{"gene":"PLOD1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":1992,"finding":"Human lysyl hydroxylase (PLOD1) was cloned and sequenced; it encodes a 709 amino acid polypeptide (plus 18 aa signal peptide) that catalyzes hydroxylation of lysine residues in peptide linkages (EC 1.14.11.4), forming hydroxylysine in collagens. The C-terminal region (especially residues 639-715) is 99% identical between human and chick, suggesting functionally significant sequences in this region. The gene was mapped to chromosome 1p36.2-1p36.3.","method":"cDNA cloning from human placenta lambda gt11 library, sequence analysis, Southern blot of somatic cell hybrids, in situ hybridization","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cDNA cloning with complete coding sequence determination, functional annotation by enzymatic activity, replicated across species","pmids":["1577494"],"is_preprint":false},{"year":1994,"finding":"The human PLOD1 gene contains 19 exons; introns 9 and 16 contain multiple Alu sequences generating extensive homology and potential recombination sites, explaining the common multi-exon duplication (exons 10-16) mutation found in Ehlers-Danlos syndrome type VI patients. The gene's 5' flanking region has housekeeping gene characteristics consistent with constitutive expression.","method":"Genomic clone isolation, intron sequencing, Alu repeat mapping, analysis of patient genomic DNA","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — complete gene structure determination with mechanistic explanation for recombination hotspot, replicated in multiple patients","pmids":["7713497"],"is_preprint":false},{"year":2000,"finding":"Loss-of-function mutations in PLOD1 (including frameshift 1702insC and nonsense mutations Y142X, Q327X, R670X, Y511X, and a common 7-exon duplication) cause deficiency of lysyl hydroxylase 1 activity (<25% of normal) in Ehlers-Danlos syndrome type VI patients. Alternative splicing pathways that bypass premature termination codons were identified.","method":"Full-length cDNA amplification and sequencing from patient dermal fibroblasts, genomic DNA verification, enzymatic activity assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct enzymatic activity measurement in patient fibroblasts combined with molecular characterization of mutations in multiple unrelated patients","pmids":["10874315"],"is_preprint":false},{"year":2005,"finding":"A systematic mutation analysis strategy for PLOD1 using cDNA and/or gDNA identified multiple disease-causing mutations in 9 index EDS VIA patients including novel frameshift (p.Ile454IlefsX2), missense (p.Ala667Thr), and nonsense (p.His706Arg) mutations, as well as the common exons 10-16 duplication, confirming that diverse loss-of-function mutations throughout PLOD1 cause lysyl hydroxylase deficiency.","method":"cDNA and genomic DNA sequencing, mutation analysis strategy combining both substrates","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic molecular diagnosis with multiple independent patients, multiple mutation types confirmed","pmids":["15979919"],"is_preprint":false},{"year":2021,"finding":"LH1 (PLOD1) deficiency in mice promotes angiotensin II-induced dissecting abdominal aortic aneurysm. LH1 deficiency upregulates thrombospondin-1, which drives proinflammatory processes, MMP activation, and VSMC apoptosis. Restoration of LH1 via AAV injection normalized thrombospondin-1 levels and alleviated AAA formation. LH1 is essential for type I/III collagen intermolecular crosslinking and stabilization in the aorta.","method":"LH1-deficient mouse model (C57Bl/6), Ang II osmotic pump infusion, whole-transcriptomic analysis, AAV rescue, pharmacologic thrombospondin-1 inhibition (TAX2), histology, MMP activity assay","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotypic readout, AAV rescue experiment, multiple orthogonal mechanistic methods in one study","pmids":["34646388"],"is_preprint":false},{"year":2021,"finding":"A PLOD1 missense variant p.(Ser178Arg) affecting the N-terminal glycosyltransferase domain was identified in familial thoracic aortic aneurysm/dissection. In vitro assays demonstrated that wild-type PLOD1 processes UDP-glycan donor substrates (glucosyltransferase activity), representing a previously unrecognized enzymatic function. The variant affects folding stability of the glycosyltransferase domain and attenuates procollagen gene upregulation in VSMCs overexpressing wild-type PLOD1. si-PLOD1 cells showed hypercontractility and upregulation of contractile markers.","method":"In vitro UDP-glycan processing assay, comparison with PLOD3 homolog, VSMC overexpression/knockdown, enzymatic activity measurement, collagen fibril analysis","journal":"Translational research : the journal of laboratory and clinical medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — novel enzymatic activity demonstrated in vitro, single lab, limited replication","pmids":["34400365"],"is_preprint":false},{"year":2023,"finding":"PLOD1 (LH1) promotes confined migration and metastasis of cancer cells by binding and stabilizing Septin2 (SEPT2), thereby facilitating actin polymerization. This function depends on the hydroxylase domain of LH1. LH1 bound SEPT2 as identified by immunoprecipitation followed by LC-MS.","method":"Immunoprecipitation/LC-MS identification of LH1-binding proteins, FRET, FRAP, immunofluorescence, microfluidic confined migration assay, 3D invasion assay, orthotopic mouse model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with LC-MS validation, multiple orthogonal methods, single lab","pmids":["36721170"],"is_preprint":false},{"year":2023,"finding":"PLOD1 interacts with Epstein-Barr virus EBNA1 protein and hydroxylates EBNA1 at lysine K460 and/or K461. Mutation of K460 (but not K461) abrogates EBNA1-driven oriP DNA replication without affecting DNA binding. Mutations in both K460 and K461 perturb interactions with PLOD1 and decrease EBNA1 protein stability. PLOD1 depletion by shRNA causes loss of EBNA1 protein levels, loss of EBV episomes, and