{"gene":"CTSL","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2022,"finding":"Cathepsin L (CTSL) is required for SARS-CoV-2 entry into lung cells; Cas13d-mediated knockdown of Ctsl mRNA in mouse lungs decreased viral burden, reduced proinflammatory cytokines/chemokines, and extended survival of lethally infected mice, establishing CTSL as a host protease essential for SARS-CoV-2 pathogenesis in vivo.","method":"Cas13d nanosystem for in vivo mRNA knockdown; viral burden measurement; cytokine/chemokine profiling; survival assay in mice","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo loss-of-function with multiple orthogonal readouts (viral burden, cytokines, survival), replicated across prevention and treatment models","pmids":["35879545"],"is_preprint":false},{"year":2024,"finding":"SARS-CoV-2 spike protein treatment of HeLa cells and iPSC-derived alveolarspheres caused time-dependent upregulation of CTSL mRNA and protein and increased CTSL promoter activity; knockout of CTSL reduced spike protein internalization, demonstrating that CTSL mediates endocytic cleavage and internalization of the spike protein.","method":"Recombinant spike protein treatment; mRNA/protein quantification; CTSL promoter-reporter assay; CTSL knockout cells with spike internalization assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, reporter, protein quantification) in a single lab study","pmids":["38971996"],"is_preprint":false},{"year":2012,"finding":"A common promoter variant (C-171A, rs3118869) in the human CTSL1 gene disrupts a xenobiotic response element (XRE), altering transcription; the aryl hydrocarbon receptor complex (AHR:ARNT) with dioxin augments CTSL1 transcription through this XRE, and the allele interacts with AHR:ARNT/dioxin stimulation; the C-171A genotype predicted blood pressure in two independent human cohorts.","method":"Promoter/luciferase reporter transfection assay; co-expression with AHR:ARNT; population genetic association in 868 + 986 patients","journal":"Journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based reporter assay with mutagenesis-equivalent allelic comparison, replicated in independent population sample; single lab","pmids":["22871890"],"is_preprint":false},{"year":2025,"finding":"USP20 is a deubiquitinase of CTSL: USP20 directly binds CTSL, mediates its deubiquitination and stabilization, thereby promoting EMT and cancer stem cell renewal. STUB1 (CHIP) promotes CTSL ubiquitination and degradation and competes with USP20 for CTSL binding. Depletion of CTSL or USP20 reduced metastatic potential and chemoresistance in HNSCC cells and in vivo.","method":"Broad-spectrum deubiquitinase inhibitor screen; mass spectrometry; confocal colocalization; Co-IP; ubiquitination assays; in vitro and in vivo tumor assays","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo validation, multiple orthogonal methods in single lab","pmids":["41261048"],"is_preprint":false},{"year":2025,"finding":"CTSL directly binds PDK1 and blocks NEDD4L-mediated ubiquitination of PDK1, thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 expression on HNSCC tumor cells — a non-proteolytic scaffolding function that promotes immune evasion. Targeting CTSL suppressed tumor growth and synergized with anti-PD-1 therapy.","method":"Co-IP/binding assays; ubiquitination assays; knockdown/overexpression; xenograft and immunocompetent mouse models; anti-PD-1 combination treatment","journal":"Neoplasia (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding assay, ubiquitination, in vivo), single lab","pmids":["40961907"],"is_preprint":false},{"year":2025,"finding":"Drug-induced nuclear trafficking of CTSL (nCTSL) is required for DNA damage response (DDR): clofarabine facilitates CTSL nuclear import via KPNB1 (importin-β1) and downregulates nuclear export protein CRM1 (XPO1). CTSL knockdown conferred resistance to the clofarabine + PARP inhibitor combination, demonstrating nCTSL's essential role in DDR including cell cycle arrest and apoptosis in ovarian cancer cells.","method":"CTSL knockdown; nuclear fractionation/trafficking assays; importin-β1 (KPNB1) functional assay; CRM1 inhibitor (KPT8602) rescue; in vivo PDX models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD with phenotypic rescue, mechanistic transport pathway identified, in vivo PDX validation; preprint, single lab","pmids":["39868276"],"is_preprint":true},{"year":2025,"finding":"Legumain is required for processing of CTSL from its single-chain to double-chain (mature) form; in legumain-deficient (LGMN−/−) cells this processing is abrogated. In cell types where CTSL preferentially localizes to the nucleus in its double-chain form, loss of legumain reduces nuclear CTSL levels. Chemical N-terminomics (NICE pipeline) identified putative nuclear substrates of CTSL involved in cell proliferation, cell cycle regulation, inflammation, and ribosomal biogenesis.","method":"Activity-based probes; immunoblot; LGMN−/− cell lines; chemical N-terminomics (NICE pipeline); recombinant legumain in vitro cleavage assay (negative for direct cleavage)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — activity-based probes + genetic KO + N-terminomics substrate identification; multiple