Affinage

CTSL

Procathepsin L · UniProt P07711

Round 2 corrected
Length
333 aa
Mass
37.6 kDa
Annotated
2026-04-28
58 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cathepsin L (CTSL) is a lysosomal cysteine endopeptidase with broad roles in protein turnover, extracellular matrix remodeling, cell cycle regulation, viral entry, and neuronal homeostasis. Synthesized as an inactive proenzyme whose prosegment occupies the active-site cleft in reverse orientation to block catalysis (PMID:8896443), CTSL is activated by legumain-dependent processing to a two-chain mature form and traffics not only to lysosomes but also to the nucleus via a signal-peptide-deficient isoform imported through KPNB1, where it cleaves the CDP/Cux transcription factor to promote G1-S progression (PMID:15099520, PMID:39868276). CTSL is the principal endosomal protease that cleaves the SARS-CoV and SARS-CoV-2 spike proteins at the S1/S2 boundary to activate membrane fusion and viral entry, a function validated by pharmacological inhibition, genetic knockout, and in vivo Cas13d-mediated knockdown (PMID:16081529, PMID:32221306, PMID:35879545). Beyond its proteolytic activities—including secreted cleavage of collagen XVIII to generate endostatin (PMID:10716919) and regulation of podocyte actin dynamics (PMID:19924101)—CTSL exerts a non-proteolytic scaffolding function by binding PDK1 to block NEDD4L-mediated ubiquitination, sustaining AKT–PD-L1 signaling in head and neck cancer (PMID:40961907).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1991 Medium

    Early evidence that cathepsin L redistributes from lysosomes in disease states established that CTSL is not confined to a housekeeping lysosomal role but may contribute to neurodegeneration through aberrant localization and extracellular release.

    Evidence Immunocytochemistry and immunoelectron microscopy of Alzheimer disease brain tissue

    PMID:1837142

    Open questions at the time
    • Correlative localization only; no causal evidence that CTSL itself drives amyloid pathology
    • No loss-of-function or gain-of-function test in neurodegeneration models at this stage
  2. 1996 High

    The crystal structure of procathepsin L resolved how the prosegment inhibits enzymatic activity, providing a structural basis for understanding zymogen activation and the molecular switch controlling CTSL protease function.

    Evidence X-ray crystallography of catalytic-mutant human procathepsin L at 2.2 Å resolution

    PMID:8896443

    Open questions at the time
    • Structure did not reveal which protease(s) remove the prosegment in vivo
    • No information on how differential isoforms or trafficking alter activation
  3. 1998 High

    Identification of SCCA1 as a cross-class serpin inhibitor of cathepsin L defined an endogenous regulatory axis controlling CTSL activity at 1:1 stoichiometry with kinetics rivaling classical serpin–serine protease pairs.

    Evidence In vitro kinetic analysis and SDS-PAGE detection of stable SCCA1–cathepsin L complexes

    PMID:9548757

    Open questions at the time
    • Physiological context of SCCA1–CTSL interaction in specific tissues not established
    • Whether SCCA1 inhibits nuclear or secreted CTSL pools was not tested
  4. 2000 High

    Demonstration that secreted cathepsin L generates endostatin from collagen XVIII at acidic pH established an extracellular, anti-angiogenic substrate-processing role distinct from lysosomal housekeeping.

    Evidence Conditioned medium proteolysis assay with cathepsin L-specific inhibitors and N-terminal sequencing of the product

    PMID:10716919

    Open questions at the time
    • In vivo relevance of CTSL-generated endostatin versus metalloprotease-generated fragments not resolved
    • Tumor microenvironment pH dependence not directly measured in situ
  5. 2004 High

    Discovery that a signal-peptide-deficient CTSL isoform localizes to the nucleus during G1-S and cleaves CDP/Cux revealed a moonlighting nuclear protease function regulating cell cycle gene expression, fundamentally expanding the functional repertoire of CTSL beyond lysosomes.

