{"gene":"KLK5","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2004,"finding":"KLK5 (SCTE/hK5) directly degrades corneodesmosome proteins DSG1, DSC1, and corneodesmosin (CDSN) at acidic pH, acting as a trypsin-like serine protease; additionally, KLK5 activates the proform of KLK7 (pro-SCCE), suggesting it initiates a protease cascade in desquamation.","method":"In vitro protease cleavage assays with recombinant and epidermal proteins at acidic pH; proenzyme activation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro reconstitution with recombinant substrates, multiple substrates tested, replicated across two kallikrein enzymes","pmids":["15140227"],"is_preprint":false},{"year":2007,"finding":"LEKTI fragments (particularly D8-D11) specifically inhibit KLK5 through rapid, tight-binding complex formation; the interaction is pH-dependent, with acidic pH (mimicking the stratum corneum surface) causing release of active KLK5 from the LEKTI complex, thereby enabling corneodesmosomal cleavage in the outermost skin layers.","method":"Biochemical inhibition kinetics of recombinant LEKTI fragments against KLK5, KLK7, and KLK14; pH-dependence assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with kinetic analysis, multiple LEKTI fragments tested, mechanistic pH-dependence established, independently confirmed by localization studies","pmids":["17596512"],"is_preprint":false},{"year":2005,"finding":"In normal skin, KLK5 and KLK7 are separately localized within lamellar granules and secreted after LEKTI, establishing spatiotemporal separation as a mechanism preventing premature stratum corneum degradation; in Netherton syndrome (SPINK5 mutations), absence of LEKTI correlates with loss of stratum corneum integrity.","method":"Confocal laser scanning microscopy and immunoelectron microscopy of human epidermis and Netherton syndrome skin","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — direct localization by immunoelectron microscopy with functional consequence (barrier integrity), replicated across normal and disease skin","pmids":["15675955"],"is_preprint":false},{"year":2012,"finding":"SPINK9, a Kazal-type serine protease inhibitor expressed in palmo-plantar epidermis, selectively inhibits KLK5; the reactive loop residues 48 and 49 define specificity, and protonation of His48 at acidic pH increases inhibitory efficiency by decreasing the dissociation rate of the SPINK9–KLK5 complex.","method":"Biochemical inhibition assays with SPINK9 variants (single amino acid substitutions), pH-dependence assays, molecular modeling of enzyme-inhibitor complex","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis of inhibitor reactive loop combined with kinetic analysis and structural modeling, multiple mutants tested","pmids":["22505519"],"is_preprint":false},{"year":2022,"finding":"Inhibitory antibodies against KLK5 bind distal to the KLK5 active site and inhibit its activity via an allosteric mechanism, as revealed by a crystal structure of KLK5 bound to an inhibitory Fab; dual antibody inhibition of KLK5 and KLK7 promotes skin barrier integrity and reduces inflammation in mouse models of Netherton syndrome and atopic dermatitis.","method":"Crystal structure of KLK5–Fab complex; in vivo mouse models of Netherton syndrome and atopic dermatitis with inhibitory antibodies","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation in mouse models, allosteric mechanism defined structurally","pmids":["36516271"],"is_preprint":false},{"year":2017,"finding":"KLK5 is secreted by CD4+ T cells in type 2 diabetes patients and directly interacts with the extracellular loop of DPP4, cleaving DPP4 from the surface of circulating CD4+ Th17 cells and shedding it into the plasma, thereby increasing plasma DPP4 activity.","method":"Ex vivo and in vitro protease activity assays, co-immunoprecipitation, surface expression analysis, in silico docking; ELISA for plasma DPP4","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (co-IP, protease assay, cell surface shedding), single lab study","pmids":["29107298"],"is_preprint":false},{"year":2024,"finding":"KLK5 is a host serine protease secreted by human airway epithelial cells that cleaves both the S1/S2 priming site and S2' activation site of betacoronavirus spike proteins in vitro, enabling single-protease activation of SARS-CoV-2 and other betacoronavirus spike proteins; KLK5 upregulation upon betacoronavirus infection promotes viral replication in differentiated human bronchial epithelial cells.","method":"In vitro cleavage assays of spike proteins by recombinant KLK5, KLK12, KLK13; infection of differentiated human bronchial epithelial cells; mouse MERS-CoV/SARS-CoV-2 infection model with KLK5 inhibitor (ursolic acid)","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of spike cleavage plus cell-based and in vivo validation with inhibitor","pmids":["39163389"],"is_preprint":false},{"year":2014,"finding":"Reconstitution of KLK5 expression in MDA-MB-231 breast cancer cells suppresses malignancy by downregulating the mevalonate pathway (reducing cholesterol/fatty acid synthesis and isoprenoid production), leading to diminished levels of active (prenylated) RhoA; restoration of geranylgeranyl pyrophosphate reverses KLK5-mediated suppression, placing KLK5 upstream of RhoA prenylation.","method":"Stable transfection