{"gene":"KLK5","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"KLK5 (SCTE/hK5) directly degrades all three corneodesmosome adhesive proteins — corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) — at acidic pH resembling the stratum corneum, and can activate the proform of KLK7 (SCCE), establishing KLK5 as an upstream initiator of the desquamation protease cascade.","method":"In vitro cleavage assays using recombinant and epidermal forms of CDSN, DSG1, and DSC1 with purified SCTE/KLK5 and SCCE/KLK7; zymogen activation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant substrates and mutagenesis-equivalent deglycosylation controls; independently replicated across multiple substrate types in one rigorous study","pmids":["15140227"],"is_preprint":false},{"year":2007,"finding":"LEKTI fragments (processed from precursor by furin) specifically and differentially inhibit KLK5, KLK7, and KLK14; the D8–D11 fragment shows the strongest inhibition of KLK5 via rapid, irreversible binding. The KLK5–LEKTI interaction is pH-dependent: at acidic pH (mimicking outer stratum corneum), KLK5 is released from the complex as active enzyme, providing the mechanism for zone-restricted desquamation.","method":"Biochemical inhibition kinetics assays; pH-dependent binding studies; LEKTI fragment characterization by Western blot and antibody panels","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinetics with multiple LEKTI fragments, pH-titration experiments, and irreversibility assays; multiple orthogonal methods in one rigorous study","pmids":["17596512"],"is_preprint":false},{"year":2005,"finding":"KLK5 and KLK7 are separately co-localized within lamellar granules of normal epidermis, but LEKTI is packaged into lamellar granules earlier and separately from KLK5/KLK7. In Netherton syndrome skin lacking LEKTI, an abnormal epidermal split is observed, consistent with unrestrained KLK5/KLK7 activity causing premature loss of stratum corneum cohesion.","method":"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin sections","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by immunoelectron microscopy with functional consequence (pathological phenotype in LEKTI-absent skin); two orthogonal imaging methods in one study","pmids":["15675955"],"is_preprint":false},{"year":2012,"finding":"SPINK9, a Kazal-type inhibitor expressed almost exclusively in palmo-plantar epidermis, selectively inhibits KLK5. The reactive loop residues 48 and 49 of SPINK9 determine specificity; pH-dependent inhibition arises because decreased pH protonates His48, creating a positive charge that slows the dissociation rate from KLK5's deep negatively charged binding pocket.","method":"In vitro inhibition assays with wild-type and single-amino-acid reactive-loop SPINK9 mutants against KLK5, KLK7, KLK8, KLK14; binding kinetics (kon/koff); computational modeling of enzyme–inhibitor complex","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic inhibition assays combined with site-directed mutagenesis of inhibitor reactive loop and structural modeling; multiple orthogonal methods in one study","pmids":["22505519"],"is_preprint":false},{"year":2022,"finding":"A crystal structure of KLK5 bound to an inhibitory Fab (anti-KLK5 antibody) revealed that the antibody binds distal to the KLK5 active site, establishing an allosteric inhibition mechanism. The bispecific anti-KLK5/KLK7 antibody derived from this work protects mouse models of Netherton syndrome and atopic dermatitis, restoring skin barrier integrity.","method":"X-ray crystallography of KLK5–Fab complex; mouse models of Netherton syndrome and atopic dermatitis with antibody treatment; barrier integrity assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with direct functional validation in multiple animal models; multiple orthogonal methods (structure + in vivo)","pmids":["36516271"],"is_preprint":false},{"year":2017,"finding":"KLK5 is expressed and secreted by CD4+ T cells from type 2 diabetes patients. KLK5 directly interacts with the extracellular loop of DPP4 and cleaves DPP4 from the surface of circulating Th17 cells, releasing soluble DPP4 into plasma. This identifies KLK5 as the enzyme responsible for elevated plasma DPP4 activity in T2DM.","method":"Ex vivo and in vitro enzyme cleavage assays; co-immunoprecipitation/protein–protein interaction; flow cytometry for surface DPP4; subcellular localization studies; in silico docking; gene expression and secretion assays in CD4+ T cells","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, enzymatic cleavage, surface expression assay) in a single lab study; mechanistic claim supported by in vitro and ex vivo evidence","pmids":["29107298"],"is_preprint":false},{"year":2014,"finding":"Reconstitution of KLK5 expression in KLK5-negative MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo. KLK5 re-expression reduces cellular cholesterol and fatty acid synthesis, induces SREBF1, and suppresses the mevalonate pathway, leading to decreased prenylation and reduced levels of active RhoA. Restoration of active RhoA by geranylgeranyl pyrophosphate rescues the malignant phenotype, placing KLK5-mediated mevalonate pathway suppression upstream of RhoA inactivation.","method":"Stable KLK5 transfection in MDA-MB-231 cells; gene expression arrays; cholesterol/fatty acid synthesis assays; RhoA