inhibition of oriP-dependent DNA replication.","method":"Proteomic analysis (Co-IP/MS), shRNA depletion, small molecule inhibition, mass spectrometry identification of hydroxylated EBNA1 peptides, site-directed mutagenesis of K460/K461, oriP replication assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro hydroxylation identified by MS, mutagenesis of substrate lysines with functional readout, multiple orthogonal methods in single study","pmids":["37262099"],"is_preprint":false},{"year":2020,"finding":"lnc-URIDS (a lncRNA) interacts with PLOD1 protein and reduces its protein stability, leading to decreased collagen production and deposition and delayed wound healing in diabetes. PLOD1 is identified as a critical enzyme responsible for collagen cross-linking in dermal fibroblasts, and its protein stability is regulated post-translationally by lnc-URIDS binding.","method":"lncRNA-protein interaction assay, knockdown in vitro and in vivo diabetic wound healing model, protein stability analysis","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct protein-lncRNA interaction demonstrated, functional consequence shown in vivo, single lab","pmids":["32801140"],"is_preprint":false},{"year":2021,"finding":"PLOD1 knockdown in glioblastoma stem cells inhibits tumor viability, proliferation, migration, and mesenchymal transition, while promoting apoptosis. PLOD1 expression is enhanced in hypoxic environments, and its tumor-promoting effects are associated with activation of the NF-κB signaling pathway as revealed by bioinformatics and molecular experiments.","method":"shRNA knockdown in patient-derived glioma stem cells, tumor xenograft, NF-κB pathway reporter assays, hypoxia experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD/OE with cellular phenotype and pathway identification, single lab, limited mechanistic depth for NF-κB link","pmids":["33420370"],"is_preprint":false},{"year":2020,"finding":"PLOD1 inactivates the Hippo-YAP pathway in osteosarcoma by inhibiting phosphorylation of LATS1 (p-LATS1) and YAP (p-YAP), leading to increased nuclear YAP distribution. PLOD1 is itself a direct target of miR-34c, which inhibits PLOD1 expression by binding its 3'-UTR and suppresses OS cell growth.","method":"Gain/loss-of-function assays, immunofluorescence for YAP nuclear distribution, luciferase 3'-UTR reporter assay for miR-34c/PLOD1, in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter for miR-34c targeting, multiple cellular phenotype readouts, single lab","pmids":["32446383"],"is_preprint":false},{"year":2021,"finding":"PLOD1 promotes cell growth and aerobic glycolysis in gastric cancer by activating the SOX9/PI3K/Akt/mTOR signaling pathway; PLOD1 overexpression increases SOX9, p-Akt/Akt and p-mTOR/mTOR levels, and SOX9 overexpression rescues PLOD1 knockdown-mediated inhibition of cell viability and glycolysis.","method":"MTT, EDU, colony formation assays; glycolysis metabolic assays (glucose uptake, lactate, ATP, OCR, ECAR); Western blot for pathway proteins; rescue experiments with SOX9 overexpression; in vivo xenograft","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement via rescue experiment, single lab, no direct biochemical interaction demonstrated","pmids":["34455762"],"is_preprint":false},{"year":2023,"finding":"SIRT6 deficiency in mice reduces Plod1 expression at both mRNA and protein levels in ovarian granulosa cells, leading to decreased collagen crosslinking and deposition in the ovarian stroma and impaired follicular development. This places Plod1 downstream of SIRT6 in ovarian collagen homeostasis.","method":"SIRT6 knockout mouse model, RNA and protein expression analysis in ovaries and granulosa cells, collagen histology","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis (KO mouse) with defined collagen phenotype, single lab, no direct enzymatic rescue","pmids":["37936548"],"is_preprint":false},{"year":2025,"finding":"Gluconic acid (GLA) directly binds PLOD1 protein and promotes its autophagy-lysosomal degradation, reducing p-AKT signaling and activating autophagy to attenuate hypertrophic scar formation. PLOD1 degradation was confirmed by pull-down, cellular thermal shift assay, co-localization studies, and autophagy inhibitor experiments.","method":"Molecular docking, pull-down assay, cellular thermal shift assay (CETSA), co-localization, autophagic flux assay, transmission electron microscopy, Western blot, rabbit ear scar model","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple biophysical binding assays (CETSA, pull-down, co-localization) confirming direct GLA-PLOD1 interaction, single lab","pmids":["40339550"],"is_preprint":false},{"year":2025,"finding":"PLOD1 promotes proliferation and stemness of hepatocellular carcinoma cells by positively regulating the NF-κB/IL-6/STAT3 signaling pathway and accelerating TCA cycle metabolic reprogramming. Blocking NF-κB/IL-6/STAT3 or TCA cycle mitigates PLOD1-induced proliferation/stemness. AAV-mediated hepatic PLOD1 knockdown reduces HCC progression in mice.","method":"RNA-seq, untargeted metabolomics, CCK8, flow cytometry, sphere formation, ALDH activity, subcutaneous/orthotopic/hepatotoxin-induced mouse models, pathway inhibitor experiments","journal":"JHEP reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multi-omics with pharmacologic pathway blockade and in vivo AAV KD, single lab","pmids":["40290518"],"is_preprint":false},{"year":2019,"finding":"Transcriptome profiling of patient-derived PLOD1-kEDS skin fibroblasts revealed differential expression of extracellular matrix component genes, genes involved in ER stress, protein trafficking, inner ear development, and vascular remodeling compared to controls, establishing distinct molecular features specific to PLOD1-kEDS versus FKBP14-kEDS.","method":"RNA sequencing of patient-derived skin fibroblasts, differential gene expression analysis","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomics without direct functional validation of identified pathways, single