    Evidence Activity-based probes, immunofluorescence, and CDP/Cux processing assay in CathL-knockout and rescue cells

    PMID:15099520

    Open questions at the time
    • Full spectrum of nuclear substrates unknown at this point
    • Mechanism of nuclear import not yet identified
  6. 2005 High

    Multiple studies established CTSL as the critical endosomal protease for SARS-CoV spike-mediated entry, with a cell-free reconstitution proving that receptor binding followed by CTSL cleavage is sufficient to trigger membrane fusion—defining a unique three-step entry mechanism.

    Evidence Pseudovirus infection assays, exogenous CTSL expression, pharmacological inhibition, and cell-free membrane fusion reconstitution

    PMID:16081529 PMID:16339146

    Open questions at the time
    • Precise cleavage site on SARS-CoV spike not yet mapped
    • Relative contribution of CTSL versus cathepsin B in different cell types not resolved
  7. 2005 High

    In vivo loss-of-function studies showed that cathepsin L is essential for endothelial progenitor cell homing and neovascularization after ischemia, establishing a non-redundant role in tissue repair through matrix degradation.

    Evidence CathL-knockout mice, hind limb ischemia model, EPC infusion, and forced CTSL expression in endothelial cells

    PMID:15665831

    Open questions at the time
    • Specific extracellular matrix substrates cleaved by CTSL in this context not identified
    • Whether CTSL acts cell-autonomously or through paracrine substrate release not distinguished
  8. 2008 High

    Mapping the CTSL cleavage site on SARS-CoV spike to the S1/S2 boundary resolved where the protease acts, showing it separates the receptor-binding and fusion subunits analogously to furin cleavage in other coronaviruses.

    Evidence Cathepsin L cleavage mapping using spike truncation mutants with cell-based fusion readout

    PMID:18562523

    Open questions at the time
    • Whether the same site is used for SARS-CoV-2 spike was not yet tested
    • Structural basis for CTSL recognition of the spike cleavage site not determined
  9. 2020 High

    Extension of the SARS-CoV paradigm to SARS-CoV-2 confirmed that cathepsin L is critical for endosomal entry of the pandemic coronavirus, validating CTSL as a host-directed therapeutic target.

    Evidence SARS-CoV-2 S pseudovirus infection assays with cathepsin L inhibitors in 293/hACE2 cells

    PMID:32221306

    Open questions at the time
    • Pseudovirus system may not fully recapitulate live virus biology
    • Cell-type-specific dependence (e.g. TMPRSS2 co-expression) not fully parsed
  10. 2021 High

    Bidirectional regulation was uncovered: SARS-CoV-2 spike upregulates CTSL expression, and elevated circulating CTSL in COVID-19 patients creates a positive feedback loop enhancing viral entry, validated by in vivo amantadine inhibition.

    Evidence Pseudovirus assays, CTSL overexpression/knockdown, ELISA in patient sera, ACE2-transgenic mouse infection with amantadine treatment

    PMID:33774649

    Open questions at the time
    • Mechanism by which spike upregulates CTSL transcription not defined
    • Amantadine's specificity for CTSL versus off-target effects not fully resolved
  11. 2022 High

    In vivo Cas13d-mediated knockdown of Ctsl mRNA prevented and treated SARS-CoV-2 infection in mice, providing genetic proof-of-concept for CTSL as a therapeutic target beyond pharmacological inhibition.

    Evidence CRISPR-Cas13d nanosystem delivery to mouse lungs, live SARS-CoV-2 challenge, survival and viral burden quantification

    PMID:35879545

    Open questions at the time
    • Long-term safety and off-target effects of Ctsl knockdown in lung not assessed
    • Whether compensatory cathepsins are upregulated not examined
  12. 2017 Medium

    Transgenic CTSL overexpression in breast cancer mice produced a metastatic proteome signature distinct from cathepsin B, demonstrating that CTSL has unique in vivo substrate specificity relevant to metastasis.