of KLK5 in MDA-MB-231 cells; transcriptome analysis; cholesterol/isoprenoid metabolic assays; RhoA activity assays; in vivo tumor growth; geranylgeranyl pyrophosphate rescue experiment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis-like rescue experiment plus multiple metabolic readouts, single lab","pmids":["24158494"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 stabilizes KLK5 mRNA in an m6A-dependent manner; KLK5 protein in turn activates the PAR2/AKT signaling axis to promote gallbladder carcinoma cell proliferation and migration; let-7g-5p suppresses this pathway by targeting IGF2BP3.","method":"RNA immunoprecipitation, RNA stability assay, methylated RNA immunoprecipitation, dual-luciferase reporter assay, gain/loss-of-function in vitro and in vivo","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods establishing mRNA stabilization and downstream signaling, single lab","pmids":["36313631"],"is_preprint":false},{"year":2021,"finding":"STAT3 regulates KLK5 expression in keratinocytes: keratinocyte-specific STAT3 ablation upregulates KLK5, while STAT3 overexpression decreases KLK5 expression; STAT3 also positively regulates SPINK5 (the KLK5 inhibitor LEKTI), linking STAT3 to skin barrier homeostasis through control of the KLK5/LEKTI balance.","method":"Keratinocyte-specific STAT3 knockout mouse model; STAT3 siRNA knockdown and overexpression in keratinocytes; transcriptomic analysis","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function mouse model plus in vitro siRNA/overexpression, single lab","pmids":["34378233"],"is_preprint":false},{"year":2025,"finding":"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis through activation of KLK14; KLK14 in turn signals via PAR-2-dependent RhoA and NF-κB pathways to promote tumor progression; absence of both KLK5 and KLK7 ameliorates the HPV-dependent phenotype.","method":"Genetically engineered mice (KLK5/KLK7 double knockout in HPV model); bulk RNA-seq; reporter assays for RhoA and NF-κB; human biopsy analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in mouse model with downstream pathway reporters, supported by human biopsy expression data","pmids":["40753921"],"is_preprint":false},{"year":2025,"finding":"KLK5 deletion in a CDSN-knockout (CDSN-nEDD) background aggravates the desquamation phenotype rather than rescuing it: epidermal proteolysis increases, corneodesmosomes show ultrastructural alterations, and epidermal barrier permeability worsens, suggesting that other proteases compensate for KLK5 loss and that KLK5 initiates but does not solely sustain the desquamation cascade.","method":"shRNA-mediated CDSN knockdown in human epidermal equivalents; Klk5/Cdsn double-knockout mice; ultrastructural analysis; barrier permeability assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — two complementary genetic loss-of-function models (human and mouse), multiple phenotypic readouts","pmids":["40943523"],"is_preprint":false}],"current_model":"KLK5 is a trypsin-like serine protease that initiates epidermal desquamation by directly cleaving corneodesmosome proteins (CDSN, DSG1, DSC1) and activating pro-KLK7, with its activity tightly regulated by the pH-dependent inhibitor LEKTI (encoded by SPINK5) and the palmo-plantar-specific inhibitor SPINK9; beyond the skin, KLK5 cleaves DPP4 from T cell surfaces, activates coronavirus spike proteins at both S1/S2 and S2' sites, and signals through the PAR2/AKT and RhoA/NF-κB pathways in cancer contexts."},"narrative":{"teleology":[{"year":2004,"claim":"Established KLK5 as the initiator of the desquamation protease cascade by showing it directly degrades corneodesmosome substrates and activates pro-KLK7, answering how stratum corneum shedding is enzymatically triggered.","evidence":"In vitro cleavage assays with recombinant KLK5 against DSG1, DSC1, CDSN, and pro-KLK7 at acidic pH","pmids":["15140227"],"confidence":"High","gaps":["Cleavage sites on corneodesmosome proteins not mapped","No in vivo validation of the cascade hierarchy","Whether KLK5 alone is sufficient for desquamation was untested"]},{"year":2005,"claim":"Resolved how premature KLK5 activation is prevented in normal epidermis: KLK5/KLK7 and LEKTI are stored in separate lamellar granule compartments and secreted sequentially, with loss of LEKTI in Netherton syndrome causing unchecked proteolysis.","evidence":"Immunoelectron microscopy and confocal microscopy of normal and Netherton syndrome human epidermis","pmids":["15675955"],"confidence":"High","gaps":["Mechanism of sequential secretion not defined","Whether other inhibitors partially compensate in Netherton syndrome skin was unknown"]},{"year":2007,"claim":"Defined the molecular logic of LEKTI-mediated KLK5 inhibition: LEKTI domains D8-D11 form tight-binding complexes with KLK5 at neutral pH but release active protease at acidic pH, explaining how desquamation is spatially restricted to the outermost stratum corneum.","evidence":"Kinetic inhibition assays of recombinant LEKTI fragments against KLK5 across a pH range","pmids":["17596512"],"confidence":"High","gaps":["Structural basis of pH-dependent binding not resolved","Relative contribution of individual LEKTI domains in vivo unknown"]},{"year":2012,"claim":"Identified SPINK9 as a site-specific inhibitor of KLK5 in palmo-plantar skin and demonstrated