orthogonal methods; preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Nervous-system-specific double knockout of CTSB and CTSL in mice (CtsB/L-NES) caused selective loss of Purkinje cells (phospholipase C β4-positive, Zebrin II-negative subpopulation), accumulation of ubiquitin-positive structures in Purkinje cell perikarya and axons, and neuronal loss in thalamic nuclei, demonstrating that both cathepsins are essential for autophagy-lysosomal proteostasis and survival of specific neuronal populations.","method":"Conditional double-knockout mice (CTSBflox/flox; CTSLflox/flox; Nestin-Cre); immunostaining; electron microscopy; behavioral analysis","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous conditional KO with multiple orthogonal readouts (behavioral, histological, ultrastructural), genetic epistasis in vivo","pmids":["40320169"],"is_preprint":false},{"year":2025,"finding":"CTSL promotes autophagy in laryngeal cancer cells via activation of the IL6-JAK-STAT3 signalling pathway; immunoprecipitation experiments confirmed CTSL involvement in this pathway, and CTSL overexpression enhanced autophagic levels and cell proliferation.","method":"CCK8 proliferation assay; Western blotting; qRT-PCR; wound healing/transwell invasion; immunoprecipitation; immunohistochemistry","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, immunoprecipitation with limited mechanistic follow-up; IL6-JAK-STAT3 pathway activation shown but direct molecular link remains indirect","pmids":["39893643"],"is_preprint":false},{"year":2017,"finding":"Transgenic overexpression of human CTSL in the MMTV-PyMT breast cancer mouse model altered the lung metastasis proteome distinctly from CTSB overexpression, with increased saposin and granulin levels; non-supervised hierarchical clustering clearly separated tgCTSL- vs tgCTSB-induced proteome changes, establishing that CTSL and CTSB impact malignant behavior through distinct molecular mechanisms.","method":"LC-MS/MS quantitative proteomics of lung metastases from transgenic mice; hierarchical clustering","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics in genetically defined mouse models with biological replicates; single lab","pmids":["29187882"],"is_preprint":false}],"current_model":"CTSL encodes a lysosomal cysteine protease that cleaves SARS-CoV-2 spike protein to facilitate viral entry, undergoes nuclear translocation (facilitated by importin KPNB1 and legumain-dependent maturation) where it participates in DNA damage response, acts as a non-proteolytic scaffold to stabilize PDK1 and sustain AKT-PD-L1 signaling, is stabilized by USP20-mediated deubiquitination and targeted for degradation by STUB1, and is transcriptionally regulated through a xenobiotic response element in its promoter that responds to AHR:ARNT signaling."},"narrative":{"mechanistic_narrative":"CTSL encodes a cysteine protease that operates across lysosomal proteostasis, viral entry, and cancer signaling, with both proteolytic and non-proteolytic functions [PMID:35879545, PMID:40961907, PMID:40320169]. As a host protease, CTSL is essential for SARS-CoV-2 pathogenesis: it mediates endocytic cleavage and internalization of the viral spike protein, and its knockdown in mouse lungs reduces viral burden, dampens proinflammatory cytokine release, and extends survival [PMID:35879545, PMID:38971996]. In the nervous system, CTSL acts together with CTSB to maintain autophagy-lysosomal proteostasis, and their combined loss causes accumulation of ubiquitin-positive structures and selective neuronal death [PMID:40320169]. CTSL maturation from its single-chain to active double-chain form requires legumain, and the double-chain enzyme can localize to the nucleus, where—imported via KPNB1 and retained through downregulation of the export factor CRM1/XPO1—it participates in the DNA damage response [PMID:39868276]. Beyond catalysis, CTSL functions as a scaffold: it binds PDK1 and blocks its NEDD4L-mediated ubiquitination, stabilizing PDK1 to sustain AKT phosphorylation and PD-L1 expression and thereby promoting tumor immune evasion [PMID:40961907]. CTSL protein stability is itself set by competing ubiquitin machinery, with USP20 deubiquitinating and stabilizing it to drive EMT and cancer stem cell renewal while STUB1/CHIP promotes its degradation [PMID:41261048]. At the transcriptional level, CTSL expression is controlled through a xenobiotic response element in its promoter that responds to AHR:ARNT signaling [PMID:22871890].","teleology":[{"year":2012,"claim":"Established that CTSL transcription is regulated by an environmental/xenobiotic axis, linking a common promoter variant to a physiological phenotype.","evidence":"Promoter-luciferase reporter with AHR:ARNT co-expression and population genetic association across two cohorts","pmids":["22871890"],"confidence":"Medium","gaps":["Mechanism linking CTSL level to blood pressure not defined","Single-lab cell-based reporter assay","No protein-level confirmation of allelic effect"]},{"year":2017,"claim":"Distinguished CTSL from its close relative CTSB by showing they remodel the metastatic proteome through distinct molecular routes.","evidence":"LC-MS/MS quantitative proteomics of lung metastases in tgCTSL vs