    Evidence LC-MS/MS quantitative proteomics of lung metastases from CTSL-transgenic PyMT mice

    PMID:29187882

    Open questions at the time
    • Direct cleavage of identified substrates (saposin, granulin) by CTSL not biochemically verified
    • Whether the metastatic phenotype is protease-activity-dependent was not tested
  13. 2024 Medium

    Detailed promoter analysis confirmed that SARS-CoV-2 spike directly increases CTSL promoter activity and that CTSL knockout reduces spike internalization, mechanistically closing the positive feedback loop between spike and CTSL.

    Evidence Spike protein treatment, CTSL promoter-reporter assay, CTSL knockout cell lines, iPSC-derived alveolarspheres

    PMID:38971996

    Open questions at the time
    • Transcription factor mediating spike-induced CTSL promoter activation not identified
    • Single lab; independent replication needed
  14. 2025 Medium

    Post-translational regulation of CTSL was elucidated: USP20 deubiquitinates and stabilizes CTSL while STUB1 promotes its ubiquitination and degradation, with this balance driving EMT and chemoresistance in HNSCC.

    Evidence DUB inhibitor screen, mass spectrometry, Co-IP, ubiquitination assays, in vivo tumor models

    PMID:41261048

    Open questions at the time
    • Ubiquitination sites on CTSL not mapped
    • Whether USP20/STUB1 regulation operates in non-cancer contexts unknown
  15. 2025 Medium

    A non-proteolytic scaffolding function was discovered: CTSL binds PDK1 and blocks NEDD4L-mediated ubiquitination to sustain AKT–PD-L1 signaling, revealing a protease-independent mechanism for immune evasion in HNSCC.

    Evidence Reciprocal Co-IP, ubiquitination assays, xenograft and immunocompetent mouse models with anti-PD-1 therapy

    PMID:40961907

    Open questions at the time
    • Whether the scaffolding function requires a catalytically dead form or coexists with active enzyme not resolved
    • Generalizability beyond HNSCC not tested
  16. 2025 High

    Conditional double knockout of CtsB and CtsL in the nervous system demonstrated that CTSL is essential for autophagy-lysosomal homeostasis in cerebellar Purkinje cells, with cell-type-selective vulnerability (Zebrin II-negative, PLCβ4-positive neurons).

    Evidence Nestin-Cre conditional double-knockout mice, immunohistochemistry, electron microscopy, behavioral testing

    PMID:40320169

    Open questions at the time
    • Individual contribution of CTSL versus CTSB cannot be separated in the double knockout
    • Whether CTSL protects through specific substrate cleavage or bulk autophagosome clearance is not defined
  17. 2025 Medium

    Legumain was identified as the protease required for processing single-chain CTSL to the two-chain mature form, and N-terminomics identified putative nuclear CTSL substrates involved in proliferation, cell cycle, and ribosomal biogenesis, expanding the nuclear substrate repertoire. (preprint)

    Evidence (preprint) Legumain-knockout cells, activity-based probes, immunoblots, NICE N-terminomics pipeline

    PMID:bio_10.1101_2025.08.17.670765

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Identified nuclear substrates are putative; direct cleavage validation required
    • Whether single-chain CTSL is catalytically active in the nucleus not tested
  18. 2025 Medium

    Drug-induced nuclear CTSL import via KPNB1 was shown to mediate DNA damage response and apoptosis in ovarian cancer, and CTSL knockdown conferred drug resistance, identifying the nuclear import pathway and a therapeutic vulnerability. (preprint)

    Evidence (preprint) CTSL knockdown, nuclear fractionation, KPNB1 import assay, CRM1 inhibition, PDX models

    PMID:39868276

    Open questions at the time
    • Preprint; not yet peer-reviewed
    • Whether CTSL acts on DNA damage repair substrates directly or indirectly not resolved
    • Generalizability beyond clofarabine/olaparib combination not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the full catalog of nuclear CTSL substrates, the structural basis for CTSL's non-proteolytic scaffolding of PDK1, whether the CTSL ubiquitination-deubiquitination regulatory circuit (USP20/STUB1) operates broadly beyond HNSCC, and the individual contribution of CTSL versus CTSB to Purkinje cell survival.
  • No comprehensive nuclear substrate validation exists
  • Structural basis of CTSL–PDK1 scaffolding interaction not determined
  • Individual CTSL versus CTSB neuronal functions require single-knockout conditional models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016787 hydrolase activity 5 GO:0060090 molecular adaptor activity 1
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 4 GO:0005634 nucleus 3 GO:0005576 extracellular region 2 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 7 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1640170 Cell Cycle 2 R-HSA-162582 Signal Transduction 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
CUX1KPNB1LGMNNEDD4LPDK1SERPINB3STUB1USP20