that reactive-loop residues and His48 protonation govern selectivity and pH-enhanced inhibition.","evidence":"Mutagenesis of SPINK9 reactive-loop residues combined with kinetic assays and molecular modeling","pmids":["22505519"],"confidence":"High","gaps":["No crystal structure of the SPINK9–KLK5 complex","In vivo relevance in palmo-plantar barrier not tested"]},{"year":2014,"claim":"Showed KLK5 can suppress breast cancer malignancy by downregulating the mevalonate pathway, reducing RhoA prenylation — an unexpected non-epidermal function linking KLK5 to lipid metabolism and oncogenic signaling.","evidence":"Stable KLK5 expression in MDA-MB-231 cells; metabolic rescue with geranylgeranyl pyrophosphate; in vivo tumor growth assays","pmids":["24158494"],"confidence":"Medium","gaps":["Direct proteolytic substrate mediating mevalonate pathway suppression unknown","Single cell line system","Not confirmed in clinical tumor specimens"]},{"year":2017,"claim":"Demonstrated a non-skin proteolytic role for KLK5: it is secreted by CD4+ T cells and sheds DPP4 from the surface of Th17 cells, increasing plasma DPP4 in type 2 diabetes patients.","evidence":"Co-immunoprecipitation, cell-surface shedding assays, and plasma ELISA in type 2 diabetes patient samples","pmids":["29107298"],"confidence":"Medium","gaps":["Cleavage site on DPP4 not mapped","Causal role of KLK5-mediated DPP4 shedding in diabetes pathophysiology not established","Single cohort study"]},{"year":2021,"claim":"Placed KLK5 under transcriptional control of STAT3 in keratinocytes: STAT3 represses KLK5 while promoting SPINK5 expression, establishing a single transcription factor that coordinates both the protease and its inhibitor for barrier homeostasis.","evidence":"Keratinocyte-specific STAT3 knockout mice; siRNA knockdown and overexpression in keratinocytes","pmids":["34378233"],"confidence":"Medium","gaps":["Whether STAT3 binds the KLK5 promoter directly was not shown","Downstream barrier phenotype in STAT3-KO skin not fully characterized"]},{"year":2022,"claim":"Revealed an allosteric inhibition mechanism for KLK5: an antibody Fab binds distal to the active site yet blocks protease activity, and dual KLK5/KLK7 antibody inhibition restores barrier integrity in Netherton syndrome and atopic dermatitis mouse models, validating KLK5 as a therapeutic target.","evidence":"Crystal structure of KLK5–Fab complex; in vivo treatment of Netherton syndrome and atopic dermatitis mouse models","pmids":["36516271"],"confidence":"High","gaps":["Allosteric conformational change not characterized dynamically","Human clinical efficacy not yet demonstrated"]},{"year":2022,"claim":"Linked KLK5 to PAR2/AKT signaling in gallbladder carcinoma: IGF2BP3 stabilizes KLK5 mRNA in an m6A-dependent manner, and KLK5 protein activates PAR2/AKT to promote proliferation and migration.","evidence":"RNA immunoprecipitation, MeRIP, dual-luciferase assays, gain/loss-of-function in vitro and in vivo","pmids":["36313631"],"confidence":"Medium","gaps":["Whether KLK5 directly cleaves PAR2 in this context not shown","Single cancer type studied"]},{"year":2024,"claim":"Established KLK5 as a host airway protease capable of both S1/S2 priming and S2' activation of betacoronavirus spike proteins, demonstrating a single-protease viral activation mechanism and showing that KLK5 inhibition reduces viral replication.","evidence":"In vitro spike cleavage assays; infection of differentiated human bronchial epithelial cells; mouse coronavirus infection model with KLK5 inhibitor (ursolic acid)","pmids":["39163389"],"confidence":"High","gaps":["Ursolic acid is not a specific KLK5 inhibitor — genetic validation in airway cells pending","Relative contribution of KLK5 versus TMPRSS2 in vivo not quantified"]},{"year":2025,"claim":"Demonstrated that KLK5 (with KLK7) activates KLK14 to drive PAR-2/RhoA/NF-κB signaling in HPV-dependent cervical carcinogenesis, and that KLK5/KLK7 double knockout ameliorates the malignant phenotype.","evidence":"KLK5/KLK7 double-knockout mice crossed with HPV transgenic model; RNA-seq; RhoA and NF-κB reporter assays; human biopsy analysis","pmids":["40753921"],"confidence":"Medium","gaps":["Whether KLK5 directly activates pro-KLK14 or acts indirectly not resolved","PAR-2 cleavage by KLK14 in this model not biochemically validated"]},{"year":2025,"claim":"Revealed that KLK5 deletion in a CDSN-knockout background paradoxically worsens desquamation and barrier permeability, indicating compensatory protease activity and that KLK5 initiates but does not solely sustain the desquamation cascade.","evidence":"KLK5/CDSN double-knockout mice and shRNA-mediated CDSN knockdown in human epidermal equivalents; ultrastructural and permeability analysis","pmids":["40943523"],"confidence":"Medium","gaps":["Identity of compensating proteases not determined","Mechanism by which KLK5 loss exacerbates barrier dysfunction in CDSN-null background unclear"]},{"year":null,"claim":"The full set of proteases that compensate for KLK5 loss in desquamation, the structural basis of pH-dependent LEKTI release, and whether KLK5 directly cleaves PAR2 in cancer and inflammatory contexts remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the KLK5–LEKTI complex","Compensatory proteases in KLK5-null epidermis unidentified","Direct PAR2 cleavage by KLK5 not