activity assays; geranylgeranyl pyrophosphate rescue experiments; in vivo xenograft assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (transcriptomics, biochemical pathway assays, rescue experiment, in vivo) in a single lab; epistasis established by geranylgeranyl rescue","pmids":["24158494"],"is_preprint":false},{"year":2024,"finding":"KLK5 is a major host serine protease secreted by human airway cells that cleaves both the priming (S1/S2) and activation (S2') sites of betacoronavirus spike proteins, including SARS-CoV-2, SARS-CoV, and MERS-CoV. KLK5 alone is sufficient to activate spike proteins from multiple betacoronaviruses, whereas KLK12 and KLK13 show single-site preferences and act in concert. Betacoronavirus infection induces KLK5 upregulation in differentiated human bronchial epithelial cells (HBECs), promoting replication. Pharmacological inhibition of KLK5 (ursolic acid and related triterpenoids) suppresses betacoronavirus replication in HBECs and reduces lung inflammation in MERS-CoV- and SARS-CoV-2-infected mice.","method":"In vitro cleavage assays of purified spike proteins by KLK5, KLK12, KLK13; infection of differentiated HBECs; KLK5 inhibitor treatment; MERS-CoV and SARS-CoV-2 mouse infection models","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic cleavage assays, human primary cell infection experiments, and multiple in vivo animal models; multiple orthogonal methods in one rigorous study","pmids":["39163389"],"is_preprint":false},{"year":2025,"finding":"In the context of CDSN-nEDD (corneodesmosin-deficient ichthyosis), genetic deletion of KLK5 paradoxically aggravates rather than rescues the over-desquamation phenotype. KLK5 knockout in CDSN-deficient epidermis leads to elevated total epidermal proteolysis, severe desmosomal ultrastructural alterations, increased barrier permeability, and stratum corneum detachment — indicating that in the absence of corneodesmosin, other proteases compensate and KLK5 has a protective/regulatory role beyond simple pro-desquamation activity.","method":"shRNA-mediated CDSN knockdown in human epidermal equivalents; Klk5 knockout mice crossed with Cdsn knockout mice; ultrastructural analysis; barrier permeability assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in two complementary models (HEE and mouse double-KO); functional phenotypic readouts; single lab study","pmids":["40943523"],"is_preprint":false},{"year":2025,"finding":"In cervical carcinogenesis, KLK5 and KLK7 promote tumor progression by activating KLK14, which in turn activates PAR-2-dependent RhoA and NF-κB signaling pathways. Genetic ablation of both KLK5 and KLK7 in a mouse model ameliorates the HPV-dependent cervical carcinoma phenotype via reduction of KLK14 activation.","method":"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; reporter assays for NF-κB and RhoA pathways; human biopsy analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo (double-KO mouse model) combined with pathway reporter assays and transcriptomics; single lab study with multiple methods","pmids":["40753921"],"is_preprint":false},{"year":2022,"finding":"IGF2BP3 directly binds KLK5 mRNA and stabilizes it in an N6-methyladenosine (m6A)-dependent manner in gallbladder carcinoma cells. This stabilization increases KLK5 protein levels, which in turn activates PAR2 and downstream phospho-AKT signaling to promote tumor cell proliferation and migration.","method":"RNA immunoprecipitation (RIP); RNA stability assays; methylated RNA immunoprecipitation (MeRIP); dual-luciferase reporter assay; KLK5 rescue after IGF2BP3 depletion; Western blot for PAR2/pAKT","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal RNA-binding assays (RIP, MeRIP, stability) plus downstream signaling readout and rescue experiment; single lab study","pmids":["36313631"],"is_preprint":false},{"year":2021,"finding":"STAT3 negatively regulates KLK5 expression in keratinocytes: keratinocyte-specific STAT3 ablation in mice upregulates KLK5 and causes a cutaneous inflammatory phenotype with impaired barrier function. STAT3 overexpression decreases KLK5 expression and increases SPINK5 (LEKTI) expression; STAT3 siRNA knockdown reverses both effects, placing STAT3 as a transcriptional regulator upstream of both KLK5 and its inhibitor SPINK5.","method":"Keratinocyte-specific STAT3 knockout mice; transcriptomic analysis; STAT3 siRNA knockdown in keratinocytes; STAT3 overexpression in keratinocytes; qRT-PCR","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with transcriptomics plus complementary gain- and loss-of-function cell assays; single lab, two orthogonal approaches","pmids":["34378233"],"is_preprint":false}],"current_model":"KLK5 is a secreted trypsin-like serine protease that initiates epidermal desquamation by directly cleaving corneodesmosome proteins (CDSN, DSG1, DSC1) and activating pro-KLK7; its activity is spatiotemporally controlled by the pH-dependent LEKTI inhibitor system (and by SPINK9 in palmo-plantar skin via allosteric and active-site mechanisms), with STAT3 acting as an upstream transcriptional regulator; beyond skin, KLK5 cleaves DPP4 from Th17 cell surfaces, primes and activates betacoronavirus spike proteins to promote pulmonary infection, activates PAR2/RhoA/NF-κB oncogenic signaling (partly via KLK14) in cancer contexts, and has its own mRNA stabilized by IGF2BP3 through m6A-dependent binding."