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Crystal structure of human procathepsin L at 2.2 Å resolution revealed that the prosegment inhibits enzymatic activity through a globular N-terminal domain (three α-helices with a hydrophobic core) that packs against the enzyme surface, while the C-terminal portion occupies the substrate-binding cleft in reverse orientation to substrates. X-ray crystallography of a catalytic mutant of human procathepsin L The EMBO journal High 8896443
1998 The serpin SCCA1 acts as a cross-class inhibitor of cathepsins K, L, and S at 1:1 stoichiometry with second-order rate constants ≥1×10⁵ M⁻¹ s⁻¹, forming stable covalent-like complexes via its reactive site loop, analogous to serpin–serine protease interactions. Kinetic analysis (in vitro enzyme inhibition assays) and SDS-PAGE detection of stable SCCA1–cathepsin complexes Biochemistry High 9548757
2000 Secreted cathepsin L is responsible for generating endostatin from collagen XVIII with the predicted N-terminus at moderately acidic pH resembling the pericellular tumor milieu; metalloproteases produce larger fragments in a parallel pathway. Conditioned medium proteolysis assay, N-terminal amino acid sequencing, use of cathepsin L-specific inhibitors The EMBO journal High 10716919
2004 A cathepsin L isoform lacking a signal peptide localizes to the nucleus during the G1-S transition and proteolytically processes the CDP/Cux transcription factor, regulating cell cycle progression; nuclear trafficking involves translation initiation at downstream AUG codons. Immunofluorescence imaging, activity-based probes for nuclear CTSL, ectopic expression in Cat L⁻/⁻ cells, in situ CDP/Cux processing assay Molecular cell High 15099520
2005 Cathepsin L is required for SARS-CoV infection of ACE2-expressing cells; cathepsin L inhibitors block infection by SARS-CoV and retrovirus pseudotyped with SARS-CoV spike protein, and exogenous cathepsin L substantially enhances SARS-CoV S protein-mediated entry. HCoV-NL63, which uses the same ACE2 receptor, does not require cathepsin L, demonstrating distinct entry mechanisms for two ACE2-using coronaviruses. Pseudovirus infection assays, pharmacological inhibition of cathepsin L, exogenous cathepsin L expression in target cells The Journal of biological chemistry High 16081529 16339146
2005 Cathepsin L inhibitors block SARS-CoV infection; in a cell-free membrane fusion system, receptor engagement followed by cathepsin L proteolysis is sufficient to activate SARS-CoV spike-mediated membrane fusion, defining a unique three-step entry mechanism: receptor binding → conformational change → cathepsin L cleavage in endosomes. Cell-free membrane fusion assay, pharmacological inhibition of cathepsin L, lysosomotropic agents, SARS-CoV S protease treatment Proceedings of the National Academy of Sciences of the United States of America High 16081529
2005 Cathepsin L is essential for endothelial progenitor cell (EPC)-mediated neovascularization: CathL-deficient mice showed impaired recovery after hind limb ischemia; CathL-deficient EPCs failed to home to ischemic tissue or promote neovascularization; forced CathL expression in mature endothelial cells conferred invasive and neovascularization capacity. CathL knockout mouse model, hind limb ischemia model, EPC infusion, in vitro matrix degradation/invasion assays, forced expression in endothelial cells Nature medicine High 15665831