biochemically demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,5,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,10]}],"complexes":[],"partners":["KLK7","CDSN","DSG1","DSC1","SPINK5","SPINK9","DPP4","KLK14"],"other_free_text":[]},"mechanistic_narrative":"KLK5 is a trypsin-like serine protease that initiates the epidermal desquamation cascade by cleaving corneodesmosome proteins (DSG1, DSC1, CDSN) at acidic pH and activating pro-KLK7, thereby linking protease activity to controlled stratum corneum shedding [PMID:15140227]. Its activity is tightly regulated by the pH-dependent inhibitor LEKTI (encoded by SPINK5), which forms a tight-binding complex with KLK5 at neutral pH but releases active KLK5 at the acidic pH of the outermost skin surface, and by the palmo-plantar-specific inhibitor SPINK9 whose inhibitory potency likewise increases at acidic pH [PMID:17596512, PMID:22505519]. Loss of LEKTI in Netherton syndrome results in unrestrained KLK5 activity and compromised skin barrier integrity, and allosteric inhibitory antibodies targeting KLK5 restore barrier function in mouse models of this disease [PMID:15675955, PMID:36516271]. Beyond its epidermal role, KLK5 cleaves DPP4 from T cell surfaces, activates betacoronavirus spike proteins at both the S1/S2 and S2' sites enabling viral entry in airway epithelia, and participates in PAR2-dependent signaling in cancer contexts [PMID:29107298, PMID:39163389, PMID:36313631]."},"prefetch_data":{"uniprot":{"accession":"Q9Y337","full_name":"Kallikrein-5","aliases":["Kallikrein-like protein 2","KLK-L2","Stratum corneum tryptic enzyme"],"length_aa":293,"mass_kda":32.0,"function":"May be involved in desquamation","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9Y337/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLK5","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLK5","total_profiled":1310},"omim":[{"mim_id":"621364","title":"MICRO RNA 382; MIR382","url":"https://www.omim.org/entry/621364"},{"mim_id":"620925","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 31; LRRC31","url":"https://www.omim.org/entry/620925"},{"mim_id":"617471","title":"SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 12; SERPINA12","url":"https://www.omim.org/entry/617471"},{"mim_id":"615868","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 6; SPINK6","url":"https://www.omim.org/entry/615868"},{"mim_id":"613511","title":"SERINE PROTEASE INHIBITOR, KAZAL-TYPE, 9; SPINK9","url":"https://www.omim.org/entry/613511"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skin 1","ntpm":195.5}],"url":"https://www.proteinatlas.org/search/KLK5"},"hgnc":{"alias_symbol":["SCTE","KLK-L2"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y337","domains":[{"cath_id":"2.40.10.10","chopping":"80-172_283-292","consensus_level":"medium","plddt":97.4348,"start":80,"end":292},{"cath_id":"2.40.10.10","chopping":"184-280","consensus_level":"medium","plddt":93.3856,"start":184,"end":280}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y337","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y337-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y337-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLK5","jax_strain_url":"https://www.jax.org/strain/search?query=KLK5"},"sequence":{"accession":"Q9Y337","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y337.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y337/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y337"}},"corpus_meta":[{"pmid":"15140227","id":"PMC_15140227","title":"Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.","date":"2004","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15140227","citation_count":366,"is_preprint":false},{"pmid":"17596512","id":"PMC_17596512","title":"LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17596512","citation_count":237,"is_preprint":false},{"pmid":"33674594","id":"PMC_33674594","title":"Identifying transposable element expression dynamics and heterogeneity during development at the single-cell level with a processing pipeline scTE.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33674594","citation_count":131,"is_preprint":false},{"pmid":"15675955","id":"PMC_15675955","title":"LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.","date":"2005","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15675955","citation_count":116,"is_preprint":false},{"pmid":"12738725","id":"PMC_12738725","title":"Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12738725","citation_count":94,"is_preprint":false},{"pmid":"10608802","id":"PMC_10608802","title":"The new kallikrein-like gene, KLK-L2. Molecular characterization, mapping, tissue expression, and hormonal regulation.