tgCTSB transgenic breast cancer mice","pmids":["29187882"],"confidence":"Medium","gaps":["Direct substrates driving the proteome shift not identified","Causal contribution to metastasis vs correlation unresolved"]},{"year":2022,"claim":"Demonstrated in vivo that CTSL is a host protease essential for SARS-CoV-2 pathogenesis, validating it as an antiviral target.","evidence":"Cas13d-mediated Ctsl mRNA knockdown in mouse lungs with viral burden, cytokine, and survival readouts","pmids":["35879545"],"confidence":"High","gaps":["Exact spike cleavage site/step not mapped here","Contribution relative to other entry proteases not quantified"]},{"year":2024,"claim":"Connected CTSL function to spike handling at the cellular level, showing it both cleaves/internalizes spike and is transcriptionally induced by spike exposure.","evidence":"Recombinant spike treatment, CTSL knockout, and promoter-reporter assays in HeLa and iPSC-derived alveolarspheres","pmids":["38971996"],"confidence":"Medium","gaps":["Signaling pathway driving spike-induced CTSL upregulation unknown","Single-lab study"]},{"year":2025,"claim":"Revealed that CTSL protein abundance is governed by a ubiquitin tug-of-war, defining USP20 and STUB1 as opposing regulators that control its oncogenic output.","evidence":"Deubiquitinase inhibitor screen, reciprocal Co-IP, ubiquitination assays, and in vivo HNSCC tumor models","pmids":["41261048"],"confidence":"Medium","gaps":["Ubiquitin linkage type and modified residues not defined","Single-lab validation"]},{"year":2025,"claim":"Uncovered a non-proteolytic scaffolding role for CTSL in stabilizing PDK1 to sustain AKT-PD-L1 signaling and tumor immune evasion.","evidence":"Binding/Co-IP and ubiquitination assays with xenograft, immunocompetent mouse, and anti-PD-1 combination models","pmids":["40961907"],"confidence":"Medium","gaps":["Structural basis of CTSL-PDK1 interaction unresolved","Whether catalytic activity is fully dispensable not definitively shown","Single-lab study"]},{"year":2025,"claim":"Defined the cathepsin pair CTSB/CTSL as essential for neuronal autophagy-lysosomal proteostasis and survival of specific neuron populations.","evidence":"Nervous-system-specific conditional CtsB/L double-knockout mice with histology, electron microscopy, and behavioral analysis","pmids":["40320169"],"confidence":"High","gaps":["Substrate(s) whose accumulation kills Purkinje cells not identified","Selective vulnerability of Zebrin II-negative cells unexplained"]},{"year":2025,"claim":"Identified legumain as required for CTSL maturation and nuclear pool generation, and CTSL nuclear import (via KPNB1) as essential for the DNA damage response.","evidence":"Activity-based probes, LGMN-/- cells, N-terminomics (NICE), nuclear fractionation, KPNB1/CRM1 manipulation, and PDX models (preprints)","pmids":["39868276"],"confidence":"Medium","gaps":["Nuclear substrates of CTSL not functionally validated","Mechanism coupling nCTSL to DDR machinery unclear","Preprint, single lab"]},{"year":2025,"claim":"Linked CTSL to autophagy promotion via IL6-JAK-STAT3 signaling in cancer cells.","evidence":"Proliferation, invasion, immunoprecipitation, and immunohistochemistry assays in laryngeal cancer cells","pmids":["39893643"],"confidence":"Low","gaps":["Direct molecular link between CTSL and the IL6-JAK-STAT3 axis remains indirect","Single-lab study with limited mechanistic follow-up"]},{"year":null,"claim":"How CTSL switches between its proteolytic (lysosomal/viral) and non-proteolytic (PDK1 scaffold, nuclear DDR) functions, and what governs its subcellular partitioning, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for catalytic vs scaffold activity","Nuclear substrate spectrum not validated","Signals determining lysosomal vs nuclear localization unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]}],"complexes":[],"partners":["PDK1","NEDD4L","USP20","STUB1","KPNB1","LGMN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07711","full_name":"Procathepsin L","aliases":["Cathepsin L1","Major excreted protein","MEP"],"length_aa":333,"mass_kda":37.6,"function":"Thiol protease important for the overall degradation of proteins in lysosomes (Probable). Plays a critical for normal cellular functions such as general protein turnover, antigen processing and bone remodeling. Involved in the solubilization of cross-linked TG/thyroglobulin and in the subsequent release of thyroid hormone thyroxine (T4) by limited proteolysis of TG/thyroglobulin in the thyroid follicle lumen (By similarity). In neuroendocrine chromaffin cells secretory vesicles, catalyzes the prohormone proenkephalin processing to the active enkephalin peptide neurotransmitter (By similarity). In thymus, regulates CD4(+) T cell positive selection by generating the major histocompatibility complex class II (MHCII) bound peptide ligands presented by cortical thymic epithelial cells. Also mediates invariant chain processing in cortical thymic epithelial cells (By similarity). Major elastin-degrading enzyme at neutral pH. Accumulates as a mature and active enzyme in the extracellular space of antigen presenting cells (APCs) to regulate degradation of the extracellular matrix in the course of inflammation (By similarity). Secreted