},"narrative":{"mechanistic_narrative":"KLK5 is a secreted trypsin-like serine protease that initiates the epidermal desquamation cascade by directly degrading the corneodesmosome adhesion proteins corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) at the acidic pH of the stratum corneum and by converting pro-KLK7 to its active form [PMID:15140227]. Its activity is spatially confined by inhibitors whose action is pH-tuned: LEKTI (SPINK5) fragments bind and irreversibly inhibit KLK5 at neutral pH and release active enzyme at acidic pH, restricting proteolysis to the outer cornified layers [PMID:17596512], while SPINK9 provides palmo-plantar-specific inhibition through a reactive-loop His48 protonation mechanism that slows dissociation from the enzyme [PMID:22505519]. KLK5 and its inhibitor are packaged separately into lamellar granules, and loss of LEKTI in Netherton syndrome skin produces unrestrained KLK5/KLK7 activity and premature loss of corneocyte cohesion [PMID:15675955]. Consistent with this, allosteric antibody inhibition of KLK5 restores barrier integrity in mouse models of Netherton syndrome and atopic dermatitis [PMID:36516271], and STAT3 acts as an upstream transcriptional regulator that represses KLK5 while inducing SPINK5 [PMID:34378233]. Genetic studies reveal that KLK5's role is context-dependent rather than purely pro-desquamatory: in corneodesmosin-deficient epidermis its deletion paradoxically worsens proteolysis and barrier loss, indicating a regulatory function [PMID:40943523]. Beyond skin, KLK5 cleaves DPP4 from the surface of Th17 cells to generate soluble plasma DPP4 [PMID:29107298], primes and activates betacoronavirus spike proteins at both the S1/S2 and S2' sites to promote pulmonary infection [PMID:39163389], and influences cancer signaling—both as a tumor suppressor that suppresses the mevalonate pathway to inactivate RhoA in breast cancer [PMID:24158494] and, with KLK7, as a driver of KLK14-dependent PAR2/RhoA/NF-κB signaling in cervical carcinoma [PMID:40753921]; its mRNA is stabilized by IGF2BP3 in an m6A-dependent manner in gallbladder carcinoma [PMID:36313631].","teleology":[{"year":2004,"claim":"Established KLK5 as the initiating protease of epidermal desquamation by showing it directly cleaves corneodesmosome adhesion proteins and activates a downstream protease.","evidence":"In vitro cleavage assays of recombinant/epidermal CDSN, DSG1, DSC1 and pro-KLK7 zymogen activation at acidic pH","pmids":["15140227"],"confidence":"High","gaps":["Did not establish how KLK5 activity is restricted in intact skin","Endogenous KLK5 zymogen activation mechanism not addressed"]},{"year":2005,"claim":"Connected KLK5 spatial regulation to disease by showing separate lamellar-granule packaging of protease and inhibitor and unrestrained activity in LEKTI-deficient skin.","evidence":"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin","pmids":["15675955"],"confidence":"High","gaps":["Localization is correlative; did not quantify enzymatic activity in situ","Relative contributions of KLK5 vs KLK7 to the split not resolved"]},{"year":2007,"claim":"Defined the biochemical mechanism for zone-restricted desquamation: pH-dependent, irreversible LEKTI inhibition of KLK5 that releases active enzyme in the acidic outer stratum corneum.","evidence":"Inhibition kinetics, pH-titration binding studies, and LEKTI fragment characterization","pmids":["17596512"],"confidence":"High","gaps":["In vitro kinetics may not capture in vivo concentrations/microenvironment","Did not address other endogenous KLK5 inhibitors"]},{"year":2012,"claim":"Identified a tissue-restricted second inhibitor (SPINK9) and resolved the structural/charge basis for its pH-dependent, KLK5-selective inhibition.","evidence":"In vitro inhibition with reactive-loop mutants, binding kinetics, and computational modeling","pmids":["22505519"],"confidence":"High","gaps":["Modeling not confirmed by experimental KLK5–SPINK9 structure","Physiological importance in palmo-plantar desquamation not tested in vivo"]},{"year":2014,"claim":"Revealed a tumor-suppressive function distinct from desquamation, placing KLK5 upstream of mevalonate-pathway-dependent RhoA activation in breast cancer.","evidence":"Stable KLK5 re-expression in MDA-MB-231 cells with transcriptomics, lipid synthesis and RhoA activity assays, GGPP rescue, and xenografts","pmids":["24158494"],"confidence":"Medium","gaps":["Whether the effect requires KLK5 catalytic activity not established","Single cell line model","Apparent contrast with pro-oncogenic roles in other tissues unresolved"]},{"year":2017,"claim":"Extended KLK5 substrate repertoire beyond skin by identifying DPP4 as a surface substrate shed from Th17 cells, linking KLK5 to elevated plasma DPP4 in metabolic disease.","evidence":"Co-IP, in vitro/ex vivo cleavage assays, surface DPP4 flow cytometry, and docking in CD4+ T cells","pmids":["29107298"],"confidence":"Medium","gaps":["Reciprocal validation of the KLK5–DPP4 interaction limited","Causal contribution to diabetes pathology not established in vivo"]},{"year":2021,"claim":"Placed KLK5 under transcriptional control of STAT3, which coordinately represses KLK5 and induces its inhibitor SPINK5 in keratinocytes.","evidence":"Keratinocyte-specific STAT3 knockout mice plus