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10608802","citation_count":89,"is_preprint":false},{"pmid":"11948967","id":"PMC_11948967","title":"Down-regulation of the human kallikrein gene 5 (KLK5) in prostate cancer tissues.","date":"2002","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/11948967","citation_count":53,"is_preprint":false},{"pmid":"29107298","id":"PMC_29107298","title":"KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes.","date":"2017","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29107298","citation_count":47,"is_preprint":false},{"pmid":"15766562","id":"PMC_15766562","title":"KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.","date":"2005","source":"Biochemical and biophysical research 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30759066","citation_count":11,"is_preprint":false},{"pmid":"23086576","id":"PMC_23086576","title":"Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate.","date":"2012","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23086576","citation_count":9,"is_preprint":false},{"pmid":"35595569","id":"PMC_35595569","title":"KLK5 is associated with the radioresistance, aggression, and progression of cervical cancer.","date":"2022","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35595569","citation_count":8,"is_preprint":false},{"pmid":"37353723","id":"PMC_37353723","title":"Mini-PBPK-Based Population Model and Covariate Analysis to Assess the Complex Pharmacokinetics and Pharmacodynamics of RO7449135, an Anti-KLK5/KLK7 Bispecific Antibody in Cynomolgus Monkeys.","date":"2023","source":"The AAPS journal","url":"https://pubmed.ncbi.nlm.nih.gov/37353723","citation_count":7,"is_preprint":false},{"pmid":"31955796","id":"PMC_31955796","title":"Kallikrein-related Peptidase 5 (KLK5) Expression and Distribution in Canine Cutaneous Squamous Cell Carcinoma.","date":"2019","source":"Journal of comparative pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31955796","citation_count":7,"is_preprint":false},{"pmid":"39163389","id":"PMC_39163389","title":"The host protease KLK5 primes and activates spike proteins to promote human betacoronavirus replication and lung inflammation.","date":"2024","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/39163389","citation_count":6,"is_preprint":false},{"pmid":"24490507","id":"PMC_24490507","title":"[The changes of skin barrier of patients with different facial dermatitis and the comparison of CE and KLK5].","date":"2013","source":"Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition","url":"https://pubmed.ncbi.nlm.nih.gov/24490507","citation_count":4,"is_preprint":false},{"pmid":"40753921","id":"PMC_40753921","title":"KLK5 and KLK7 drive cervical carcinoma via KLK14-dependent RhoA and NF-κB pathways.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40753921","citation_count":1,"is_preprint":false},{"pmid":"41668756","id":"PMC_41668756","title":"Lithospermic acid, a novel KLK5 inhibitor, ameliorates rosacea by suppressing the TLR4/NF-κB signaling pathway and rectifying phenylalanine metabolism.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41668756","citation_count":0,"is_preprint":false},{"pmid":"40943523","id":"PMC_40943523","title":"Deletion of the Epidermal Protease KLK5 Aggravates the Symptoms of Congenital Ichthyosis CDSN-nEDD.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40943523","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.25.640192","title":"Distinct roles for thymic stromal lymphopoietin (TSLP) and IL-33 in experimental eosinophilic esophagitis","date":"2025-03-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.25.640192","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22674,"output_tokens":3123,"usd":0.057433},"stage2":{"model":"claude-opus-4-6","input_tokens":6481,"output_tokens":3097,"usd":0.164745},"total_usd":0.222178,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"KLK5 (SCTE/hK5) directly degrades corneodesmosome proteins DSG1, DSC1, and corneodesmosin (CDSN) at acidic pH, acting as a trypsin-like serine protease; additionally, KLK5 activates the proform of KLK7 (pro-SCCE), suggesting it initiates a protease cascade in desquamation.\",\n      \"method\": \"In vitro protease cleavage assays with recombinant and epidermal proteins at acidic pH; proenzyme activation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro reconstitution with recombinant substrates, multiple substrates tested, replicated across two kallikrein enzymes\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LEKTI fragments (particularly D8-D11) specifically inhibit KLK5 through rapid, tight-binding complex formation; the interaction is pH-dependent, with acidic pH (mimicking the stratum corneum surface) causing release of active KLK5 from the LEKTI complex, thereby enabling corneodesmosomal cleavage in the outermost skin layers.\",\n      \"method\": \"Biochemical inhibition kinetics of recombinant LEKTI fragments against KLK5, KLK7, and KLK14; pH-dependence assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with kinetic analysis, multiple LEKTI fragments tested, mechanistic pH-dependence established, independently confirmed by localization studies\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In normal skin, KLK5 and KLK7 are separately localized within lamellar granules and secreted after LEKTI, establishing spatiotemporal separation as a mechanism preventing premature stratum corneum degradation; in Netherton syndrome (SPINK5 mutations), absence of LEKTI correlates with loss of stratum corneum integrity.\",\n      \"method\": \"Confocal laser scanning microscopy and immunoelectron microscopy of human epidermis and Netherton syndrome skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunoelectron microscopy with functional consequence (barrier integrity), replicated across normal and disease skin\",\n      \"pmids\": [\"15675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SPINK9, a Kazal-type serine protease inhibitor expressed in palmo-plantar epidermis, selectively inhibits KLK5; the reactive loop residues 48 and 49 define specificity, and protonation of His48 at acidic pH increases inhibitory efficiency by decreasing the dissociation rate of the SPINK9–KLK5 complex.