2008 Cathepsin L activates SARS-CoV spike protein membrane fusion function by cleaving the spike at the S1/S2 boundary region (upstream of the fusion peptide), mirroring where furin cleaves in other coronaviruses, thereby separating the receptor-binding from the fusion subunit. Cell-based fusion assays, cathepsin L cleavage mapping of spike protein truncation mutants Journal of virology High 18562523
2009 Cytosolic cathepsin L cleaves essential regulators of podocyte actin dynamics, resulting in a motile podocyte phenotype and proteinuria, establishing CTSL as an enzymatic driver of podocyte dysfunction. Review synthesizing cell biological experiments including subcellular fractionation, CTSL activity assays, and podocyte actin dynamics readouts Kidney international Medium 19924101
2012 A functional promoter variant C-171A (rs3118869) disrupts a xenobiotic response element (XRE) in the CTSL1 proximal promoter; AHR:ARNT complex with its ligand dioxin augments CTSL1 transcription, and the C-171A allele modulates this response, with genotype predicting blood pressure in two independent cohorts. Promoter/luciferase reporter transfection, co-expression of AHR:ARNT with dioxin, re-sequencing of CTSL1 locus, association analysis Journal of hypertension Medium 22871890
2020 SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, and cathepsin L is critical for this entry process, as established using the SARS-CoV-2 S protein pseudovirus system. SARS-CoV-2 S pseudovirus infection assay, pharmacological inhibition (PIKfyve, TPC2, cathepsin L inhibitors) Nature communications High 32221306
2021 CTSL cleaves the SARS-CoV-2 spike protein and enhances virus entry; circulating CTSL is elevated in COVID-19 patients; SARS-CoV-2 pseudovirus infection increases CTSL expression in human cells and humanized ACE2-transgenic mice; CTSL overexpression enhances pseudovirus infection while knockdown reduces it; amantadine inhibits CTSL activity and prevents infection in vitro and in vivo. Pseudovirus infection assays, CTSL overexpression/knockdown, CTSL inhibitor treatment in vivo (ACE2-transgenic mice), ELISA measurement of circulating CTSL in patients Signal transduction and targeted therapy High 33774649
2022 In vivo Cas13d-mediated knockdown of lung Ctsl mRNA via a nanosystem prevents and treats SARS-CoV-2 infection in mice, extending survival of lethally infected mice and reducing lung viral burden, proinflammatory cytokines, and pulmonary inflammation. CRISPR-Cas13d mRNA knockdown delivered by nanosystem in vivo; mouse SARS-CoV-2 infection model; viral burden quantification; cytokine measurement Nature chemical biology High 35879545
2024 SARS-CoV-2 spike protein treatment of HeLa cells and iPSC-derived alveolarspheres induces upregulation of cathepsin L mRNA and protein levels in a time-dependent manner and increases cathepsin L promoter activity; knockout of cathepsin L reduces spike protein internalization, confirming a bidirectional relationship between CTSL and SARS-CoV-2 spike entry. Recombinant spike protein treatment, qRT-PCR, Western blot, CTSL promoter-reporter assay, CTSL knockout cell lines, spike protein internalization assay Journal of cellular biochemistry Medium 38971996