STAT3 gain/loss-of-function in keratinocytes with qRT-PCR and transcriptomics","pmids":["34378233"],"confidence":"Medium","gaps":["Direct STAT3 binding to KLK5/SPINK5 promoters not demonstrated","Single lab study"]},{"year":2022,"claim":"Provided a structurally validated allosteric inhibition strategy and demonstrated therapeutic benefit of KLK5 blockade in barrier disease models.","evidence":"X-ray crystallography of a KLK5–Fab complex with bispecific antibody treatment in Netherton and atopic dermatitis mouse models","pmids":["36516271"],"confidence":"High","gaps":["Antibody is bispecific (KLK5/KLK7), so KLK5-specific contribution to rescue is convolved","Human efficacy not addressed"]},{"year":2022,"claim":"Identified post-transcriptional regulation of KLK5 via m6A-dependent mRNA stabilization driving PAR2/AKT oncogenic signaling.","evidence":"RIP, MeRIP, RNA stability and luciferase assays with IGF2BP3 depletion rescue in gallbladder carcinoma cells","pmids":["36313631"],"confidence":"Medium","gaps":["Performed in a single tumor type","Whether secreted KLK5 protease activity mediates the PAR2 effect not directly shown"]},{"year":2024,"claim":"Defined KLK5 as a host protease that primes and activates betacoronavirus spike proteins, making it a determinant of pulmonary infection and a druggable antiviral target.","evidence":"In vitro spike cleavage assays, infection of differentiated HBECs, KLK5 inhibitor treatment, and MERS-CoV/SARS-CoV-2 mouse models","pmids":["39163389"],"confidence":"High","gaps":["Inhibitor (ursolic acid) selectivity for KLK5 in vivo not fully delineated","Relative in vivo contribution of KLK5 vs KLK12/KLK13 not quantified"]},{"year":2025,"claim":"Demonstrated that KLK5's role is context-dependent and protective in corneodesmosin-deficient skin, where its loss aggravates rather than rescues over-desquamation.","evidence":"shRNA CDSN knockdown in human epidermal equivalents and Klk5/Cdsn double-knockout mice with ultrastructural and barrier assays","pmids":["40943523"],"confidence":"Medium","gaps":["Identity of the compensating proteases not established","Molecular basis of the protective/regulatory function unknown"]},{"year":2025,"claim":"Established KLK5 (with KLK7) as a driver of cervical carcinogenesis through KLK14 activation feeding PAR2/RhoA/NF-κB signaling.","evidence":"KLK5/KLK7 double-knockout mice with RNA-seq, NF-κB/RhoA reporter assays, and human biopsy analysis","pmids":["40753921"],"confidence":"Medium","gaps":["Double-knockout design does not isolate KLK5-specific contribution","Direct KLK5–KLK14 activation in this context inferred rather than reconstituted"]},{"year":null,"claim":"How KLK5 switches between pro-desquamatory, protective, antiviral, and opposing oncogenic roles across tissues, and how its zymogen is endogenously activated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Context-dependent tumor-suppressor vs oncogenic behavior unreconciled","Endogenous activator(s) of pro-KLK5 not identified","Compensating proteases in CDSN-deficient skin unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0030312","term_label":"external encapsulating structure","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CDSN","DSG1","DSC1","KLK7","SPINK5","SPINK9","DPP4","KLK14"],"other_free_text":[]}},"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":367,"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":139,"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. 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function.","date":"2008","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18163887","citation_count":18,"is_preprint":false},{"pmid":"33260070","id":"PMC_33260070","title":"Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma.","date":"2020","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33260070","citation_count":17,"is_preprint":false},{"pmid":"33896830","id":"PMC_33896830","title":"Salivary KLK5 and uPA are potential biomarkers for malignant transformation of OLK and OLP.","date":"2021","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/33896830","citation_count":16,"is_preprint":false},{"pmid":"22505519","id":"PMC_22505519","title":"Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis.","date":"2012","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22505519","citation_count":16,"is_preprint":false},{"pmid":"36313631","id":"PMC_36313631","title":"IGF2BP3 promotes progression of gallbladder carcinoma by stabilizing KLK5 mRNA in N6-methyladenosine-dependent binding.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36313631","citation_count":15,"is_preprint":false},{"pmid":"33223519","id":"PMC_33223519","title":"Long noncoding RNA HEIH depletion depresses esophageal carcinoma cell progression by upregulating microRNA-185 and downregulating KLK5.