Affinage

CTSB

Cathepsin B · UniProt P07858

Round 2 corrected
Length
339 aa
Mass
37.8 kDa
Annotated
2026-04-28
93 papers in source corpus 27 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cathepsin B is a lysosomal cysteine protease with dual endopeptidase and dipeptidyl carboxypeptidase activity, conferred by a unique occluding loop (His110/His111) that anchors substrate C-termini and restricts cystatin-family inhibitor access (PMID:1868826, PMID:6203523). It processes a broad spectrum of substrates including pro-uPA, aggrecan, PARP-1, MCOLN1/TRPML1 (thereby controlling TFEB-dependent lysosome/autophagosome biogenesis), ferroportin, fibronectin, and Ebola virus glycoprotein GP1 (PMID:1900515, PMID:1326552, PMID:11536009, PMID:27786577, PMID:15831716, PMID:39960586); upon lysosomal membrane permeabilization it activates the NLRP3 inflammasome to drive pyroptosis and IL-1β maturation (PMID:21508263, PMID:36713420). Beyond its intracellular roles, muscle-secreted CTSB functions as an exercise-induced myokine that promotes hippocampal BDNF expression and neurogenesis via P11 (PMID:27345423); its activity is regulated post-translationally by O-GlcNAcylation at Ser210 and by K33-linked deubiquitination (PMID:36084651, PMID:41035046), and gain-of-function mutations or upstream enhancer duplications cause palmoplantar keratoderma and keratolytic winter erythema, respectively (PMID:32683719, PMID:28457472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1984 High

    Before physiological regulators of cathepsin B were known, identification of cystatin C as a potent endogenous inhibitor established that cathepsin B activity is tightly controlled extracellularly by cystatin-family proteins.

    Evidence Enzyme inhibition kinetics with purified cystatin C against cathepsin B and related cysteine proteases

    PMID:6203523

    Open questions at the time
    • Intracellular regulation of CTSB activity by endogenous inhibitors not addressed
    • Tissue-specific relevance of cystatin C–CTSB interaction not explored
  2. 1986 High

    Cloning of preprocathepsin B cDNA revealed the full precursor architecture—signal peptide, propeptide, mature chain, and C-terminal extension—establishing the multi-step processing pathway required for enzyme maturation.

    Evidence cDNA cloning and sequencing from human hepatoma and kidney libraries

    PMID:3463996

    Open questions at the time
    • Precise sites and proteases responsible for each processing step not identified
    • Regulation of propeptide removal in different tissues unknown
  3. 1991 High

    The 2.15 Å crystal structure resolved the long-standing question of how cathepsin B achieves both endo- and exopeptidase activity: an occluding loop (His110/His111) blocks the primed subsites, anchoring substrate C-termini for dipeptidyl carboxypeptidase activity and sterically preventing cystatin binding.

    Evidence X-ray crystallography at 2.15 Å resolution with structural comparison to papain/actinidin

    PMID:1868826

    Open questions at the time
    • Dynamic behavior of the occluding loop and endo/exo switching mechanism not captured by static structure
    • Structural basis for substrate selectivity at the S2 subsite incompletely characterized
  4. 1991 High

    Demonstration that cathepsin B activates pro-uPA at the same Lys158-Ile159 bond as plasmin established CTSB as a direct activator of pericellular plasminogen signaling, linking it to extracellular matrix remodeling and tumor invasion.

    Evidence In vitro cleavage of purified pro-uPA with N-terminal sequencing and E-64 inhibitor blocking; cell surface activation on U937 cells

    PMID:1900515

    Open questions at the time
    • In vivo relevance of CTSB-mediated pro-uPA activation not demonstrated
    • Relative contribution versus other activating proteases unclear
  5. 1991 High

    Immunoelectron microscopy of Alzheimer disease brains revealed cathepsin B mislocalization from lysosomes to neuronal perikarya and senile plaques, establishing lysosomal dysfunction and CTSB redistribution as features of AD neurodegeneration.

    Evidence Immunocytochemistry and immunoelectron microscopy on human post-mortem AD vs. control brain tissue

    PMID:1837142

    Open questions at the time
    • Whether CTSB mislocalization is causative or consequential in AD pathology not resolved
    • Specific CTSB substrates contributing to amyloidogenesis not identified in this study
  6. 1992 High

    Identification of CTSB cleavage of aggrecan at a specific Gly-Val bond in the interglobular domain, near the MMP cleavage site, established cathepsin B as a cartilage-degrading protease relevant to joint pathology.

