, luciferase reporter assay, CCK-8, flow cytometry, JC-1 staining, xenograft model Molecular carcinogenesis Medium 37157950
2024 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. In vitro succinyltransferase assay, mass spectrometry identification of succinylation sites, mutagenesis, western blotting, functional metabolic assays Molecular cell High 38176415
2023 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. Metabolomic, transcriptomic, and functional investigations; Suclg2 interference experiments; NF-κB signaling assays Journal of autoimmunity Medium 37216870
2024 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. Mouse knockout and tubule-specific overexpression, genetic epistasis (double-KO), lipidomic studies in mouse and human, in vivo kidney injury models Cell metabolism High 39561766
2024 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. LACTB knockout and ectopic overexpression, western blot, in vivo xenograft, p53-binding site mutation experiments Redox biology Medium 39047638
2025 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. LACTB knockdown/overexpression, cytochrome c release assays, purified protein membrane remodeling assay with cardiolipin-enriched nanotubes, apoptosis flow cytometry Science advances High 41223265
2025 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. In vitro DAEP activity assay with peptide substrates, structural comparison with bacterial paenidase The Journal of biological chemistry High 40286848
2025 LACTB destabilizes OMA1 protein, thereby modulating OPA1-mediated mitochondrial fusion; upstream, acetylated KLF5 (at K369) acts as a transcriptional repressor of LACTB. CRISPR/Cas9 KLF5 knockout, acetylation-mimic and deacetylation-mimic KLF5 mutants, protein-protein and protein-DNA interaction assays, xenograft model, western blot International journal of biological macromolecules Medium 41213373
2026 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. Co-immunoprecipitation, LACTB overexpression and knockdown in vivo and in vitro, HFD mouse model, western blot Diabetes, obesity & metabolism Medium 41527692
2024 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. Mutagenesis, PSMB7 activity assays, protein stability assays, in vitro and in vivo overexpression, drug binding/inhibition assay Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 39324579

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature 152 28329758
2018 LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation. Oncogene 76 29899406
2009 LACTB is a filament-forming protein localized in mitochondria. Proceedings of the National Academy of Sciences of the United States of America 72 19858488
2024 OXCT1 functions as a succinyltransferase, contributing to hepatocellular carcinoma via succinylating LACTB. Molecular cell 65 38176415
2020 LACTB Regulates PIK3R3 to Promote Autophagy and Inhibit EMT and Proliferation Through the PI3K/AKT/mTOR Signaling Pathway in Colorectal Cancer. Cancer management and research 49 32636680
2001 Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain. Genomics 38 11707067
2015 MicroRNA-125b-5p attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production by targeting inhibiting LACTB in THP-1 macrophages. Archives of biochemistry and biophysics 32 26603571
2021 LACTB suppresses melanoma progression by attenuating PP1A and YAP interaction. Cancer letters 31 33675985
2017 Overexpression of LACTB, a Mitochondrial Protein That Inhibits Proliferation and Invasion in Glioma Cells. Oncology research 30 28835318
2020 LACTB promotes metastasis of nasopharyngeal carcinoma via activation of ERBB3/EGFR-ERK signaling resulting in unfavorable patient survival. Cancer letters 26 33152401
2023 PCBP1 protects bladder cancer cells from mitochondria injury and ferroptosis by inducing LACTB mRNA degradation. Molecular carcinogenesis 24 37157950
2024 LACTB suppresses liver cancer progression through regulation of ferroptosis. Redox biology 21 39047638
2021 LACTB induced apoptosis of oxaliplatin-resistant gastric cancer through regulating autophagy-mediated mitochondrial apoptosis pathway. American journal of translational research 19 33594312
2020 MicroRNA-1276 Promotes Colon Cancer Cell Proliferation by Negatively Regulating LACTB. Cancer management and research 19 33273855