form generates endostatin from COL18A1 (PubMed:10716919). Critical for cardiac morphology and function. Plays an important role in hair follicle morphogenesis and cycling, as well as epidermal differentiation (By similarity). Required for maximal stimulation of steroidogenesis by TIMP1 (By similarity) (Microbial infection) In cells lacking TMPRSS2 expression, facilitates human coronaviruses SARS-CoV and SARS-CoV-2 infections via a slow acid-activated route with the proteolysis of coronavirus spike (S) glycoproteins in lysosome for entry into host cell (PubMed:16339146, PubMed:18562523, PubMed:32142651, PubMed:32221306, PubMed:37990007). Proteolysis within lysosomes is sufficient to activate membrane fusion by coronaviruses SARS-CoV and EMC (HCoV-EMC) S as well as Zaire ebolavirus glycoproteins (PubMed:16081529, PubMed:18562523, PubMed:26953343) Functions in the regulation of cell cycle progression through proteolytic processing of the CUX1 transcription factor (PubMed:15099520). Translation initiation at downstream start sites allows the synthesis of isoforms that are devoid of a signal peptide and localize to the nucleus where they cleave the CUX1 transcription factor and modify its DNA binding properties (PubMed:15099520)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P07711/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTSL","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CTSL","total_profiled":1310},"omim":[{"mim_id":"617609","title":"NEPHROTIC SYNDROME, TYPE 15; NPHS15","url":"https://www.omim.org/entry/617609"},{"mim_id":"610008","title":"ARYLSULFATASE G; ARSG","url":"https://www.omim.org/entry/610008"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"607311","title":"PROGESTERONE RECEPTOR; PGR","url":"https://www.omim.org/entry/607311"},{"mim_id":"606382","title":"MEMBRANE-ASSOCIATED GUANYLATE KINASE, WW AND PDZ DOMAINS-CONTAINING, 2; MAGI2","url":"https://www.omim.org/entry/606382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"placenta","ntpm":529.1}],"url":"https://www.proteinatlas.org/search/CTSL"},"hgnc":{"alias_symbol":["FLJ31037"],"prev_symbol":["CTSL1"]},"alphafold":{"accession":"P07711","domains":[{"cath_id":"3.90.70.10","chopping":"88-331","consensus_level":"high","plddt":96.2624,"start":88,"end":331},{"cath_id":"1.10.287","chopping":"24-71","consensus_level":"high","plddt":95.6065,"start":24,"end":71}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07711","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07711-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07711-F1-predicted_aligned_error_v6.png","plddt_mean":93.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTSL","jax_strain_url":"https://www.jax.org/strain/search?query=CTSL"},"sequence":{"accession":"P07711","fasta_url":"https://rest.uniprot.org/uniprotkb/P07711.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07711/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07711"}},"corpus_meta":[{"pmid":"35879545","id":"PMC_35879545","title":"Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection.","date":"2022","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/35879545","citation_count":48,"is_preprint":false},{"pmid":"33933142","id":"PMC_33933142","title":"The lnc-CTSLP8 upregulates CTSL1 as a competitive endogenous RNA and promotes ovarian cancer metastasis.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33933142","citation_count":46,"is_preprint":false},{"pmid":"32835700","id":"PMC_32835700","title":"Variability in genes related to SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its potential use in association studies.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32835700","citation_count":44,"is_preprint":false},{"pmid":"35414771","id":"PMC_35414771","title":"COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35414771","citation_count":27,"is_preprint":false},{"pmid":"35941174","id":"PMC_35941174","title":"A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer.","date":"2022","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35941174","citation_count":23,"is_preprint":false},{"pmid":"15932404","id":"PMC_15932404","title":"SNP analysis of AMY2 and CTSL genes in Litopenaeus vannamei and Penaeus monodon shrimp.","date":"2005","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15932404","citation_count":19,"is_preprint":false},{"pmid":"33231569","id":"PMC_33231569","title":"Genomic, epigenomic, and immune subtype analysis of CTSL/B and SARS-CoV-2 receptor ACE2 in pan-cancer.