Affinage

LGMN

Legumain · UniProt Q99538

Length
433 aa
Mass
49.4 kDa
Annotated
2026-06-10
19 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGMN (legumain/asparagine endopeptidase) is a conserved lysosomal cysteine endopeptidase that controls lysosomal/autophagic proteolytic capacity and functions across macrophage immunobiology and tumor progression (PMID:8893817, PMID:38582932). Within the endolysosomal system, LGMN is required for maturation of cathepsins L, V, B, and D from single-chain to two-chain form and for nuclear localization of cathepsin L; this processing is indirect, since recombinant legumain does not directly cleave these cathepsins [PMID:bio_10.1101_2025.08.17.670765]. Loss of LGMN impairs lysosomal/autophagic degradation and reduces the migratory, invasive, and metastatic capacity of cancer cells, where it acts upstream of MMP2/MMP9 and within an AKT/mTOR/autophagy axis (PMID:27656894, PMID:36464174, PMID:38582932). LGMN translation is enhanced by METTL3-deposited m6A modification of its mRNA read by YTHDF1, and in macrophages elevated LGMN drives ox-LDL-induced ferroptosis, lipid deposition, and inflammation to promote atherosclerotic plaque formation (PMID:41506595). In tumor-associated and M2 macrophages, LGMN supports a tumor-supportive, pro-fibrotic program: macrophage-specific deletion reprograms TAMs toward an anti-tumor phenotype, reduces Treg infiltration, increases CD8+ T cell infiltration, and lowers VEGF-A, while pharmacological LGMN inhibition reduces TGF-β1 secretion and macrophage-fibroblast crosstalk (PMID:42058204, PMID:42051490). LGMN also assembles into an ITGA5/FAPα/LGMN complex that promotes osteosarcoma progression (PMID:41086694).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1996 Medium

    Established LGMN as a distinct human cysteine protease, defining the gene product and placing it within a conserved protease family.

    Evidence cDNA cloning, sequence analysis, and FISH chromosomal mapping to 14q32.1

    PMID:8893817

    Open questions at the time
    • No enzymatic activity validated in this study
    • Substrate repertoire and subcellular localization not defined
  2. 2016 Medium

    Placed LGMN upstream of matrix metalloproteinases in cancer cell invasion, linking the protease to an extracellular degradation program.

    Evidence shRNA knockdown in breast cancer cells with MMP2/MMP9 immunoblot and invasion assays

    PMID:27656894

    Open questions at the time
    • Mechanism linking LGMN to MMP2/MMP9 expression not resolved
    • Direct substrates not identified
  3. 2022 Medium

    Positioned LGMN within the AKT/mTOR/autophagy axis by showing its suppression phenocopies metformin-induced inhibition of proliferation and invasion.

    Evidence siRNA knockdown, pharmacological autophagy modulation, and xenograft in choriocarcinoma cells

    PMID:36464174

    Open questions at the time
    • Whether LGMN acts directly on AKT/mTOR components or downstream is unresolved
    • Causality vs. correlation in autophagy induction not fully dissected
  4. 2024 Medium

    Demonstrated that LGMN is genetically required for lysosomal/autophagic degradation and metastatic capacity, moving beyond expression correlations to loss-of-function.

    Evidence CRISPR/Cas9 editing via LNP delivery with invasion/migration and lung metastasis models in breast cancer cells

    PMID:38582932

    Open questions at the time
    • Molecular substrates underlying degradation defect not identified
    • Single tumor type tested
  5. 2025 Medium

    Defined LGMN's lysosomal mechanism by showing it is required for cathepsin (L/V/B/D) maturation and cathepsin L nuclear localization, while establishing the action is indirect.

    Evidence LGMN-knockout cells, activity-based probes, negative recombinant cleavage assay, and N-terminomics (NICE)

    PMID:bio_10.1101_2025.08.17.670765

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Intermediary linking LGMN to cathepsin processing unidentified
    • Putative nuclear substrates not validated
  6. 2025 Medium

    Identified an ITGA5/FAPα/LGMN protein complex driving osteosarcoma progression, defining LGMN's first characterized physical partners.

    Evidence Reciprocal Co-IP, immunofluorescence, and xenograft with individual inhibitor treatments

    PMID:41086694

    Open questions at the time
    • Mechanism by which the complex drives progression not dissected
    • Stoichiometry and direct vs. bridged interactions unresolved
  7. 2025 Low

    Proposed CST6 as a regulatory interaction partner of LGMN in placental endothelial dysfunction.

    Evidence Recombinant CST6 treatment with expression analysis in TNFα-treated endothelial cells and trophoblast model

    PMID:40234537

    Open questions at the time
    • No direct binding assay performed; interaction inferred from expression changes
    • Functional consequence on LGMN enzymatic activity not measured
  8. 2026 High

    Traced an m6A regulatory circuit (METTL3 writer → YTHDF1 reader) that boosts LGMN translation in macrophages to drive ferroptosis and atherosclerosis.