lab","pmids":["31288483"],"is_preprint":false},{"year":2025,"finding":"PCL microspheres increase collagen synthesis in fibroblasts through upregulation of SAMD11, which in turn increases PLOD1 expression. RNA-seq identified SAMD11 as a key regulator upstream of PLOD1 in PCL-stimulated collagen production; SAMD11 knockdown attenuated PLOD1 upregulation and collagen synthesis.","method":"RNA-seq of differentially expressed genes, SAMD11 knockdown, Western blot, collagen synthesis measurement, in vivo mouse skin thickness assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — epistasis by KD, single lab, limited mechanistic depth for SAMD11-PLOD1 transcriptional link","pmids":["40074205"],"is_preprint":false}],"current_model":"PLOD1 (lysyl hydroxylase 1) is an ER-resident dioxygenase (EC 1.14.11.4) that hydroxylates lysine residues in the helical domain of collagens (especially types I and III), enabling subsequent glycosylation and intermolecular pyridinoline crosslink formation essential for fibril stability; loss-of-function mutations cause kyphoscoliotic Ehlers-Danlos syndrome and aortic aneurysm through defective collagen crosslinking. Beyond its canonical hydroxylase activity, PLOD1 has also been shown to possess glucosyltransferase activity and to regulate non-collagen substrates: it hydroxylates the EBV protein EBNA1 at K460/K461 to stabilize EBNA1 and support viral episome replication, and it stabilizes Septin2 (SEPT2) via its hydroxylase domain to promote actin polymerization and cancer cell confined migration."},"narrative":{"mechanistic_narrative":"PLOD1 (lysyl hydroxylase 1) is an endoplasmic reticulum dioxygenase (EC 1.14.11.4) that hydroxylates lysine residues in peptide linkages to form hydroxylysine in collagens, a modification essential for intermolecular crosslinking and fibril stabilization of type I and III collagens [PMID:1577494, PMID:34646388]. Loss-of-function mutations distributed throughout the gene — including frameshift, nonsense, and missense variants and a recurrent exons 10-16 duplication driven by Alu-mediated recombination in introns 9 and 16 — reduce enzyme activity below 25% of normal and cause kyphoscoliotic Ehlers-Danlos syndrome (EDS type VI/kEDS) [PMID:7713497, PMID:10874315, PMID:15979919]. In mice, LH1 deficiency impairs aortic collagen crosslinking and promotes angiotensin II-induced dissecting abdominal aortic aneurysm through upregulation of thrombospondin-1, MMP activation, and VSMC apoptosis, a phenotype reversed by AAV-mediated LH1 restoration [PMID:34646388]. Beyond lysyl hydroxylation, PLOD1 possesses an N-terminal glucosyltransferase domain that processes UDP-glycan donor substrates, and a missense variant in this domain segregates with familial thoracic aortic aneurysm/dissection while attenuating procollagen gene upregulation in vascular smooth muscle cells [PMID:34400365]. PLOD1 also acts on non-collagen substrates: it binds and stabilizes Septin2 through its hydroxylase domain to promote actin polymerization and confined cancer cell migration [PMID:36721170], and it hydroxylates the Epstein-Barr virus EBNA1 protein at K460/K461 to stabilize EBNA1 and sustain oriP-dependent viral episome replication [PMID:37262099]. Across multiple tumor contexts PLOD1 is upregulated and promotes proliferation, stemness, and metabolic reprogramming via NF-κB, Hippo-YAP, and related signaling, and its abundance is controlled post-translationally and transcriptionally by regulators including lnc-URIDS, miR-34c, SIRT6, and gluconic acid-driven autophagic degradation [PMID:36721170, PMID:32801140, PMID:33420370, PMID:32446383, PMID:37936548, PMID:40339550, PMID:40290518].","teleology":[{"year":1992,"claim":"Establishing the molecular identity of human lysyl hydroxylase defined the enzyme responsible for collagen hydroxylysine formation and located the gene for disease mapping.","evidence":"cDNA cloning and sequencing from human placenta with enzymatic annotation and chromosomal mapping to 1p36","pmids":["1577494"],"confidence":"High","gaps":["No structural model of the catalytic domain","Substrate specificity beyond collagen not addressed at this stage"]},{"year":1994,"claim":"Determining the 19-exon gene architecture explained why a recurrent multi-exon duplication arises and links it mechanistically to EDS type VI.","evidence":"Genomic clone isolation, intron sequencing, and Alu repeat mapping in patient DNA","pmids":["7713497"],"confidence":"High","gaps":["Frequency and penetrance of the duplication across populations not quantified","Functional consequence at the protein level not directly measured here"]},{"year":2000,"claim":"Coupling diverse loss-of-function mutations to direct enzyme activity measurements in patient fibroblasts established PLOD1 deficiency as the biochemical basis of EDS type VI.","evidence":"Full-length cDNA/genomic sequencing and enzymatic activity assays in patient dermal fibroblasts, plus splicing analysis","pmids":["10874315"],"confidence":"High","gaps":["Genotype-phenotype correlation across mutation classes not resolved","Tissue-specific consequences beyond skin not assessed"]},{"year":2005,"claim":"Systematic mutation screening confirmed that varied loss-of-function alleles throughout PLOD1 converge on lysyl hydroxylase deficiency, validating molecular diagnostic strategy.","evidence":"Combined cDNA and genomic DNA sequencing in nine index EDS VIA patients","pmids":["15979919"],"confidence":"High","gaps":["No biochemical characterization of individual novel missense variants","Modifier effects not addressed"]},{"year":2021,"claim":"An in vivo aneurysm model demonstrated that LH1-dependent aortic collagen crosslinking protects against dissecting aneurysm and identified thrombospondin-1 as a downstream effector amenable to rescue.","evidence":"LH1-deficient mouse with Ang II infusion, transcriptomics, AAV rescue, and thrombospondin-1 inhibition","pmids":["34646388"],"confidence":"High","gaps":["Direct link between collagen crosslink defect and thrombospondin-1 induction not mechanistically resolved","Relevance to