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33231569","citation_count":16,"is_preprint":false},{"pmid":"22871890","id":"PMC_22871890","title":"Genes and environment: novel, functional polymorphism in the human cathepsin L (CTSL1) promoter disrupts a xenobiotic response element (XRE) to alter transcription and blood pressure.","date":"2012","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/22871890","citation_count":14,"is_preprint":false},{"pmid":"29187882","id":"PMC_29187882","title":"Proteomic analysis of lung metastases in a murine breast cancer model reveals divergent influence of CTSB and CTSL overexpression.","date":"2017","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29187882","citation_count":11,"is_preprint":false},{"pmid":"34807310","id":"PMC_34807310","title":"Expressions and significances of CTSL, the target of COVID-19 on GBM.","date":"2021","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34807310","citation_count":10,"is_preprint":false},{"pmid":"20374908","id":"PMC_20374908","title":"Association between cathepsin L (CTSL) and cathepsin S (CTSS) polymorphisms and meat production and carcass traits in Italian Large White pigs.","date":"2010","source":"Meat science","url":"https://pubmed.ncbi.nlm.nih.gov/20374908","citation_count":10,"is_preprint":false},{"pmid":"36504894","id":"PMC_36504894","title":"Methionine deprivation inhibits glioma growth through downregulation of CTSL.","date":"2022","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36504894","citation_count":7,"is_preprint":false},{"pmid":"35155389","id":"PMC_35155389","title":"Comprehensive and Integrative Analysis of Two Novel SARS-CoV-2 Entry Associated Proteases CTSB and CTSL in Healthy Individuals and Cancer Patients.","date":"2022","source":"Frontiers in bioengineering and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35155389","citation_count":7,"is_preprint":false},{"pmid":"40058477","id":"PMC_40058477","title":"Astragalus injection inhibits the growth of osteosarcoma by activating cytotoxic T lymphocyte and targeting CTSL.","date":"2025","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40058477","citation_count":6,"is_preprint":false},{"pmid":"11978977","id":"PMC_11978977","title":"Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21-->q22 and SSC10q11-->q12.","date":"2001","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11978977","citation_count":6,"is_preprint":false},{"pmid":"39893643","id":"PMC_39893643","title":"CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway.","date":"2025","source":"Journal of cellular and molecular 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(New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40961907","citation_count":2,"is_preprint":false},{"pmid":"39868276","id":"PMC_39868276","title":"Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39868276","citation_count":2,"is_preprint":false},{"pmid":"26374357","id":"PMC_26374357","title":"Association Between Polymorphism in the Human Cathepsin L (CTSL1) Promoter with Hypertension in the Uygur, Kazak and Han Populations in China.","date":"2015","source":"Journal of the College of Physicians and Surgeons--Pakistan : JCPSP","url":"https://pubmed.ncbi.nlm.nih.gov/26374357","citation_count":2,"is_preprint":false},{"pmid":"38971996","id":"PMC_38971996","title":"SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres.","date":"2024","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38971996","citation_count":1,"is_preprint":false},{"pmid":"41261048","id":"PMC_41261048","title":"USP20 competitively binds to STUB1 to enhance CTSL expression and promote epithelial-mesenchymal transition in head and neck squamous cell carcinoma.","date":"2025","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41261048","citation_count":1,"is_preprint":false},{"pmid":"39864211","id":"PMC_39864211","title":"High expression of SERPINE1 and CTSL in keratinocytes in pressure injury caused by ischemia-reperfusion injury.","date":"2025","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/39864211","citation_count":1,"is_preprint":false},{"pmid":"40275325","id":"PMC_40275325","title":"CTSL-2 upon specifically recognizing Vibrio splendidus directly cleaves complement C3 to promote the bacterial phagocytosis and degradation in oyster.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40275325","citation_count":1,"is_preprint":false},{"pmid":"40320169","id":"PMC_40320169","title":"Uncovering the Unique Roles of Cathepsins B and L in Purkinje Cells Using Nervous System-Specific CTSB and CTSL Double-Deficient Mice.","date":"2025","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40320169","citation_count":0,"is_preprint":false},{"pmid":"27792712","id":"PMC_27792712","title":"[Level of expression of gene CTSL and its correlation with natural killer T-Cells in mexican pediatric patients with recent-onset type 1 diabetes].","date":"2016","source":"Gaceta medica de Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/27792712","citation_count":0,"is_preprint":false},{"pmid":"41807810","id":"PMC_41807810","title":"Pinostrobin attenuates microglia-mediated neuroinflammation after subarachnoid hemorrhage through modulation of the MYC-CTSL signaling axis.","date":"2026","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41807810","citation_count":0,"is_preprint":false},{"pmid":"42248036","id":"PMC_42248036","title":"PM2.5 promotes lung cancer progression by upregulating CTSL to relieve autophagic flux blockade and enhance the malignant cellular phenotype.","date":"2026","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/42248036","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.17.670765","title":"Legumain drives processing of cathepsins and nuclear localisation of cathepsin