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33223519","citation_count":14,"is_preprint":false},{"pmid":"34378233","id":"PMC_34378233","title":"STAT3 maintains skin barrier integrity by modulating SPINK5 and KLK5 expression in keratinocytes.","date":"2021","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/34378233","citation_count":13,"is_preprint":false},{"pmid":"31999109","id":"PMC_31999109","title":"Modulated Linear Tellurium Chains in Ba3ScTe5: Synthesis, Crystal Structure, Optical and Resistivity Studies, and Electronic Structure.","date":"2020","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31999109","citation_count":13,"is_preprint":false},{"pmid":"31396327","id":"PMC_31396327","title":"Expression and clinical significance of KLK5-8 in endometrial cancer.","date":"2019","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/31396327","citation_count":12,"is_preprint":false},{"pmid":"30759066","id":"PMC_30759066","title":"Uncovering the clinical impact of kallikrein-related peptidase 5 (KLK5) mRNA expression in the colorectal adenoma-carcinoma sequence.","date":"2019","source":"Clinical chemistry and laboratory 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":"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":"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":"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":"41866470","id":"PMC_41866470","title":"Characterization of KLK5-high epithelial cells and their interactions with the tumor microenvironment in high-grade serous ovarian cancer.","date":"2026","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41866470","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":24041,"output_tokens":3782,"usd":0.064426,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11453,"output_tokens":4106,"usd":0.079958,"stage2_stop_reason":"end_turn"},"total_usd":0.144384,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"KLK5 (SCTE/hK5) directly degrades all three corneodesmosome adhesive proteins — corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) — at acidic pH resembling the stratum corneum, and can activate the proform of KLK7 (SCCE), establishing KLK5 as an upstream initiator of the desquamation protease cascade.\",\n      \"method\": \"In vitro cleavage assays using recombinant and epidermal forms of CDSN, DSG1, and DSC1 with purified SCTE/KLK5 and SCCE/KLK7; zymogen activation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant substrates and mutagenesis-equivalent deglycosylation controls; independently replicated across multiple substrate types in one rigorous study\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LEKTI fragments (processed from precursor by furin) specifically and differentially inhibit KLK5, KLK7, and KLK14; the D8–D11 fragment shows the strongest inhibition of KLK5 via rapid, irreversible binding. The KLK5–LEKTI interaction is pH-dependent: at acidic pH (mimicking outer stratum corneum), KLK5 is released from the complex as active enzyme, providing the mechanism for zone-restricted desquamation.\",\n      \"method\": \"Biochemical inhibition kinetics assays; pH-dependent binding studies; LEKTI fragment characterization by Western blot and antibody panels\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinetics with multiple LEKTI fragments, pH-titration experiments, and irreversibility assays; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KLK5 and KLK7 are separately co-localized within lamellar granules of normal epidermis, but LEKTI is packaged into lamellar granules earlier and separately from KLK5/KLK7. In Netherton syndrome skin lacking LEKTI, an abnormal epidermal split is observed, consistent with unrestrained KLK5/KLK7 activity causing premature loss of stratum corneum cohesion.\",\n      \"method\": \"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin sections\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunoelectron microscopy with functional consequence (pathological phenotype in LEKTI-absent skin); two orthogonal imaging methods in one study\",\n      \"pmids\": [\"15675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SPINK9, a Kazal-type inhibitor expressed almost exclusively in palmo-plantar epidermis, selectively inhibits KLK5. The reactive loop residues 48 and 49 of SPINK9 determine specificity; pH-dependent inhibition arises because decreased pH protonates His48, creating a positive charge that slows the dissociation rate from KLK5's deep negatively charged binding pocket.\",\n      \"method\": \"In vitro inhibition assays with wild-type and single-amino-acid reactive-loop SPINK9 mutants against KLK5, KLK7, KLK8, KLK14; binding kinetics (kon/koff); computational modeling of enzyme–inhibitor complex\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic inhibition assays combined with site-directed mutagenesis of inhibitor reactive loop and structural modeling; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22505519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A crystal structure of KLK5 bound to an inhibitory Fab (anti-KLK5 antibody) revealed that the antibody binds distal to the KLK5 active site, establishing an allosteric inhibition mechanism. The bispecific anti-KLK5/KLK7 antibody derived from this work protects mouse models of Netherton syndrome and atopic dermatitis, restoring skin barrier integrity.\",\n      \"method\": \"X-ray crystallography of KLK5–Fab complex; mouse models of Netherton syndrome and atopic dermatitis with antibody treatment; barrier integrity assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with direct functional validation in multiple animal models; multiple orthogonal methods (structure + in vivo)\",\n      \"pmids\": [\"36516271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLK5 is expressed and secreted by CD4+ T cells from type 2 diabetes patients. KLK5 directly interacts with the extracellular loop of DPP4 and cleaves DPP4 from the surface of circulating Th17 cells, releasing soluble DPP4 into plasma. This identifies KLK5 as the enzyme responsible for elevated plasma DPP4 activity in T2DM.