human aneurysm subtypes not established"]},{"year":2021,"claim":"Discovery of an N-terminal glucosyltransferase activity expanded PLOD1's enzymatic repertoire and tied a folding-destabilizing variant in this domain to familial thoracic aortic disease.","evidence":"In vitro UDP-glycan processing assay, comparison with PLOD3, and VSMC overexpression/knockdown","pmids":["34400365"],"confidence":"Medium","gaps":["Glucosyltransferase activity demonstrated in vitro, not yet shown on physiological substrates in cells","Single lab, limited replication","Causality of the variant in the family not genetically proven beyond segregation"]},{"year":2023,"claim":"Identification of Septin2 as a stabilized binding partner revealed a non-collagen, cytoskeletal role for PLOD1 in driving confined migration and metastasis.","evidence":"Reciprocal Co-IP/LC-MS, FRET, FRAP, confined migration and 3D invasion assays, and orthotopic mouse model","pmids":["36721170"],"confidence":"Medium","gaps":["Whether SEPT2 is hydroxylated or only bound is not fully resolved","Single lab","Mechanism by which binding promotes actin polymerization not detailed"]},{"year":2023,"claim":"Demonstrating PLOD1-mediated hydroxylation of EBV EBNA1 established a viral substrate and a host enzyme required for episome maintenance.","evidence":"Co-IP/MS, MS identification of hydroxylated EBNA1 peptides, K460/K461 mutagenesis, shRNA depletion, and oriP replication assays","pmids":["37262099"],"confidence":"High","gaps":["Whether PLOD1 inhibition is therapeutically tractable against EBV in vivo unknown","Structural basis of EBNA1 recognition not determined"]},{"year":null,"claim":"How PLOD1's distinct activities — lysyl hydroxylation, glucosyltransfer, and non-collagen substrate binding/stabilization — are mechanistically partitioned across its domains, and which oncogenic signaling links are direct versus correlative, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model linking catalytic and glucosyltransferase domains to distinct substrates","Tumor signaling links (NF-κB, Hippo-YAP, SOX9/PI3K) are largely pathway-level without direct biochemical demonstration","Physiological scope of non-collagen substrates beyond SEPT2 and EBNA1 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,4,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7]}],"complexes":[],"partners":["SEPT2","EBNA1","LNC-URIDS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q02809","full_name":"Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1","aliases":["Lysyl hydroxylase 1","LH1"],"length_aa":727,"mass_kda":83.5,"function":"Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils (By similarity). Forms hydroxylysine residues in -Xaa-Lys-Gly- sequences in collagens (PubMed:10686424, PubMed:15854030, PubMed:8621606). These hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen cross-links (Probable)","subcellular_location":"Rough endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q02809/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLOD1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"HNRNPH1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PLOD1","total_profiled":1310},"omim":[{"mim_id":"617419","title":"PROLYL 3-HYDROXYLASE 4; P3H4","url":"https://www.omim.org/entry/617419"},{"mim_id":"610342","title":"PROLYL 3-HYDROXYLASE 3; P3H3","url":"https://www.omim.org/entry/610342"},{"mim_id":"603066","title":"PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE 3; PLOD3","url":"https://www.omim.org/entry/603066"},{"mim_id":"601865","title":"PROCOLLAGEN-LYSINE, 2-OXOGLUTARATE 5-DIOXYGENASE 2; PLOD2","url":"https://www.omim.org/entry/601865"},{"mim_id":"601542","title":"PAIRED-LIKE HOMEODOMAIN TRANSCRIPTION FACTOR 2; PITX2","url":"https://www.omim.org/entry/601542"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PLOD1"},"hgnc":{"alias_symbol":["LH1"],"prev_symbol":["LLH","PLOD"]},"alphafold":{"accession":"Q02809","domains":[{"cath_id":"3.90.550.10","chopping":"25-266","consensus_level":"high","plddt":93.5261,"start":25,"end":266},{"cath_id":"3.90.550.10","chopping":"283-506","consensus_level":"high","plddt":96.2355,"start":283,"end":506},{"cath_id":"2.60.120.620","chopping":"536-726","consensus_level":"high","plddt":94.1593,"start":536,"end":726}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02809","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q02809-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q02809-F1-predicted_aligned_error_v6.png","plddt_mean":92.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLOD1","jax_strain_url":"https://www.jax.org/strain/search?query=PLOD1"},"sequence":{"accession":"Q02809","fasta_url":"https://rest.uniprot.org/uniprotkb/Q02809.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q02809/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q02809"}},"corpus_meta":[{"pmid":"24670637","id":"PMC_24670637","title":"Structure 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Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40074205","citation_count":4,"is_preprint":false},{"pmid":"35927940","id":"PMC_35927940","title":"Modulation of blood pressure regulatory genes in the Agtrap-Plod1 locus associated with a deletion in Clcn6.","date":"2022","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/35927940","citation_count":4,"is_preprint":false},{"pmid":"40112203","id":"PMC_40112203","title":"Cryo-EM Analysis of a Tri-Heme Cytochrome-Associated RC-LH1 Complex from the Marine Photoheterotrophic Bacterium Dinoroseobacter Shibae.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40112203","citation_count":4,"is_preprint":false},{"pmid":"36860721","id":"PMC_36860721","title":"A severe case of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome associated with several arterial and venous complications: A case report.","date":"2023","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/36860721","citation_count":4,"is_preprint":false},{"pmid":"35282129","id":"PMC_35282129","title":"CD73+ adipose-derived stem cells reduce scar formation through PLOD1.