L","date":"2025-08-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.17.670765","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.08.25325108","title":"Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome”","date":"2025-04-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.08.25325108","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.19.24315794","title":"Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.19.24315794","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.12.657772","title":"A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.657772","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20308,"output_tokens":2789,"usd":0.05138,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10105,"output_tokens":3290,"usd":0.066388,"stage2_stop_reason":"end_turn"},"total_usd":0.117768,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"Cathepsin L (CTSL) is required for SARS-CoV-2 entry into lung cells; Cas13d-mediated knockdown of Ctsl mRNA in mouse lungs decreased viral burden, reduced proinflammatory cytokines/chemokines, and extended survival of lethally infected mice, establishing CTSL as a host protease essential for SARS-CoV-2 pathogenesis in vivo.\",\n      \"method\": \"Cas13d nanosystem for in vivo mRNA knockdown; viral burden measurement; cytokine/chemokine profiling; survival assay in mice\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo loss-of-function with multiple orthogonal readouts (viral burden, cytokines, survival), replicated across prevention and treatment models\",\n      \"pmids\": [\"35879545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SARS-CoV-2 spike protein treatment of HeLa cells and iPSC-derived alveolarspheres caused time-dependent upregulation of CTSL mRNA and protein and increased CTSL promoter activity; knockout of CTSL reduced spike protein internalization, demonstrating that CTSL mediates endocytic cleavage and internalization of the spike protein.\",\n      \"method\": \"Recombinant spike protein treatment; mRNA/protein quantification; CTSL promoter-reporter assay; CTSL knockout cells with spike internalization assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, reporter, protein quantification) in a single lab study\",\n      \"pmids\": [\"38971996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A common promoter variant (C-171A, rs3118869) in the human CTSL1 gene disrupts a xenobiotic response element (XRE), altering transcription; the aryl hydrocarbon receptor complex (AHR:ARNT) with dioxin augments CTSL1 transcription through this XRE, and the allele interacts with AHR:ARNT/dioxin stimulation; the C-171A genotype predicted blood pressure in two independent human cohorts.\",\n      \"method\": \"Promoter/luciferase reporter transfection assay; co-expression with AHR:ARNT; population genetic association in 868 + 986 patients\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based reporter assay with mutagenesis-equivalent allelic comparison, replicated in independent population sample; single lab\",\n      \"pmids\": [\"22871890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP20 is a deubiquitinase of CTSL: USP20 directly binds CTSL, mediates its deubiquitination and stabilization, thereby promoting EMT and cancer stem cell renewal. STUB1 (CHIP) promotes CTSL ubiquitination and degradation and competes with USP20 for CTSL binding. Depletion of CTSL or USP20 reduced metastatic potential and chemoresistance in HNSCC cells and in vivo.\",\n      \"method\": \"Broad-spectrum deubiquitinase inhibitor screen; mass spectrometry; confocal colocalization; Co-IP; ubiquitination assays; in vitro and in vivo tumor assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ubiquitination assay, in vivo validation, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"41261048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTSL directly binds PDK1 and blocks NEDD4L-mediated ubiquitination of PDK1, thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 expression on HNSCC tumor cells — a non-proteolytic scaffolding function that promotes immune evasion. Targeting CTSL suppressed tumor growth and synergized with anti-PD-1 therapy.\",\n      \"method\": \"Co-IP/binding assays; ubiquitination assays; knockdown/overexpression; xenograft and immunocompetent mouse models; anti-PD-1 combination treatment\",\n      \"journal\": \"Neoplasia (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding assay, ubiquitination, in vivo), single lab\",\n      \"pmids\": [\"40961907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Drug-induced nuclear trafficking of CTSL (nCTSL) is required for DNA damage response (DDR): clofarabine facilitates CTSL nuclear import via KPNB1 (importin-β1) and downregulates nuclear export protein CRM1 (XPO1). CTSL knockdown conferred resistance to the clofarabine + PARP inhibitor combination, demonstrating nCTSL's essential role in DDR including cell cycle arrest and apoptosis in ovarian cancer cells.