2025 Legumain is required for processing of cathepsin L from single-chain to two-chain (mature) form; in legumain-deficient cells, CTSL remains in its single-chain form and nuclear CTSL levels are reduced in cell types where the double-chain form predominates in the nucleus. N-terminomics (NICE pipeline) identified putative nuclear substrates of CTSL involved in cell proliferation, cell cycle regulation, inflammation, and ribosomal biogenesis. Legumain-knockout (LGMN⁻/⁻) cells, activity-based probes (chemical), immunoblots, N-terminomics pipeline (NICE) bioRxivpreprint Medium bio_10.1101_2025.08.17.670765
2025 CTSL directly binds PDK1 in HNSCC cells, blocks NEDD4L-mediated ubiquitination of PDK1 (a non-proteolytic scaffolding function), thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 expression on tumor cells, driving immune evasion. Co-immunoprecipitation, ubiquitination assays, xenograft and immunocompetent mouse models, anti-PD-1 combination therapy Neoplasia (New York, N.Y.) Medium 40961907
2025 USP20 deubiquitinates and stabilizes CTSL protein in HNSCC, competing with STUB1 which promotes CTSL ubiquitination and degradation; USP20-mediated CTSL stabilization drives epithelial-to-mesenchymal transition, cancer stem cell renewal, and chemoresistance. Broad-spectrum deubiquitinase inhibitor screen, mass spectrometry identification of USP20, confocal colocalization, Co-IP, ubiquitination assays, in vitro and in vivo tumor models Clinical and translational medicine Medium 41261048
2025 Nervous system-specific double knockout of CtsB and CtsL in mice causes selective loss of Purkinje cells (phospholipase C β4-positive, Zebrin II-negative) in cerebellar striped patterns, accumulation of ubiquitin-positive structures in perikarya and axons, reduction in synaptic vesicles, and neuronal loss in thalamic nuclei, demonstrating that CtsL (with CtsB) is essential for autophagy-lysosomal degradation in cerebellar Purkinje cells. Conditional double-knockout mice (Nestin-Cre; CTSBflox/flox; CTSLflox/flox), immunohistochemistry, electron microscopy, behavioral tests The American journal of pathology High 40320169
2025 Drug-induced nuclear trafficking of CTSL (via KPNB1-mediated import and CRM1/XPO1-mediated export regulation) is critical for the DNA damage response in ovarian cancer cells; nuclear CTSL mediates cell cycle arrest and apoptosis; CTSL knockdown confers resistance to the clofarabine + olaparib combination. CTSL knockdown, nuclear fractionation, KPNB1 import assay, CRM1 inhibition, patient-derived ovarian ascites ex vivo, PDX xenograft models bioRxivpreprint Medium 39868276
1991 Lysosomal cathepsins including cathepsin L are abnormally distributed in Alzheimer disease brains, accumulating in enlarged lysosomes of cortical neurons and appearing extracellularly in senile plaques, suggesting that lysosome dysfunction and liberation of cathepsins from degenerating neurons may contribute to amyloid precursor protein proteolysis and β-amyloid formation. Immunocytochemistry, immunoelectron microscopy, enzyme histochemistry in human brain tissue Proceedings of the National Academy of Sciences of the United States of America Medium 1837142
2017 Transgenic overexpression of human CTSL in PyMT breast cancer mice increases metastatic burden and produces a distinct metastatic proteome signature compared with CTSB overexpression, including elevated saposin and granulin levels, demonstrating that CTSL has unique downstream substrate targets in vivo distinct from cathepsin B. LC-MS/MS quantitative proteomics of lung metastases from transgenic mice, hierarchical clustering Journal of Cancer Medium 29187882