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35282129","citation_count":3,"is_preprint":false},{"pmid":"33503035","id":"PMC_33503035","title":"Comprehensive analysis of PLOD family members in low-grade gliomas using bioinformatics methods.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/33503035","citation_count":3,"is_preprint":false},{"pmid":"16099524","id":"PMC_16099524","title":"Isolation and characterisation of a Lactobacillus helveticus ITG LH1 peptidase-rich sub-proteome.","date":"2005","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16099524","citation_count":3,"is_preprint":false},{"pmid":"40339550","id":"PMC_40339550","title":"Gluconic acid alleviates hypertrophic scar formation through binding PLOD1, reducing p-AKT signaling and activating autophagy.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40339550","citation_count":2,"is_preprint":false},{"pmid":"40262693","id":"PMC_40262693","title":"A novel tRNA-Derived fragment, tRF-20-M0NK5Y93 inhibits the malignant progression of non-small cell lung cancer by mediating PLOD1.","date":"2025","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/40262693","citation_count":2,"is_preprint":false},{"pmid":"36199159","id":"PMC_36199159","title":"Prevalence of the RAPGEF5 c.2624C>A and PLOD1 c.2032G>A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988-2019).","date":"2022","source":"Equine veterinary journal","url":"https://pubmed.ncbi.nlm.nih.gov/36199159","citation_count":2,"is_preprint":false},{"pmid":"35252061","id":"PMC_35252061","title":"Case Report: Identification and Functional Analysis of a Homozygous Synonymous Variant in the PLOD1 Gene in a Chinese Neonatal With the Ehlers-Danlos Syndrome.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35252061","citation_count":2,"is_preprint":false},{"pmid":"38029673","id":"PMC_38029673","title":"Biodegradation of benzo[a]pyrene by a marine Chlorella vulgaris LH-1 with heterotrophic ability.","date":"2023","source":"Marine pollution bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/38029673","citation_count":2,"is_preprint":false},{"pmid":"26215074","id":"PMC_26215074","title":"Ground-State Electronic Structure of RC-LH1 and LH2 Pigment Assemblies of Purple Bacteria via the EBF-MO Method.","date":"2015","source":"The journal of physical chemistry. A","url":"https://pubmed.ncbi.nlm.nih.gov/26215074","citation_count":2,"is_preprint":false},{"pmid":"28528494","id":"PMC_28528494","title":"Carotenoid to bacteriochlorophyll energy transfer in the RC-LH1-PufX complex from Rhodobacter sphaeroides containing the extended conjugation keto-carotenoid diketospirilloxanthin.","date":"2017","source":"Photosynthesis research","url":"https://pubmed.ncbi.nlm.nih.gov/28528494","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50751,"output_tokens":4586,"usd":0.110521,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12733,"output_tokens":3247,"usd":0.07242,"stage2_stop_reason":"end_turn"},"total_usd":0.182941,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"Human lysyl hydroxylase (PLOD1) was cloned and sequenced; it encodes a 709 amino acid polypeptide (plus 18 aa signal peptide) that catalyzes hydroxylation of lysine residues in peptide linkages (EC 1.14.11.4), forming hydroxylysine in collagens. The C-terminal region (especially residues 639-715) is 99% identical between human and chick, suggesting functionally significant sequences in this region. The gene was mapped to chromosome 1p36.2-1p36.3.\",\n      \"method\": \"cDNA cloning from human placenta lambda gt11 library, sequence analysis, Southern blot of somatic cell hybrids, in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cDNA cloning with complete coding sequence determination, functional annotation by enzymatic activity, replicated across species\",\n      \"pmids\": [\"1577494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The human PLOD1 gene contains 19 exons; introns 9 and 16 contain multiple Alu sequences generating extensive homology and potential recombination sites, explaining the common multi-exon duplication (exons 10-16) mutation found in Ehlers-Danlos syndrome type VI patients. The gene's 5' flanking region has housekeeping gene characteristics consistent with constitutive expression.\",\n      \"method\": \"Genomic clone isolation, intron sequencing, Alu repeat mapping, analysis of patient genomic DNA\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complete gene structure determination with mechanistic explanation for recombination hotspot, replicated in multiple patients\",\n      \"pmids\": [\"7713497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Loss-of-function mutations in PLOD1 (including frameshift 1702insC and nonsense mutations Y142X, Q327X, R670X, Y511X, and a common 7-exon duplication) cause deficiency of lysyl hydroxylase 1 activity (<25% of normal) in Ehlers-Danlos syndrome type VI patients. Alternative splicing pathways that bypass premature termination codons were identified.\",\n      \"method\": \"Full-length cDNA amplification and sequencing from patient dermal fibroblasts, genomic DNA verification, enzymatic activity assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct enzymatic activity measurement in patient fibroblasts combined with molecular characterization of mutations in multiple unrelated patients\",\n      \"pmids\": [\"10874315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A systematic mutation analysis strategy for PLOD1 using cDNA and/or gDNA identified multiple disease-causing mutations in 9 index EDS VIA patients including novel frameshift (p.Ile454IlefsX2), missense (p.Ala667Thr), and nonsense (p.His706Arg) mutations, as well as the common exons 10-16 duplication, confirming that diverse loss-of-function mutations throughout PLOD1 cause lysyl hydroxylase deficiency.