\",\n      \"method\": \"CTSL knockdown; nuclear fractionation/trafficking assays; importin-β1 (KPNB1) functional assay; CRM1 inhibitor (KPT8602) rescue; in vivo PDX models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD with phenotypic rescue, mechanistic transport pathway identified, in vivo PDX validation; preprint, single lab\",\n      \"pmids\": [\"39868276\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Legumain is required for processing of CTSL from its single-chain to double-chain (mature) form; in legumain-deficient (LGMN−/−) cells this processing is abrogated. In cell types where CTSL preferentially localizes to the nucleus in its double-chain form, loss of legumain reduces nuclear CTSL levels. Chemical N-terminomics (NICE pipeline) identified putative nuclear substrates of CTSL involved in cell proliferation, cell cycle regulation, inflammation, and ribosomal biogenesis.\",\n      \"method\": \"Activity-based probes; immunoblot; LGMN−/− cell lines; chemical N-terminomics (NICE pipeline); recombinant legumain in vitro cleavage assay (negative for direct cleavage)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — activity-based probes + genetic KO + N-terminomics substrate identification; multiple orthogonal methods; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nervous-system-specific double knockout of CTSB and CTSL in mice (CtsB/L-NES) caused selective loss of Purkinje cells (phospholipase C β4-positive, Zebrin II-negative subpopulation), accumulation of ubiquitin-positive structures in Purkinje cell perikarya and axons, and neuronal loss in thalamic nuclei, demonstrating that both cathepsins are essential for autophagy-lysosomal proteostasis and survival of specific neuronal populations.\",\n      \"method\": \"Conditional double-knockout mice (CTSBflox/flox; CTSLflox/flox; Nestin-Cre); immunostaining; electron microscopy; behavioral analysis\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous conditional KO with multiple orthogonal readouts (behavioral, histological, ultrastructural), genetic epistasis in vivo\",\n      \"pmids\": [\"40320169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTSL promotes autophagy in laryngeal cancer cells via activation of the IL6-JAK-STAT3 signalling pathway; immunoprecipitation experiments confirmed CTSL involvement in this pathway, and CTSL overexpression enhanced autophagic levels and cell proliferation.\",\n      \"method\": \"CCK8 proliferation assay; Western blotting; qRT-PCR; wound healing/transwell invasion; immunoprecipitation; immunohistochemistry\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, immunoprecipitation with limited mechanistic follow-up; IL6-JAK-STAT3 pathway activation shown but direct molecular link remains indirect\",\n      \"pmids\": [\"39893643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Transgenic overexpression of human CTSL in the MMTV-PyMT breast cancer mouse model altered the lung metastasis proteome distinctly from CTSB overexpression, with increased saposin and granulin levels; non-supervised hierarchical clustering clearly separated tgCTSL- vs tgCTSB-induced proteome changes, establishing that CTSL and CTSB impact malignant behavior through distinct molecular mechanisms.\",\n      \"method\": \"LC-MS/MS quantitative proteomics of lung metastases from transgenic mice; hierarchical clustering\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics in genetically defined mouse models with biological replicates; single lab\",\n      \"pmids\": [\"29187882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTSL encodes a lysosomal cysteine protease that cleaves SARS-CoV-2 spike protein to facilitate viral entry, undergoes nuclear translocation (facilitated by importin KPNB1 and legumain-dependent maturation) where it participates in DNA damage response, acts as a non-proteolytic scaffold to stabilize PDK1 and sustain AKT-PD-L1 signaling, is stabilized by USP20-mediated deubiquitination and targeted for degradation by STUB1, and is transcriptionally regulated through a xenobiotic response element in its promoter that responds to AHR:ARNT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTSL encodes a cysteine protease that operates across lysosomal proteostasis, viral entry, and cancer signaling, with both proteolytic and non-proteolytic functions [#0, #4, #7]. As a host protease, CTSL is essential for SARS-CoV-2 pathogenesis: it mediates endocytic cleavage and internalization of the viral spike protein, and its knockdown in mouse lungs reduces viral burden, dampens proinflammatory cytokine release, and extends survival [#0, #1]. In the nervous system, CTSL acts together with CTSB to maintain autophagy-lysosomal proteostasis, and their combined loss causes accumulation of ubiquitin-positive structures and selective neuronal death [#7]. CTSL maturation from its single-chain to active double-chain form requires legumain, and the double-chain enzyme can localize to the nucleus, where—imported via KPNB1 and retained through downregulation of the export factor CRM1/XPO1—it participates in the DNA damage response [#6, #5]. Beyond catalysis, CTSL functions as a scaffold: it binds PDK1 and blocks its NEDD4L-mediated ubiquitination, stabilizing PDK1 to sustain AKT phosphorylation and PD-L1 expression and thereby promoting tumor immune evasion [#4]. CTSL protein stability is itself set by competing ubiquitin machinery, with USP20 deubiquitinating and stabilizing it to drive EMT and cancer stem cell renewal while STUB1/CHIP promotes its degradation [#3]. At the transcriptional level, CTSL expression is controlled through a xenobiotic response element in its promoter that responds to AHR:ARNT signaling [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that CTSL transcription is regulated by an environmental/xenobiotic axis, linking a common promoter variant to a physiological phenotype.