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nature communications 2296 32221306
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nature biotechnology 1176 12754519
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2005 Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proceedings of the National Academy of Sciences of the United States of America 839 16081529
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2021 Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development. Signal transduction and targeted therapy 412 33774649
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2000 Secreted cathepsin L generates endostatin from collagen XVIII. The EMBO journal 373 10716919
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
1996 Structure of human procathepsin L reveals the molecular basis of inhibition by the prosegment. The EMBO journal 316 8896443
2004 A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor. Molecular cell 300 15099520
2005 SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells. The Journal of biological chemistry 299 16339146
2013 TMPRSS2 activates the human coronavirus 229E for cathepsin-independent host cell entry and is expressed in viral target cells in the respiratory epithelium. Journal of virology 268 23536651
1991 Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 262 1837142
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2020 Proteolytic Cleavage of the SARS-CoV-2 Spike Protein and the Role of the Novel S1/S2 Site. iScience 252 32512386
2004 An investigation into the human serum "interactome". Electrophoresis 247 15174051
1998 Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis. Biochemistry 242 9548757
2005 Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nature medicine 237 15665831
2008 Cathepsin L functionally cleaves the severe acute respiratory syndrome coronavirus class I fusion protein upstream of rather than adjacent to the fusion peptide. Journal of virology 232 18562523
2009 Proteinuria: an enzymatic disease of the podocyte? Kidney international 222 19924101
2022 Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection. Nature chemical biology 47 35879545
2021 The lnc-CTSLP8 upregulates CTSL1 as a competitive endogenous RNA and promotes ovarian cancer metastasis. Journal of experimental & clinical cancer research : CR 46 33933142
2020 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. Life sciences 44 32835700
2022 COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2. International journal of biological sciences 27 35414771
2022 A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer. British journal of cancer 22 35941174
2005 SNP analysis of AMY2 and CTSL genes in Litopenaeus vannamei and Penaeus monodon shrimp. Animal genetics 19 15932404
2020 Genomic, epigenomic, and immune subtype analysis of CTSL/B and SARS-CoV-2 receptor ACE2 in pan-cancer. Aging 16 33231569
2012 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. Journal of hypertension 13 22871890
2017 Proteomic analysis of lung metastases in a murine breast cancer model reveals divergent influence of CTSB and CTSL overexpression. Journal of Cancer 11 29187882
2021 Expressions and significances of CTSL, the target of COVID-19 on GBM. Journal of cancer research and clinical oncology 10 34807310
2010 Association between cathepsin L (CTSL) and cathepsin S (CTSS) polymorphisms and meat production and carcass traits in Italian Large White pigs. Meat science 10 20374908
2022 Comprehensive and Integrative Analysis of Two Novel SARS-CoV-2 Entry Associated Proteases CTSB and CTSL in Healthy Individuals and Cancer Patients. Frontiers in bioengineering and biotechnology 7 35155389
2025 Astragalus injection inhibits the growth of osteosarcoma by activating cytotoxic T lymphocyte and targeting CTSL. Journal of ethnopharmacology 6 40058477
2022 Methionine deprivation inhibits glioma growth through downregulation of CTSL. American journal of cancer research 6 36504894
2001 Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21-->q22 and SSC10q11-->q12. Cytogenetics and cell genetics 6 11978977
2025 CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway. Journal of cellular and molecular medicine 5 39893643
2011 Association between polymorphisms in cathepsin and cystatin genes with meat production and carcass traits in Italian Duroc pigs: confirmation of the effects of a cathepsin L (CTSL) gene marker. Molecular biology reports 4 21598116
2023 Large-scale whole exome sequencing studies identify two genes,CTSL and APOE, associated with lung cancer. PLoS genetics 3 37738239
2025 Targeting lysosomal protease CTSL promotes anti-tumor immunity and sensitizes HNSCC to PD-1 blockade by stabilizing PDK1 and activating Akt-PD-L1 axis. Neoplasia (New York, N.Y.) 2 40961907
2015 Association Between Polymorphism in the Human Cathepsin L (CTSL1) Promoter with Hypertension in the Uygur, Kazak and Han Populations in China. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 2 26374357
2025 Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications. bioRxiv : the preprint server for biology 1 39868276
2025 CTSL-2 upon specifically recognizing Vibrio splendidus directly cleaves complement C3 to promote the bacterial phagocytosis and degradation in oyster. Cell communication and signaling : CCS 1 40275325
2025 USP20 competitively binds to STUB1 to enhance CTSL expression and promote epithelial-mesenchymal transition in head and neck squamous cell carcinoma. Clinical and translational medicine 1 41261048
2026 Pinostrobin attenuates microglia-mediated neuroinflammation after subarachnoid hemorrhage through modulation of the MYC-CTSL signaling axis. Naunyn-Schmiedeberg's archives of pharmacology 0 41807810
2025 High expression of SERPINE1 and CTSL in keratinocytes in pressure injury caused by ischemia-reperfusion injury. Tissue & cell 0 39864211
2025 Uncovering the Unique Roles of Cathepsins B and L in Purkinje Cells Using Nervous System-Specific CTSB and CTSL Double-Deficient Mice. The American journal of pathology 0 40320169
2024 SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres. Journal of cellular biochemistry 0 38971996
2016 [Level of expression of gene CTSL and its correlation with natural killer T-Cells in mexican pediatric patients with recent-onset type 1 diabetes]. Gaceta medica de Mexico 0 27792712