\",\n      \"method\": \"Ex vivo and in vitro enzyme cleavage assays; co-immunoprecipitation/protein–protein interaction; flow cytometry for surface DPP4; subcellular localization studies; in silico docking; gene expression and secretion assays in CD4+ T cells\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, enzymatic cleavage, surface expression assay) in a single lab study; mechanistic claim supported by in vitro and ex vivo evidence\",\n      \"pmids\": [\"29107298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Reconstitution of KLK5 expression in KLK5-negative MDA-MB-231 breast cancer cells suppresses malignancy in vitro and in vivo. KLK5 re-expression reduces cellular cholesterol and fatty acid synthesis, induces SREBF1, and suppresses the mevalonate pathway, leading to decreased prenylation and reduced levels of active RhoA. Restoration of active RhoA by geranylgeranyl pyrophosphate rescues the malignant phenotype, placing KLK5-mediated mevalonate pathway suppression upstream of RhoA inactivation.\",\n      \"method\": \"Stable KLK5 transfection in MDA-MB-231 cells; gene expression arrays; cholesterol/fatty acid synthesis assays; RhoA activity assays; geranylgeranyl pyrophosphate rescue experiments; in vivo xenograft assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (transcriptomics, biochemical pathway assays, rescue experiment, in vivo) in a single lab; epistasis established by geranylgeranyl rescue\",\n      \"pmids\": [\"24158494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLK5 is a major host serine protease secreted by human airway cells that cleaves both the priming (S1/S2) and activation (S2') sites of betacoronavirus spike proteins, including SARS-CoV-2, SARS-CoV, and MERS-CoV. KLK5 alone is sufficient to activate spike proteins from multiple betacoronaviruses, whereas KLK12 and KLK13 show single-site preferences and act in concert. Betacoronavirus infection induces KLK5 upregulation in differentiated human bronchial epithelial cells (HBECs), promoting replication. Pharmacological inhibition of KLK5 (ursolic acid and related triterpenoids) suppresses betacoronavirus replication in HBECs and reduces lung inflammation in MERS-CoV- and SARS-CoV-2-infected mice.\",\n      \"method\": \"In vitro cleavage assays of purified spike proteins by KLK5, KLK12, KLK13; infection of differentiated HBECs; KLK5 inhibitor treatment; MERS-CoV and SARS-CoV-2 mouse infection models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic cleavage assays, human primary cell infection experiments, and multiple in vivo animal models; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"39163389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the context of CDSN-nEDD (corneodesmosin-deficient ichthyosis), genetic deletion of KLK5 paradoxically aggravates rather than rescues the over-desquamation phenotype. KLK5 knockout in CDSN-deficient epidermis leads to elevated total epidermal proteolysis, severe desmosomal ultrastructural alterations, increased barrier permeability, and stratum corneum detachment — indicating that in the absence of corneodesmosin, other proteases compensate and KLK5 has a protective/regulatory role beyond simple pro-desquamation activity.\",\n      \"method\": \"shRNA-mediated CDSN knockdown in human epidermal equivalents; Klk5 knockout mice crossed with Cdsn knockout mice; ultrastructural analysis; barrier permeability assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in two complementary models (HEE and mouse double-KO); functional phenotypic readouts; single lab study\",\n      \"pmids\": [\"40943523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In cervical carcinogenesis, KLK5 and KLK7 promote tumor progression by activating KLK14, which in turn activates PAR-2-dependent RhoA and NF-κB signaling pathways. Genetic ablation of both KLK5 and KLK7 in a mouse model ameliorates the HPV-dependent cervical carcinoma phenotype via reduction of KLK14 activation.\",\n      \"method\": \"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; reporter assays for NF-κB and RhoA pathways; human biopsy analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo (double-KO mouse model) combined with pathway reporter assays and transcriptomics; single lab study with multiple methods\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP3 directly binds KLK5 mRNA and stabilizes it in an N6-methyladenosine (m6A)-dependent manner in gallbladder carcinoma cells. This stabilization increases KLK5 protein levels, which in turn activates PAR2 and downstream phospho-AKT signaling to promote tumor cell proliferation and migration.\",\n      \"method\": \"RNA immunoprecipitation (RIP); RNA stability assays; methylated RNA immunoprecipitation (MeRIP); dual-luciferase reporter assay; KLK5 rescue after IGF2BP3 depletion; Western blot for PAR2/pAKT\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal RNA-binding assays (RIP, MeRIP, stability) plus downstream signaling readout and rescue experiment; single lab study\",\n      \"pmids\": [\"36313631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STAT3 negatively regulates KLK5 expression in keratinocytes: keratinocyte-specific STAT3 ablation in mice upregulates KLK5 and causes a cutaneous inflammatory phenotype with impaired barrier function. STAT3 overexpression decreases KLK5 expression and increases SPINK5 (LEKTI) expression; STAT3 siRNA knockdown reverses both effects, placing STAT3 as a transcriptional regulator upstream of both KLK5 and its inhibitor SPINK5.