    Evidence In vitro proteolysis of purified aggrecan G1-G2 domain with fragment analysis by SDS-PAGE

    PMID:1326552

    Open questions at the time
    • In vivo contribution of CTSB to aggrecanolysis versus MMPs not quantified
  7. 2001 High

    Discovery that cathepsin B (released during necrosis) generates a distinct ~50 kDa PARP-1 fragment not produced by caspases revealed a necrosis-specific proteolytic signature and distinguished cathepsin-mediated cell death from apoptosis.

    Evidence In vitro cleavage of purified PARP-1 by cathepsin B; comparison with necrotic cell lysates; caspase inhibitor (zVAD-fmk) insensitivity

    PMID:11536009

    Open questions at the time
    • PARP-1 cleavage site by CTSB not mapped
    • Functional consequences of the ~50 kDa PARP-1 fragment not characterized
  8. 2005 High

    Cathepsin B was shown to be required for endosomal cleavage of Ebola virus GP1 to enable membrane fusion and viral entry, defining CTSB as a host-factor dependency for filovirus infection.

    Evidence Selective protease inhibitors, protease-deficient cell lines, VSV pseudotype entry assays, and infectious Ebola virus multiplication assays

    PMID:15831716

    Open questions at the time
    • Precise cleavage sites on GP1 by CTSB not fully mapped
    • Extent of cathepsin L redundancy in vivo not settled
  9. 2011 High

    Demonstration that cathepsin B mediates SAA-induced NLRP3 inflammasome activation in macrophages established the paradigm that lysosomal membrane permeabilization and cytoplasmic CTSB release are upstream triggers of inflammasome-driven IL-1β maturation.

    Evidence Cathepsin B inhibitor, siRNA knockdown of NLRP3/ASC, ASC-KO macrophages, IL-1β ELISA in human and mouse macrophages

    PMID:21508263

    Open questions at the time
    • Whether CTSB directly cleaves an NLRP3 component or acts indirectly not resolved
    • Relative contribution of CTSB versus other lysosomal cathepsins to inflammasome activation unclear
  10. 2014 High

    Genetic deletion of cathepsin B in transgenic mouse cancer models demonstrated a causal role in tumor initiation, growth, angiogenesis, and metastasis, with CTSB associating with the tumor cell plasma membrane at elevated expression, establishing its non-redundant function in cancer progression.

    Evidence CTSB knockout in MMTV-PyMT and RIP1-Tag2 transgenic mouse models with tumor growth, metastasis, and apoptosis quantification

    PMID:24677670

    Open questions at the time
    • Specific tumor-promoting substrates cleaved by membrane-associated CTSB not identified
    • Cell-type-specific contributions (tumor vs. stroma) not fully dissected
  11. 2016 High

    CTSB was found to cleave the lysosomal calcium channel MCOLN1/TRPML1, thereby suppressing TFEB activation and limiting lysosome/autophagosome biogenesis under homeostatic conditions—a mechanism co-opted by intracellular bacteria to enhance survival.

    Evidence CTSB KO cells and mice, MCOLN1 cleavage assay, TFEB reporter, lysosome/autophagosome quantification, Francisella novicida infection model

    PMID:27786577

    Open questions at the time
    • Cleavage site on MCOLN1 not mapped
    • Whether CTSB regulation of TFEB is a general homeostatic mechanism or context-specific not fully established
  12. 2016 High

    Identification of cathepsin B as an exercise-induced myokine that promotes hippocampal BDNF/DCX expression and neurogenesis through P11 provided the first direct mechanistic link between a muscle-secreted protease and exercise-dependent cognitive enhancement.

    Evidence CTSB KO mice fail to show running-induced neurogenesis; recombinant CTSB rescues hippocampal progenitor differentiation via P11; plasma CTSB correlates with fitness in humans

    PMID:27345423

    Open questions at the time
    • Mechanism by which circulating CTSB crosses the blood-brain barrier not established
    • Direct proteolytic target of CTSB that engages P11 signaling not identified
  13. 2017 High

    Tandem duplications of a keratinocyte enhancer upstream of CTSB were shown to segregate with keratolytic winter erythema in two independent populations, establishing CTSB overexpression as the genetic cause of KWE.