2005 Expression and purification of the mitochondrial serine protease LACTB as an N-terminal GST fusion protein in Escherichia coli. Protein expression and purification 18 16202624
2023 Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation. Journal of autoimmunity 16 37216870
2022 Structural basis for the catalytic activity of filamentous human serine beta-lactamase-like protein LACTB. Structure (London, England : 1993) 14 35247327
2022 LACTB suppresses carcinogenesis in lung cancer and regulates the EMT pathway. Experimental and therapeutic medicine 13 35222724
2022 Unveiling the Function of the Mitochondrial Filament-Forming Protein LACTB in Lipid Metabolism and Cancer. Cells 13 35626737
2022 The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. PLoS biology 11 36534696
2020 Pinocembrin Inhibits the Proliferation, Migration, Invasiveness, and Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Regulating LACTB. Cancer biotherapy & radiopharmaceuticals 11 33395536
2024 Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome. Cell metabolism 10 39561766
2022 LACTB induces cancer cell death through the activation of the intrinsic caspase-independent pathway in breast cancer. Apoptosis : an international journal on programmed cell death 10 36282364
2021 Targeted Nanotherapeutics Using LACTB Gene Therapy Against Melanoma. International journal of nanomedicine 10 34819728
2022 LACTB suppresses migration and invasion of glioblastoma via downregulating RHOC/Cofilin signaling pathway. Biochemical and biophysical research communications 9 36088805
2021 LACTB and LC3 could serve as potential biomarkers of gastric cancer to neoadjuvant chemotherapy with oxaliplatin plus S-1. Oncology letters 8 33907580
2022 LACTB, a Metabolic Therapeutic Target in Clinical Cancer Application. Cells 7 36078157
2022 LACTB exerts tumor suppressor properties in epithelial ovarian cancer through regulation of Slug. Life science alliance 7 36375842
2024 SNPs Give LACTB Oncogene-Like Functions and Prompt Tumor Progression via Dual-Regulating p53. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 39324579
2025 The Pivotal Role of LACTB in the Process of Cancer Development. International journal of molecular sciences 3 39941048
2023 A potential therapeutic approach for gastric cancer: inhibition of LACTB transcript 1. Aging 3 38149985
2025 Discovery and biochemical characterization of the D-aspartyl endopeptidase activity of the serine protease LACTB. The Journal of biological chemistry 2 40286848
2025 Study on the regulation of gastric cancer cell apoptosis by LACTB through mitochondrial autophagy pathway. Scientific reports 2 40603395
2025 A Near-Infrared Fluorescent Probe for Monitoring of LACTB Activity in NSCLC Diagnosis and Therapy. Analytical chemistry 2 40711831
2025 EBV-miR-BART14-3p Targets LACTB to Enhance Gastric Cancer Cell Proliferation and Migration. Biochemical genetics 1 39903432
2025 LACTB promotes cell differentiation and inhibits cell proliferation in colorectal cancer. Biochimica et biophysica acta. General subjects 1 40354832
2021 [Alternative Splicing Analysis of LACTB Gene and Expression Characteristics of Different Transcripts in Leukemia Cell Lines]. Zhongguo shi yan xue ye xue za zhi 1 34362477
2026 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. Diabetes, obesity & metabolism 0 41527692
2026 LINC00852 inhibits colorectal cancer progression by regulating cell apoptosis, epithelial‒mesenchymal transition, invasion, and cuproptosis through miR-1276/LACTB. RNA biology 0 41775345
2026 Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine levels and reduced Alzheimers disease risk. bioRxiv : the preprint server for biology 0 41929023
2026 Fiber type-specific expression of LACTB leverages a function in oxidative metabolism. Histochemistry and cell biology 0 42000972
2025 Acetylated KLF5 inhibits LACTB transcription, mediates mitochondrial dynamics, and regulates colorectal cancer cell stemness and differentiation. International journal of biological macromolecules 0 41213373
2025 The tumor suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis. Science advances 0 41223265
2024 Protocol for identifying OXCT1-mediated LACTB succinylation sites in vitro. STAR protocols 0 38787728