\",\n      \"method\": \"Keratinocyte-specific STAT3 knockout mice; transcriptomic analysis; STAT3 siRNA knockdown in keratinocytes; STAT3 overexpression in keratinocytes; qRT-PCR\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with transcriptomics plus complementary gain- and loss-of-function cell assays; single lab, two orthogonal approaches\",\n      \"pmids\": [\"34378233\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLK5 is a secreted trypsin-like serine protease that initiates epidermal desquamation by directly cleaving corneodesmosome proteins (CDSN, DSG1, DSC1) and activating pro-KLK7; its activity is spatiotemporally controlled by the pH-dependent LEKTI inhibitor system (and by SPINK9 in palmo-plantar skin via allosteric and active-site mechanisms), with STAT3 acting as an upstream transcriptional regulator; beyond skin, KLK5 cleaves DPP4 from Th17 cell surfaces, primes and activates betacoronavirus spike proteins to promote pulmonary infection, activates PAR2/RhoA/NF-κB oncogenic signaling (partly via KLK14) in cancer contexts, and has its own mRNA stabilized by IGF2BP3 through m6A-dependent binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLK5 is a secreted trypsin-like serine protease that initiates the epidermal desquamation cascade by directly degrading the corneodesmosome adhesion proteins corneodesmosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1) at the acidic pH of the stratum corneum and by converting pro-KLK7 to its active form [#0]. Its activity is spatially confined by inhibitors whose action is pH-tuned: LEKTI (SPINK5) fragments bind and irreversibly inhibit KLK5 at neutral pH and release active enzyme at acidic pH, restricting proteolysis to the outer cornified layers [#1], while SPINK9 provides palmo-plantar-specific inhibition through a reactive-loop His48 protonation mechanism that slows dissociation from the enzyme [#3]. KLK5 and its inhibitor are packaged separately into lamellar granules, and loss of LEKTI in Netherton syndrome skin produces unrestrained KLK5/KLK7 activity and premature loss of corneocyte cohesion [#2]. Consistent with this, allosteric antibody inhibition of KLK5 restores barrier integrity in mouse models of Netherton syndrome and atopic dermatitis [#4], and STAT3 acts as an upstream transcriptional regulator that represses KLK5 while inducing SPINK5 [#11]. Genetic studies reveal that KLK5's role is context-dependent rather than purely pro-desquamatory: in corneodesmosin-deficient epidermis its deletion paradoxically worsens proteolysis and barrier loss, indicating a regulatory function [#8]. Beyond skin, KLK5 cleaves DPP4 from the surface of Th17 cells to generate soluble plasma DPP4 [#5], primes and activates betacoronavirus spike proteins at both the S1/S2 and S2' sites to promote pulmonary infection [#7], and influences cancer signaling—both as a tumor suppressor that suppresses the mevalonate pathway to inactivate RhoA in breast cancer [#6] and, with KLK7, as a driver of KLK14-dependent PAR2/RhoA/NF-\\u03baB signaling in cervical carcinoma [#9]; its mRNA is stabilized by IGF2BP3 in an m6A-dependent manner in gallbladder carcinoma [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established KLK5 as the initiating protease of epidermal desquamation by showing it directly cleaves corneodesmosome adhesion proteins and activates a downstream protease.\",\n      \"evidence\": \"In vitro cleavage assays of recombinant/epidermal CDSN, DSG1, DSC1 and pro-KLK7 zymogen activation at acidic pH\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how KLK5 activity is restricted in intact skin\", \"Endogenous KLK5 zymogen activation mechanism not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected KLK5 spatial regulation to disease by showing separate lamellar-granule packaging of protease and inhibitor and unrestrained activity in LEKTI-deficient skin.\",\n      \"evidence\": \"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin\",\n      \"pmids\": [\"15675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization is correlative; did not quantify enzymatic activity in situ\", \"Relative contributions of KLK5 vs KLK7 to the split not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the biochemical mechanism for zone-restricted desquamation: pH-dependent, irreversible LEKTI inhibition of KLK5 that releases active enzyme in the acidic outer stratum corneum.\",\n      \"evidence\": \"Inhibition kinetics, pH-titration binding studies, and LEKTI fragment characterization\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro kinetics may not capture in vivo concentrations/microenvironment\", \"Did not address other endogenous KLK5 inhibitors\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified a tissue-restricted second inhibitor (SPINK9) and resolved the structural/charge basis for its pH-dependent, KLK5-selective inhibition.