\",\n      \"method\": \"Biochemical inhibition assays with SPINK9 variants (single amino acid substitutions), pH-dependence assays, molecular modeling of enzyme-inhibitor complex\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of inhibitor reactive loop combined with kinetic analysis and structural modeling, multiple mutants tested\",\n      \"pmids\": [\"22505519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibitory antibodies against KLK5 bind distal to the KLK5 active site and inhibit its activity via an allosteric mechanism, as revealed by a crystal structure of KLK5 bound to an inhibitory Fab; dual antibody inhibition of KLK5 and KLK7 promotes skin barrier integrity and reduces inflammation in mouse models of Netherton syndrome and atopic dermatitis.\",\n      \"method\": \"Crystal structure of KLK5–Fab complex; in vivo mouse models of Netherton syndrome and atopic dermatitis with inhibitory antibodies\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation in mouse models, allosteric mechanism defined structurally\",\n      \"pmids\": [\"36516271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLK5 is secreted by CD4+ T cells in type 2 diabetes patients and directly interacts with the extracellular loop of DPP4, cleaving DPP4 from the surface of circulating CD4+ Th17 cells and shedding it into the plasma, thereby increasing plasma DPP4 activity.\",\n      \"method\": \"Ex vivo and in vitro protease activity assays, co-immunoprecipitation, surface expression analysis, in silico docking; ELISA for plasma DPP4\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (co-IP, protease assay, cell surface shedding), single lab study\",\n      \"pmids\": [\"29107298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLK5 is a host serine protease secreted by human airway epithelial cells that cleaves both the S1/S2 priming site and S2' activation site of betacoronavirus spike proteins in vitro, enabling single-protease activation of SARS-CoV-2 and other betacoronavirus spike proteins; KLK5 upregulation upon betacoronavirus infection promotes viral replication in differentiated human bronchial epithelial cells.\",\n      \"method\": \"In vitro cleavage assays of spike proteins by recombinant KLK5, KLK12, KLK13; infection of differentiated human bronchial epithelial cells; mouse MERS-CoV/SARS-CoV-2 infection model with KLK5 inhibitor (ursolic acid)\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of spike cleavage plus cell-based and in vivo validation with inhibitor\",\n      \"pmids\": [\"39163389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Reconstitution of KLK5 expression in MDA-MB-231 breast cancer cells suppresses malignancy by downregulating the mevalonate pathway (reducing cholesterol/fatty acid synthesis and isoprenoid production), leading to diminished levels of active (prenylated) RhoA; restoration of geranylgeranyl pyrophosphate reverses KLK5-mediated suppression, placing KLK5 upstream of RhoA prenylation.\",\n      \"method\": \"Stable transfection of KLK5 in MDA-MB-231 cells; transcriptome analysis; cholesterol/isoprenoid metabolic assays; RhoA activity assays; in vivo tumor growth; geranylgeranyl pyrophosphate rescue experiment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-like rescue experiment plus multiple metabolic readouts, single lab\",\n      \"pmids\": [\"24158494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 stabilizes KLK5 mRNA in an m6A-dependent manner; KLK5 protein in turn activates the PAR2/AKT signaling axis to promote gallbladder carcinoma cell proliferation and migration; let-7g-5p suppresses this pathway by targeting IGF2BP3.\",\n      \"method\": \"RNA immunoprecipitation, RNA stability assay, methylated RNA immunoprecipitation, dual-luciferase reporter assay, gain/loss-of-function in vitro and in vivo\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods establishing mRNA stabilization and downstream signaling, single lab\",\n      \"pmids\": [\"36313631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STAT3 regulates KLK5 expression in keratinocytes: keratinocyte-specific STAT3 ablation upregulates KLK5, while STAT3 overexpression decreases KLK5 expression; STAT3 also positively regulates SPINK5 (the KLK5 inhibitor LEKTI), linking STAT3 to skin barrier homeostasis through control of the KLK5/LEKTI balance.\",\n      \"method\": \"Keratinocyte-specific STAT3 knockout mouse model; STAT3 siRNA knockdown and overexpression in keratinocytes; transcriptomic analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function mouse model plus in vitro siRNA/overexpression, single lab\",\n      \"pmids\": [\"34378233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis through activation of KLK14; KLK14 in turn signals via PAR-2-dependent RhoA and NF-κB pathways to promote tumor progression; absence of both KLK5 and KLK7 ameliorates the HPV-dependent phenotype.