    Evidence m6A analysis, YTHDF1 binding, METTL3 perturbation, macrophage-specific LGMN knockdown, and mouse atherosclerosis model

    PMID:41506595

    Open questions at the time
    • Protease substrates mediating ferroptosis not identified
    • Link between LGMN catalytic activity and lipid peroxidation unresolved
  9. 2026 Medium

    Showed macrophage LGMN sustains a tumor-supportive and pro-fibrotic microenvironment via TAM polarization, T-cell modulation, VEGF-A, and TGF-β1.

    Evidence Macrophage-specific conditional knockout (gastric cancer) and RR-11a pharmacological inhibition (bleomycin lung fibrosis) with scRNA-seq, immunofluorescence, and secretion assays

    PMID:42051490 PMID:42058204

    Open questions at the time
    • Direct LGMN substrates controlling VEGF-A and TGF-β1 not defined
    • Whether effects are cell-autonomous to macrophages or via cathepsin processing is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct proteolytic substrates of LGMN that link its asparagine endopeptidase activity to the diverse phenotypes (cathepsin maturation, MMP regulation, ferroptosis, immune reprogramming) remain unidentified.
  • No validated direct substrate connects catalytic activity to downstream effectors
  • Indirect mechanism of cathepsin processing not mechanistically resolved
  • Structural basis of partner interactions (ITGA5/FAPα) unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005764 lysosome 2
Pathway
R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-392499 Metabolism of proteins 1
Partners
CST6FAPALPHAITGA5
Complex memberships
ITGA5/FAPα/LGMN complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 LGMN (PRSC1) encodes a novel human cysteine protease of 433 amino acids with 40% sequence identity to Schistosoma japonicum hemoglobinase and 36% identity to a soybean vacuolar-processing cysteine protease, establishing it as a conserved cysteine protease family member; chromosomal location determined at 14q32.1 by fluorescence in situ hybridization. cDNA cloning, sequence analysis, northern blot, fluorescence in situ hybridization Cytogenetics and cell genetics Medium 8893817
2016 Knockdown of LGMN in breast cancer cells downregulates MMP2 and MMP9 expression and impairs colony formation, migration, and invasion, placing LGMN upstream of matrix metalloproteinases in breast cancer invasiveness. shRNA-mediated knockdown, western blotting, colony formation assay, invasion assay PloS one Medium 27656894
2022 Metformin induces autophagy in choriocarcinoma cells by suppressing LGMN expression through the AKT/mTOR/LC3II signaling pathway; LGMN knockdown phenocopies metformin-induced inhibition of proliferation and invasion, placing LGMN within the AKT/mTOR autophagy axis. siRNA knockdown, western blotting, high-throughput sequencing, autophagy inhibitor/inducer pharmacological experiments, xenograft model Gene Medium 36464174
2024 CRISPR/Cas9-mediated editing of LGMN impairs lysosomal/autophagic degradation and reduces migration, invasion, and experimental lung metastasis of breast cancer cells, demonstrating that LGMN is required for lysosomal/autophagic function and metastatic capacity. CRISPR/Cas9 gene editing via lipid nanoparticle delivery of Cas9 mRNA + gRNA, invasion/migration assays, experimental lung metastasis model Scientific reports Medium 38582932
2025 LGMN is required for processing of cathepsins L, V, B, and D from single-chain to two-chain form in cells; in LGMN-knockout cells this processing is abrogated. The mechanism is indirect since recombinant legumain does not directly cleave cathepsins in vitro. Loss of LGMN also reduces nuclear localization of cathepsin L (which preferentially exists in double-chain form in the nucleus). N-terminomics (NICE pipeline) identified putative nuclear substrates of LGMN and cathepsin L, suggesting roles in cell proliferation, cell cycle regulation, inflammation, and ribosomal biogenesis. LGMN-knockout cell lines, chemical activity-based probes, immunoblots, recombinant protein cleavage assay (negative for direct cleavage), chemical N-terminomics (NICE pipeline) bioRxivpreprint Medium bio_10.1101_2025.08.17.670765
2026 METTL3-dependent N6-methyladenosine (m6A) modification of LGMN mRNA enhances its translation via YTHDF1 binding to m6A-methylated LGMN mRNA; elevated LGMN in macrophages promotes ox-LDL-induced ferroptosis, lipid deposition, and inflammatory responses, driving atherosclerosis plaque formation. Macrophage-specific LGMN knockdown reduces plaque formation and ferroptosis in vivo. RNA-sequencing, m6A modification analysis, YTHDF1 binding assay, macrophage-specific LGMN knockdown (in vivo and in vitro), METTL3 knockdown/overexpression, ferroptosis assays, lipid deposition assays, mouse atherosclerosis model Journal of molecular and cellular cardiology High 41506595
2026 Macrophage-specific conditional knockout of LGMN (LGMNflox/flox; Lyz2-Cre) inhibits gastric cancer tumor growth by reprogramming TAMs toward an anti-tumor phenotype, reducing Treg cell infiltration, enhancing CD8+ T cell infiltration, and inhibiting tumor angiogenesis by downregulating VEGF-A expression. Macrophage-specific conditional knockout mouse model, subcutaneous xenograft model, immunofluorescence, tube formation assay, scRNA-seq, bulk RNA-seq analysis Frontiers in immunology Medium 42058204
2026 LGMN is elevated in M2 macrophages and co-localizes with CD206 in fibrotic lung tissue; pharmacological inhibition of LGMN with RR-11a reduces TGF-β1 secretion from M2 macrophages, thereby diminishing macrophage-fibroblast crosstalk and alleviating bleomycin-induced pulmonary fibrosis in mice. LGMN inhibitor (RR-11a) treatment, immunofluorescence co-localization, TGF-β1 secretion assay, bleomycin pulmonary fibrosis mouse model, in vitro M2 macrophage culture Frontiers in immunology Medium 42051490
2025 LGMN forms a protein complex with ITGA5 and FAPα in osteosarcoma cells, as confirmed by co-immunoprecipitation and immunofluorescence; polyethylene microplastic exposure upregulates ITGA5, which promotes assembly of this complex and drives cancer progression in a dose-dependent manner. Inhibitors targeting ITGA5, FAPα, or LGMN individually partially alleviate tumor growth in vivo. Co-immunoprecipitation (Co-IP), immunofluorescence staining, high-throughput sequencing, subcutaneous xenograft mouse model, pharmacological inhibition Ecotoxicology and environmental safety Medium 41086694
2025 CST6 (Cystatin 6), a cysteine protease inhibitor, is a high-affinity target interaction partner of LGMN in the placenta; administration of recombinant CST6 to endothelial cells enhances endothelial dysfunction markers and LGMN expression in the presence of TNFα, suggesting a regulatory relationship between CST6 and LGMN activity. mRNA expression analysis, recombinant protein treatment, endothelial cell dysfunction assays (TNFα model), human trophoblast stem cell differentiation model Scientific reports Low 40234537