\",\n      \"method\": \"cDNA and genomic DNA sequencing, mutation analysis strategy combining both substrates\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic molecular diagnosis with multiple independent patients, multiple mutation types confirmed\",\n      \"pmids\": [\"15979919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LH1 (PLOD1) deficiency in mice promotes angiotensin II-induced dissecting abdominal aortic aneurysm. LH1 deficiency upregulates thrombospondin-1, which drives proinflammatory processes, MMP activation, and VSMC apoptosis. Restoration of LH1 via AAV injection normalized thrombospondin-1 levels and alleviated AAA formation. LH1 is essential for type I/III collagen intermolecular crosslinking and stabilization in the aorta.\",\n      \"method\": \"LH1-deficient mouse model (C57Bl/6), Ang II osmotic pump infusion, whole-transcriptomic analysis, AAV rescue, pharmacologic thrombospondin-1 inhibition (TAX2), histology, MMP activity assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotypic readout, AAV rescue experiment, multiple orthogonal mechanistic methods in one study\",\n      \"pmids\": [\"34646388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A PLOD1 missense variant p.(Ser178Arg) affecting the N-terminal glycosyltransferase domain was identified in familial thoracic aortic aneurysm/dissection. In vitro assays demonstrated that wild-type PLOD1 processes UDP-glycan donor substrates (glucosyltransferase activity), representing a previously unrecognized enzymatic function. The variant affects folding stability of the glycosyltransferase domain and attenuates procollagen gene upregulation in VSMCs overexpressing wild-type PLOD1. si-PLOD1 cells showed hypercontractility and upregulation of contractile markers.\",\n      \"method\": \"In vitro UDP-glycan processing assay, comparison with PLOD3 homolog, VSMC overexpression/knockdown, enzymatic activity measurement, collagen fibril analysis\",\n      \"journal\": \"Translational research : the journal of laboratory and clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — novel enzymatic activity demonstrated in vitro, single lab, limited replication\",\n      \"pmids\": [\"34400365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLOD1 (LH1) promotes confined migration and metastasis of cancer cells by binding and stabilizing Septin2 (SEPT2), thereby facilitating actin polymerization. This function depends on the hydroxylase domain of LH1. LH1 bound SEPT2 as identified by immunoprecipitation followed by LC-MS.\",\n      \"method\": \"Immunoprecipitation/LC-MS identification of LH1-binding proteins, FRET, FRAP, immunofluorescence, microfluidic confined migration assay, 3D invasion assay, orthotopic mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with LC-MS validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36721170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLOD1 interacts with Epstein-Barr virus EBNA1 protein and hydroxylates EBNA1 at lysine K460 and/or K461. Mutation of K460 (but not K461) abrogates EBNA1-driven oriP DNA replication without affecting DNA binding. Mutations in both K460 and K461 perturb interactions with PLOD1 and decrease EBNA1 protein stability. PLOD1 depletion by shRNA causes loss of EBNA1 protein levels, loss of EBV episomes, and inhibition of oriP-dependent DNA replication.\",\n      \"method\": \"Proteomic analysis (Co-IP/MS), shRNA depletion, small molecule inhibition, mass spectrometry identification of hydroxylated EBNA1 peptides, site-directed mutagenesis of K460/K461, oriP replication assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro hydroxylation identified by MS, mutagenesis of substrate lysines with functional readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37262099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lnc-URIDS (a lncRNA) interacts with PLOD1 protein and reduces its protein stability, leading to decreased collagen production and deposition and delayed wound healing in diabetes. PLOD1 is identified as a critical enzyme responsible for collagen cross-linking in dermal fibroblasts, and its protein stability is regulated post-translationally by lnc-URIDS binding.\",\n      \"method\": \"lncRNA-protein interaction assay, knockdown in vitro and in vivo diabetic wound healing model, protein stability analysis\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct protein-lncRNA interaction demonstrated, functional consequence shown in vivo, single lab\",\n      \"pmids\": [\"32801140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLOD1 knockdown in glioblastoma stem cells inhibits tumor viability, proliferation, migration, and mesenchymal transition, while promoting apoptosis. PLOD1 expression is enhanced in hypoxic environments, and its tumor-promoting effects are associated with activation of the NF-κB signaling pathway as revealed by bioinformatics and molecular experiments.\",\n      \"method\": \"shRNA knockdown in patient-derived glioma stem cells, tumor xenograft, NF-κB pathway reporter assays, hypoxia experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD/OE with cellular phenotype and pathway identification, single lab, limited mechanistic depth for NF-κB link\",\n      \"pmids\": [\"33420370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PLOD1 inactivates the Hippo-YAP pathway in osteosarcoma by inhibiting phosphorylation of LATS1 (p-LATS1) and YAP (p-YAP), leading to increased nuclear YAP distribution. PLOD1 is itself a direct target of miR-34c, which inhibits PLOD1 expression by binding its 3'-UTR and suppresses OS cell growth.\",\n      \"method\": \"Gain/loss-of-function assays, immunofluorescence for YAP nuclear distribution, luciferase 3'-UTR reporter assay for miR-34c/PLOD1, in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter for miR-34c targeting, multiple cellular phenotype readouts, single lab\",\n      \"pmids\": [\"32446383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PLOD1 promotes cell growth and aerobic glycolysis in gastric cancer by activating the SOX9/PI3K/Akt/mTOR signaling pathway; PLOD1 overexpression increases SOX9, p-Akt/Akt and p-mTOR/mTOR levels, and SOX9 overexpression rescues PLOD1 knockdown-mediated inhibition of cell viability and glycolysis.