\",\n      \"method\": \"Genetically engineered mice (KLK5/KLK7 double knockout in HPV model); bulk RNA-seq; reporter assays for RhoA and NF-κB; human biopsy analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse model with downstream pathway reporters, supported by human biopsy expression data\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK5 deletion in a CDSN-knockout (CDSN-nEDD) background aggravates the desquamation phenotype rather than rescuing it: epidermal proteolysis increases, corneodesmosomes show ultrastructural alterations, and epidermal barrier permeability worsens, suggesting that other proteases compensate for KLK5 loss and that KLK5 initiates but does not solely sustain the desquamation cascade.\",\n      \"method\": \"shRNA-mediated CDSN knockdown in human epidermal equivalents; Klk5/Cdsn double-knockout mice; ultrastructural analysis; barrier permeability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two complementary genetic loss-of-function models (human and mouse), multiple phenotypic readouts\",\n      \"pmids\": [\"40943523\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLK5 is a trypsin-like serine protease that initiates epidermal desquamation by directly cleaving corneodesmosome proteins (CDSN, DSG1, DSC1) and activating pro-KLK7, with its activity tightly regulated by the pH-dependent inhibitor LEKTI (encoded by SPINK5) and the palmo-plantar-specific inhibitor SPINK9; beyond the skin, KLK5 cleaves DPP4 from T cell surfaces, activates coronavirus spike proteins at both S1/S2 and S2' sites, and signals through the PAR2/AKT and RhoA/NF-κB pathways in cancer contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KLK5 is a trypsin-like serine protease that initiates the epidermal desquamation cascade by cleaving corneodesmosome proteins (DSG1, DSC1, CDSN) at acidic pH and activating pro-KLK7, thereby linking protease activity to controlled stratum corneum shedding [PMID:15140227]. Its activity is tightly regulated by the pH-dependent inhibitor LEKTI (encoded by SPINK5), which forms a tight-binding complex with KLK5 at neutral pH but releases active KLK5 at the acidic pH of the outermost skin surface, and by the palmo-plantar-specific inhibitor SPINK9 whose inhibitory potency likewise increases at acidic pH [PMID:17596512, PMID:22505519]. Loss of LEKTI in Netherton syndrome results in unrestrained KLK5 activity and compromised skin barrier integrity, and allosteric inhibitory antibodies targeting KLK5 restore barrier function in mouse models of this disease [PMID:15675955, PMID:36516271]. Beyond its epidermal role, KLK5 cleaves DPP4 from T cell surfaces, activates betacoronavirus spike proteins at both the S1/S2 and S2' sites enabling viral entry in airway epithelia, and participates in PAR2-dependent signaling in cancer contexts [PMID:29107298, PMID:39163389, PMID:36313631].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established KLK5 as the initiator of the desquamation protease cascade by showing it directly degrades corneodesmosome substrates and activates pro-KLK7, answering how stratum corneum shedding is enzymatically triggered.\",\n      \"evidence\": \"In vitro cleavage assays with recombinant KLK5 against DSG1, DSC1, CDSN, and pro-KLK7 at acidic pH\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage sites on corneodesmosome proteins not mapped\", \"No in vivo validation of the cascade hierarchy\", \"Whether KLK5 alone is sufficient for desquamation was untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved how premature KLK5 activation is prevented in normal epidermis: KLK5/KLK7 and LEKTI are stored in separate lamellar granule compartments and secreted sequentially, with loss of LEKTI in Netherton syndrome causing unchecked proteolysis.\",\n      \"evidence\": \"Immunoelectron microscopy and confocal microscopy of normal and Netherton syndrome human epidermis\",\n      \"pmids\": [\"15675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of sequential secretion not defined\", \"Whether other inhibitors partially compensate in Netherton syndrome skin was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the molecular logic of LEKTI-mediated KLK5 inhibition: LEKTI domains D8-D11 form tight-binding complexes with KLK5 at neutral pH but release active protease at acidic pH, explaining how desquamation is spatially restricted to the outermost stratum corneum.\",\n      \"evidence\": \"Kinetic inhibition assays of recombinant LEKTI fragments against KLK5 across a pH range\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of pH-dependent binding not resolved\", \"Relative contribution of individual LEKTI domains in vivo unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified SPINK9 as a site-specific inhibitor of KLK5 in palmo-plantar skin and demonstrated that reactive-loop residues and His48 protonation govern selectivity and pH-enhanced inhibition.\",\n      \"evidence\": \"Mutagenesis of SPINK9 reactive-loop residues combined with kinetic assays and molecular modeling\",\n      \"pmids\": [\"22505519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the SPINK9–KLK5 complex\", \"In vivo relevance in palmo-plantar barrier not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed KLK5 can suppress breast cancer malignancy by downregulating the mevalonate pathway, reducing RhoA prenylation — an unexpected non-epidermal function linking KLK5 to lipid metabolism and oncogenic signaling.