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 The extracellular vesicular pseudogene LGMNP1 induces M2-like macrophage polarization by upregulating LGMN and serves as a novel promising predictive biomarker for ovarian endometriosis recurrence. Human reproduction (Oxford, England) 43 34893848
2021 Circular RNA circLGMN facilitates glioblastoma progression by targeting miR-127-3p/LGMN axis. Cancer letters 35 34582975
2023 Role of LGMN in tumor development and its progression and connection with the tumor microenvironment. Frontiers in molecular biosciences 33 36825203
2020 The LGMN pseudogene promotes tumor progression by acting as a miR-495-3p sponge in glioblastoma. Cancer letters 30 32711096
1996 Molecular cloning of a human cDNA encoding putative cysteine protease (PRSC1) and its chromosome assignment to 14q32.1. Cytogenetics and cell genetics 16 8893817
2024 Co-delivery of Cas9 mRNA and guide RNAs for editing of LGMN gene represses breast cancer cell metastasis. Scientific reports 12 38582932
2023 Integrative analysis of TBI data reveals Lgmn as a key player in immune cell-mediated ferroptosis. BMC genomics 12 38057699
2020 Down-regulation of lncRNA PCGEM1 inhibits cervical carcinoma by modulating the miR-642a-5p/LGMN axis. Experimental and molecular pathology 11 33121976
2022 Metformin regulates autophagy via LGMN to inhibit choriocarcinoma. Gene 8 36464174
2020 Lack of association between LGMN and Alzheimer's disease in the Southern Han Chinese population. The European journal of neuroscience 6 32506655
2016 MiRNA-Embedded ShRNAs for Radiation-Inducible LGMN Knockdown and the Antitumor Effects on Breast Cancer. PloS one 5 27656894
2025 Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia. Scientific reports 4 40234537
2023 Immune modulation of goat monocytes by Fasciola gigantica Legumain-1 protein (Fg-LGMN-1). Experimental parasitology 3 38081528
2025 Polyethylene microplastics trigger osteosarcoma progression via ITGA5/FAPα/LGMN cancer promoting complex: A novel environmental cancer promoting mechanism. Ecotoxicology and environmental safety 1 41086694
2026 METTL3-dependent N6-methyladenosine modification on LGMN mRNA promotes macrophage ferroptosis and atherosclerosis. Journal of molecular and cellular cardiology 0 41506595
2026 Lgmn targets two distinct GPCRs, PAR2 and µ-OR1, and induces cell death in acute lymphoblastic leukemia through an intracellular Ca²⁺ imbalance triggered by ER Ca²⁺ release. Cell death discovery 0 41792098
2026 LGMN promotes crosstalk between macrophages and fibroblasts in pulmonary fibrosis: a potential therapeutic target. Frontiers in immunology 0 42051490
2026 LGMN+ macrophage promotes the formation of a tumor-supportive microenvironment in gastric cancer. Frontiers in immunology 0 42058204
2025 Comparing the Interactions of Trichomonas vaginalis/gallinae Legumain-Like Cysteine Protease 1 (LEGU-1) and Human Legumain (LGMN) Protein Sequences with Proton Pump Inhibitor Drugs (Lansoprazole, Omeprazole, and Esomeprazole) by Bioinformatics Analyses. Acta parasitologica 0 41410717

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