\",\n      \"evidence\": \"Promoter-luciferase reporter with AHR:ARNT co-expression and population genetic association across two cohorts\",\n      \"pmids\": [\"22871890\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism linking CTSL level to blood pressure not defined\", \"Single-lab cell-based reporter assay\", \"No protein-level confirmation of allelic effect\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished CTSL from its close relative CTSB by showing they remodel the metastatic proteome through distinct molecular routes.\",\n      \"evidence\": \"LC-MS/MS quantitative proteomics of lung metastases in tgCTSL vs tgCTSB transgenic breast cancer mice\",\n      \"pmids\": [\"29187882\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct substrates driving the proteome shift not identified\", \"Causal contribution to metastasis vs correlation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in vivo that CTSL is a host protease essential for SARS-CoV-2 pathogenesis, validating it as an antiviral target.\",\n      \"evidence\": \"Cas13d-mediated Ctsl mRNA knockdown in mouse lungs with viral burden, cytokine, and survival readouts\",\n      \"pmids\": [\"35879545\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Exact spike cleavage site/step not mapped here\", \"Contribution relative to other entry proteases not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected CTSL function to spike handling at the cellular level, showing it both cleaves/internalizes spike and is transcriptionally induced by spike exposure.\",\n      \"evidence\": \"Recombinant spike treatment, CTSL knockout, and promoter-reporter assays in HeLa and iPSC-derived alveolarspheres\",\n      \"pmids\": [\"38971996\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Signaling pathway driving spike-induced CTSL upregulation unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that CTSL protein abundance is governed by a ubiquitin tug-of-war, defining USP20 and STUB1 as opposing regulators that control its oncogenic output.\",\n      \"evidence\": \"Deubiquitinase inhibitor screen, reciprocal Co-IP, ubiquitination assays, and in vivo HNSCC tumor models\",\n      \"pmids\": [\"41261048\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Ubiquitin linkage type and modified residues not defined\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-proteolytic scaffolding role for CTSL in stabilizing PDK1 to sustain AKT-PD-L1 signaling and tumor immune evasion.\",\n      \"evidence\": \"Binding/Co-IP and ubiquitination assays with xenograft, immunocompetent mouse, and anti-PD-1 combination models\",\n      \"pmids\": [\"40961907\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of CTSL-PDK1 interaction unresolved\", \"Whether catalytic activity is fully dispensable not definitively shown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the cathepsin pair CTSB/CTSL as essential for neuronal autophagy-lysosomal proteostasis and survival of specific neuron populations.\",\n      \"evidence\": \"Nervous-system-specific conditional CtsB/L double-knockout mice with histology, electron microscopy, and behavioral analysis\",\n      \"pmids\": [\"40320169\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Substrate(s) whose accumulation kills Purkinje cells not identified\", \"Selective vulnerability of Zebrin II-negative cells unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified legumain as required for CTSL maturation and nuclear pool generation, and CTSL nuclear import (via KPNB1) as essential for the DNA damage response.\",\n      \"evidence\": \"Activity-based probes, LGMN-/- cells, N-terminomics (NICE), nuclear fractionation, KPNB1/CRM1 manipulation, and PDX models (preprints)\",\n      \"pmids\": [\"39868276\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Nuclear substrates of CTSL not functionally validated\", \"Mechanism coupling nCTSL to DDR machinery unclear\", \"Preprint, single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked CTSL to autophagy promotion via IL6-JAK-STAT3 signaling in cancer cells.\",\n      \"evidence\": \"Proliferation, invasion, immunoprecipitation, and immunohistochemistry assays in laryngeal cancer cells\",\n      \"pmids\": [\"39893643\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between CTSL and the IL6-JAK-STAT3 axis remains indirect\", \"Single-lab study with limited mechanistic follow-up\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CTSL switches between its proteolytic (lysosomal/viral) and non-proteolytic (PDK1 scaffold, nuclear DDR) functions, and what governs its subcellular partitioning, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying model for catalytic vs scaffold activity\", \"Nuclear substrate spectrum not validated\", \"Signals determining lysosomal vs nuclear localization unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDK1\", \"NEDD4L\", \"USP20\", \"STUB1\", \"KPNB1\", \"LGMN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}