\",\n      \"evidence\": \"Stable KLK5 expression in MDA-MB-231 cells; metabolic rescue with geranylgeranyl pyrophosphate; in vivo tumor growth assays\",\n      \"pmids\": [\"24158494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct proteolytic substrate mediating mevalonate pathway suppression unknown\", \"Single cell line system\", \"Not confirmed in clinical tumor specimens\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a non-skin proteolytic role for KLK5: it is secreted by CD4+ T cells and sheds DPP4 from the surface of Th17 cells, increasing plasma DPP4 in type 2 diabetes patients.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-surface shedding assays, and plasma ELISA in type 2 diabetes patient samples\",\n      \"pmids\": [\"29107298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site on DPP4 not mapped\", \"Causal role of KLK5-mediated DPP4 shedding in diabetes pathophysiology not established\", \"Single cohort study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed KLK5 under transcriptional control of STAT3 in keratinocytes: STAT3 represses KLK5 while promoting SPINK5 expression, establishing a single transcription factor that coordinates both the protease and its inhibitor for barrier homeostasis.\",\n      \"evidence\": \"Keratinocyte-specific STAT3 knockout mice; siRNA knockdown and overexpression in keratinocytes\",\n      \"pmids\": [\"34378233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3 binds the KLK5 promoter directly was not shown\", \"Downstream barrier phenotype in STAT3-KO skin not fully characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an allosteric inhibition mechanism for KLK5: an antibody Fab binds distal to the active site yet blocks protease activity, and dual KLK5/KLK7 antibody inhibition restores barrier integrity in Netherton syndrome and atopic dermatitis mouse models, validating KLK5 as a therapeutic target.\",\n      \"evidence\": \"Crystal structure of KLK5–Fab complex; in vivo treatment of Netherton syndrome and atopic dermatitis mouse models\",\n      \"pmids\": [\"36516271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric conformational change not characterized dynamically\", \"Human clinical efficacy not yet demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked KLK5 to PAR2/AKT signaling in gallbladder carcinoma: IGF2BP3 stabilizes KLK5 mRNA in an m6A-dependent manner, and KLK5 protein activates PAR2/AKT to promote proliferation and migration.\",\n      \"evidence\": \"RNA immunoprecipitation, MeRIP, dual-luciferase assays, gain/loss-of-function in vitro and in vivo\",\n      \"pmids\": [\"36313631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KLK5 directly cleaves PAR2 in this context not shown\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established KLK5 as a host airway protease capable of both S1/S2 priming and S2' activation of betacoronavirus spike proteins, demonstrating a single-protease viral activation mechanism and showing that KLK5 inhibition reduces viral replication.\",\n      \"evidence\": \"In vitro spike cleavage assays; infection of differentiated human bronchial epithelial cells; mouse coronavirus infection model with KLK5 inhibitor (ursolic acid)\",\n      \"pmids\": [\"39163389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ursolic acid is not a specific KLK5 inhibitor — genetic validation in airway cells pending\", \"Relative contribution of KLK5 versus TMPRSS2 in vivo not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that KLK5 (with KLK7) activates KLK14 to drive PAR-2/RhoA/NF-κB signaling in HPV-dependent cervical carcinogenesis, and that KLK5/KLK7 double knockout ameliorates the malignant phenotype.\",\n      \"evidence\": \"KLK5/KLK7 double-knockout mice crossed with HPV transgenic model; RNA-seq; RhoA and NF-κB reporter assays; human biopsy analysis\",\n      \"pmids\": [\"40753921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KLK5 directly activates pro-KLK14 or acts indirectly not resolved\", \"PAR-2 cleavage by KLK14 in this model not biochemically validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that KLK5 deletion in a CDSN-knockout background paradoxically worsens desquamation and barrier permeability, indicating compensatory protease activity and that KLK5 initiates but does not solely sustain the desquamation cascade.\",\n      \"evidence\": \"KLK5/CDSN double-knockout mice and shRNA-mediated CDSN knockdown in human epidermal equivalents; ultrastructural and permeability analysis\",\n      \"pmids\": [\"40943523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of compensating proteases not determined\", \"Mechanism by which KLK5 loss exacerbates barrier dysfunction in CDSN-null background unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full set of proteases that compensate for KLK5 loss in desquamation, the structural basis of pH-dependent LEKTI release, and whether KLK5 directly cleaves PAR2 in cancer and inflammatory contexts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the KLK5–LEKTI complex\", \"Compensatory proteases in KLK5-null epidermis unidentified\", \"Direct PAR2 cleavage by KLK5 not biochemically demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KLK7\", \"CDSN\", \"DSG1\", \"DSC1\", \"SPINK5\", \"SPINK9\", \"DPP4\", \"KLK14\"],\n    \"other_free_text\": []\n  }\n}\n```"}