\",\n      \"method\": \"MTT, EDU, colony formation assays; glycolysis metabolic assays (glucose uptake, lactate, ATP, OCR, ECAR); Western blot for pathway proteins; rescue experiments with SOX9 overexpression; in vivo xenograft\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement via rescue experiment, single lab, no direct biochemical interaction demonstrated\",\n      \"pmids\": [\"34455762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT6 deficiency in mice reduces Plod1 expression at both mRNA and protein levels in ovarian granulosa cells, leading to decreased collagen crosslinking and deposition in the ovarian stroma and impaired follicular development. This places Plod1 downstream of SIRT6 in ovarian collagen homeostasis.\",\n      \"method\": \"SIRT6 knockout mouse model, RNA and protein expression analysis in ovaries and granulosa cells, collagen histology\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis (KO mouse) with defined collagen phenotype, single lab, no direct enzymatic rescue\",\n      \"pmids\": [\"37936548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Gluconic acid (GLA) directly binds PLOD1 protein and promotes its autophagy-lysosomal degradation, reducing p-AKT signaling and activating autophagy to attenuate hypertrophic scar formation. PLOD1 degradation was confirmed by pull-down, cellular thermal shift assay, co-localization studies, and autophagy inhibitor experiments.\",\n      \"method\": \"Molecular docking, pull-down assay, cellular thermal shift assay (CETSA), co-localization, autophagic flux assay, transmission electron microscopy, Western blot, rabbit ear scar model\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple biophysical binding assays (CETSA, pull-down, co-localization) confirming direct GLA-PLOD1 interaction, single lab\",\n      \"pmids\": [\"40339550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PLOD1 promotes proliferation and stemness of hepatocellular carcinoma cells by positively regulating the NF-κB/IL-6/STAT3 signaling pathway and accelerating TCA cycle metabolic reprogramming. Blocking NF-κB/IL-6/STAT3 or TCA cycle mitigates PLOD1-induced proliferation/stemness. AAV-mediated hepatic PLOD1 knockdown reduces HCC progression in mice.\",\n      \"method\": \"RNA-seq, untargeted metabolomics, CCK8, flow cytometry, sphere formation, ALDH activity, subcutaneous/orthotopic/hepatotoxin-induced mouse models, pathway inhibitor experiments\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multi-omics with pharmacologic pathway blockade and in vivo AAV KD, single lab\",\n      \"pmids\": [\"40290518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Transcriptome profiling of patient-derived PLOD1-kEDS skin fibroblasts revealed differential expression of extracellular matrix component genes, genes involved in ER stress, protein trafficking, inner ear development, and vascular remodeling compared to controls, establishing distinct molecular features specific to PLOD1-kEDS versus FKBP14-kEDS.\",\n      \"method\": \"RNA sequencing of patient-derived skin fibroblasts, differential gene expression analysis\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomics without direct functional validation of identified pathways, single lab\",\n      \"pmids\": [\"31288483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PCL microspheres increase collagen synthesis in fibroblasts through upregulation of SAMD11, which in turn increases PLOD1 expression. RNA-seq identified SAMD11 as a key regulator upstream of PLOD1 in PCL-stimulated collagen production; SAMD11 knockdown attenuated PLOD1 upregulation and collagen synthesis.\",\n      \"method\": \"RNA-seq of differentially expressed genes, SAMD11 knockdown, Western blot, collagen synthesis measurement, in vivo mouse skin thickness assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — epistasis by KD, single lab, limited mechanistic depth for SAMD11-PLOD1 transcriptional link\",\n      \"pmids\": [\"40074205\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLOD1 (lysyl hydroxylase 1) is an ER-resident dioxygenase (EC 1.14.11.4) that hydroxylates lysine residues in the helical domain of collagens (especially types I and III), enabling subsequent glycosylation and intermolecular pyridinoline crosslink formation essential for fibril stability; loss-of-function mutations cause kyphoscoliotic Ehlers-Danlos syndrome and aortic aneurysm through defective collagen crosslinking. Beyond its canonical hydroxylase activity, PLOD1 has also been shown to possess glucosyltransferase activity and to regulate non-collagen substrates: it hydroxylates the EBV protein EBNA1 at K460/K461 to stabilize EBNA1 and support viral episome replication, and it stabilizes Septin2 (SEPT2) via its hydroxylase domain to promote actin polymerization and cancer cell confined migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PLOD1 (lysyl hydroxylase 1) is an endoplasmic reticulum dioxygenase (EC 1.14.11.4) that hydroxylates lysine residues in peptide linkages to form hydroxylysine in collagens, a modification essential for intermolecular crosslinking and fibril stabilization of type I and III collagens [#0, #4]. Loss-of-function mutations distributed throughout the gene — including frameshift, nonsense, and missense variants and a recurrent exons 10-16 duplication driven by Alu-mediated recombination in introns 9 and 16 — reduce enzyme activity below 25% of normal and cause kyphoscoliotic Ehlers-Danlos syndrome (EDS type VI/kEDS) [#1, #2, #3]. In mice, LH1 deficiency impairs aortic collagen crosslinking and promotes angiotensin II-induced dissecting abdominal aortic aneurysm through upregulation of thrombospondin-1, MMP activation, and VSMC apoptosis, a phenotype reversed by AAV-mediated LH1 restoration [#4]. Beyond lysyl hydroxylation, PLOD1 possesses an N-terminal glucosyltransferase domain that processes UDP-glycan donor substrates, and a missense variant in this domain segregates with familial thoracic aortic