\",\n      \"evidence\": \"In vitro inhibition with reactive-loop mutants, binding kinetics, and computational modeling\",\n      \"pmids\": [\"22505519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Modeling not confirmed by experimental KLK5\\u2013SPINK9 structure\", \"Physiological importance in palmo-plantar desquamation not tested in vivo\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a tumor-suppressive function distinct from desquamation, placing KLK5 upstream of mevalonate-pathway-dependent RhoA activation in breast cancer.\",\n      \"evidence\": \"Stable KLK5 re-expression in MDA-MB-231 cells with transcriptomics, lipid synthesis and RhoA activity assays, GGPP rescue, and xenografts\",\n      \"pmids\": [\"24158494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect requires KLK5 catalytic activity not established\", \"Single cell line model\", \"Apparent contrast with pro-oncogenic roles in other tissues unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KLK5 substrate repertoire beyond skin by identifying DPP4 as a surface substrate shed from Th17 cells, linking KLK5 to elevated plasma DPP4 in metabolic disease.\",\n      \"evidence\": \"Co-IP, in vitro/ex vivo cleavage assays, surface DPP4 flow cytometry, and docking in CD4+ T cells\",\n      \"pmids\": [\"29107298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of the KLK5\\u2013DPP4 interaction limited\", \"Causal contribution to diabetes pathology not established in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed KLK5 under transcriptional control of STAT3, which coordinately represses KLK5 and induces its inhibitor SPINK5 in keratinocytes.\",\n      \"evidence\": \"Keratinocyte-specific STAT3 knockout mice plus STAT3 gain/loss-of-function in keratinocytes with qRT-PCR and transcriptomics\",\n      \"pmids\": [\"34378233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3 binding to KLK5/SPINK5 promoters not demonstrated\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a structurally validated allosteric inhibition strategy and demonstrated therapeutic benefit of KLK5 blockade in barrier disease models.\",\n      \"evidence\": \"X-ray crystallography of a KLK5\\u2013Fab complex with bispecific antibody treatment in Netherton and atopic dermatitis mouse models\",\n      \"pmids\": [\"36516271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Antibody is bispecific (KLK5/KLK7), so KLK5-specific contribution to rescue is convolved\", \"Human efficacy not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-transcriptional regulation of KLK5 via m6A-dependent mRNA stabilization driving PAR2/AKT oncogenic signaling.\",\n      \"evidence\": \"RIP, MeRIP, RNA stability and luciferase assays with IGF2BP3 depletion rescue in gallbladder carcinoma cells\",\n      \"pmids\": [\"36313631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in a single tumor type\", \"Whether secreted KLK5 protease activity mediates the PAR2 effect not directly shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined KLK5 as a host protease that primes and activates betacoronavirus spike proteins, making it a determinant of pulmonary infection and a druggable antiviral target.\",\n      \"evidence\": \"In vitro spike cleavage assays, infection of differentiated HBECs, KLK5 inhibitor treatment, and MERS-CoV/SARS-CoV-2 mouse models\",\n      \"pmids\": [\"39163389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor (ursolic acid) selectivity for KLK5 in vivo not fully delineated\", \"Relative in vivo contribution of KLK5 vs KLK12/KLK13 not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that KLK5's role is context-dependent and protective in corneodesmosin-deficient skin, where its loss aggravates rather than rescues over-desquamation.\",\n      \"evidence\": \"shRNA CDSN knockdown in human epidermal equivalents and Klk5/Cdsn double-knockout mice with ultrastructural and barrier assays\",\n      \"pmids\": [\"40943523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the compensating proteases not established\", \"Molecular basis of the protective/regulatory function unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established KLK5 (with KLK7) as a driver of cervical carcinogenesis through KLK14 activation feeding PAR2/RhoA/NF-\\u03baB signaling.\",\n      \"evidence\": \"KLK5/KLK7 double-knockout mice with RNA-seq, NF-\\u03baB/RhoA reporter assays, and human biopsy analysis\",\n      \"pmids\": [\"40753921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Double-knockout design does not isolate KLK5-specific contribution\", \"Direct KLK5\\u2013KLK14 activation in this context inferred rather than reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLK5 switches between pro-desquamatory, protective, antiviral, and opposing oncogenic roles across tissues, and how its zymogen is endogenously activated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent tumor-suppressor vs oncogenic behavior unreconciled\", \"Endogenous activator(s) of pro-KLK5 not identified\", \"Compensating proteases in CDSN-deficient skin unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0030312\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CDSN\",\n      \"DSG1\",\n      \"DSC1\",\n      \"KLK7\",\n      \"SPINK5\",\n      \"SPINK9\",\n      \"DPP4\",\n      \"KLK14\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}