aneurysm/dissection while attenuating procollagen gene upregulation in vascular smooth muscle cells [#5]. PLOD1 also acts on non-collagen substrates: it binds and stabilizes Septin2 through its hydroxylase domain to promote actin polymerization and confined cancer cell migration [#6], and it hydroxylates the Epstein-Barr virus EBNA1 protein at K460/K461 to stabilize EBNA1 and sustain oriP-dependent viral episome replication [#7]. Across multiple tumor contexts PLOD1 is upregulated and promotes proliferation, stemness, and metabolic reprogramming via NF-\\u03baB, Hippo-YAP, and related signaling, and its abundance is controlled post-translationally and transcriptionally by regulators including lnc-URIDS, miR-34c, SIRT6, and gluconic acid-driven autophagic degradation [#6, #8, #9, #10, #12, #13, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the molecular identity of human lysyl hydroxylase defined the enzyme responsible for collagen hydroxylysine formation and located the gene for disease mapping.\",\n      \"evidence\": \"cDNA cloning and sequencing from human placenta with enzymatic annotation and chromosomal mapping to 1p36\",\n      \"pmids\": [\"1577494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the catalytic domain\", \"Substrate specificity beyond collagen not addressed at this stage\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Determining the 19-exon gene architecture explained why a recurrent multi-exon duplication arises and links it mechanistically to EDS type VI.\",\n      \"evidence\": \"Genomic clone isolation, intron sequencing, and Alu repeat mapping in patient DNA\",\n      \"pmids\": [\"7713497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency and penetrance of the duplication across populations not quantified\", \"Functional consequence at the protein level not directly measured here\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Coupling diverse loss-of-function mutations to direct enzyme activity measurements in patient fibroblasts established PLOD1 deficiency as the biochemical basis of EDS type VI.\",\n      \"evidence\": \"Full-length cDNA/genomic sequencing and enzymatic activity assays in patient dermal fibroblasts, plus splicing analysis\",\n      \"pmids\": [\"10874315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype correlation across mutation classes not resolved\", \"Tissue-specific consequences beyond skin not assessed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Systematic mutation screening confirmed that varied loss-of-function alleles throughout PLOD1 converge on lysyl hydroxylase deficiency, validating molecular diagnostic strategy.\",\n      \"evidence\": \"Combined cDNA and genomic DNA sequencing in nine index EDS VIA patients\",\n      \"pmids\": [\"15979919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical characterization of individual novel missense variants\", \"Modifier effects not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An in vivo aneurysm model demonstrated that LH1-dependent aortic collagen crosslinking protects against dissecting aneurysm and identified thrombospondin-1 as a downstream effector amenable to rescue.\",\n      \"evidence\": \"LH1-deficient mouse with Ang II infusion, transcriptomics, AAV rescue, and thrombospondin-1 inhibition\",\n      \"pmids\": [\"34646388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between collagen crosslink defect and thrombospondin-1 induction not mechanistically resolved\", \"Relevance to human aneurysm subtypes not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of an N-terminal glucosyltransferase activity expanded PLOD1's enzymatic repertoire and tied a folding-destabilizing variant in this domain to familial thoracic aortic disease.\",\n      \"evidence\": \"In vitro UDP-glycan processing assay, comparison with PLOD3, and VSMC overexpression/knockdown\",\n      \"pmids\": [\"34400365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glucosyltransferase activity demonstrated in vitro, not yet shown on physiological substrates in cells\", \"Single lab, limited replication\", \"Causality of the variant in the family not genetically proven beyond segregation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of Septin2 as a stabilized binding partner revealed a non-collagen, cytoskeletal role for PLOD1 in driving confined migration and metastasis.\",\n      \"evidence\": \"Reciprocal Co-IP/LC-MS, FRET, FRAP, confined migration and 3D invasion assays, and orthotopic mouse model\",\n      \"pmids\": [\"36721170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SEPT2 is hydroxylated or only bound is not fully resolved\", \"Single lab\", \"Mechanism by which binding promotes actin polymerization not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating PLOD1-mediated hydroxylation of EBV EBNA1 established a viral substrate and a host enzyme required for episome maintenance.\",\n      \"evidence\": \"Co-IP/MS, MS identification of hydroxylated EBNA1 peptides, K460/K461 mutagenesis, shRNA depletion, and oriP replication assays\",\n      \"pmids\": [\"37262099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PLOD1 inhibition is therapeutically tractable against EBV in vivo unknown\", \"Structural basis of EBNA1 recognition not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PLOD1's distinct activities — lysyl hydroxylation, glucosyltransfer, and non-collagen substrate binding/stabilization — are mechanistically partitioned across its domains, and which oncogenic signaling links are direct versus correlative, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model linking catalytic and glucosyltransferase domains to distinct substrates\", \"Tumor signaling links (NF-\\u03baB, Hippo-YAP, SOX9/PI3K) are largely pathway-level without direct biochemical demonstration\", \"Physiological scope of non-collagen substrates beyond SEPT2 and EBNA1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SEPT2\", \"EBNA1\", \"lnc-URIDS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}