    Evidence Targeted resequencing, WGS, enhancer activity assays in keratinocytes, qPCR, ChIA-PET chromatin interaction analysis in South African and Norwegian families

    PMID:28457472

    Open questions at the time
    • Downstream keratinocyte substrates whose excessive cleavage causes erythrokeratolysis not identified
    • Whether enhancer duplication alters CTSB expression in non-epidermal tissues unknown
  14. 2020 Medium

    A gain-of-function missense mutation in CTSB was identified as causing autosomal dominant diffuse palmoplantar keratoderma, confirmed by elevated enzymatic activity, representing the first gain-of-function CTSB point mutation linked to Mendelian disease.

    Evidence Whole exome sequencing, protein modeling, and cathepsin B enzymatic activity assay on patient-derived material (single case)

    PMID:32683719

    Open questions at the time
    • Single patient without independent replication
    • Precise mechanism by which increased CTSB activity causes keratoderma not determined
    • The specific residue affected and structural consequence not fully validated by crystal structure
  15. 2022 High

    Discovery that O-GlcNAcylation of cathepsin B at Ser210 by lysosome-localized OGT stabilizes and promotes CTSB secretion in tumor-associated macrophages revealed a metabolic post-translational control mechanism linking glucose metabolism to metastasis.

    Evidence Mass spectrometry identification of Ser210 O-GlcNAcylation, site-directed mutagenesis, OGT KO macrophages, in vivo metastasis assays

    PMID:36084651

    Open questions at the time
    • Whether O-GlcNAcylation at Ser210 affects catalytic activity directly or only protein stability not distinguished
    • Generalizability beyond tumor-associated macrophages not tested
  16. 2022 Medium

    CTSB was shown to degrade ferroportin in ox-LDL-stimulated macrophages, disrupting iron export and inducing ferroptosis, providing a direct mechanistic link between CTSB and iron-dependent cell death in atherosclerosis.

    Evidence Co-immunoprecipitation of CTSB-FPN, CTSB knockdown/inhibition rescuing FPN levels, ferroptosis markers, ApoE-KO mouse and rat atherosclerosis models

    PMID:39960586

    Open questions at the time
    • Ferroportin cleavage site by CTSB not mapped
    • Co-IP without reciprocal validation reported
    • Single lab study
  17. 2025 Medium

    Identification of K33-linked deubiquitination of CTSB by ZRANB1, modulated by MINPP1, revealed a previously unknown ubiquitin-dependent regulatory layer controlling CTSB protein stability and ferroptosis in HBV-positive hepatocellular carcinoma.

    Evidence Immunoprecipitation, K33-linkage ubiquitin analysis, CTSB stability assays, in vivo xenograft experiments

    PMID:41035046

    Open questions at the time
    • Specific ubiquitination sites on CTSB not mapped
    • Whether K33-linked regulation operates beyond HBV-positive HCC context unknown
    • Single lab study
  18. 2025 Medium

    METTL3-mediated m6A methylation of CTSB mRNA was shown to upregulate CTSB expression in chondrocytes, with CTSB overexpression rescuing ferroptosis and inflammatory phenotypes upon METTL3 silencing, establishing an epitranscriptomic regulatory axis for CTSB in osteoarthritis.

    Evidence m6A RIP, dual-luciferase reporter assay, METTL3/CTSB siRNA knockdown with rescue, ferroptosis and apoptosis readouts in human chondrocytes

    PMID:41466292

    Open questions at the time
    • Specific m6A site(s) on CTSB mRNA not mapped at nucleotide resolution
    • In vivo validation in OA models not yet reported
    • Single lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) the direct molecular mechanism by which cytoplasmic CTSB activates the NLRP3 inflammasome (whether via direct NLRP3 cleavage or indirect signaling), (2) the structural basis for the occluding loop's dynamic endo-to-exopeptidase switching in physiological contexts, and (3) the identity of blood-brain barrier transit mechanisms enabling circulating CTSB to promote hippocampal neurogenesis.
  • No structural study of the occluding loop in a dynamic or membrane-associated context
  • Direct NLRP3 cleavage by CTSB never reconstituted with purified components
  • BBB crossing mechanism for myokine CTSB undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 6
Localization
GO:0005764 lysosome 7 GO:0005829 cytosol 4 GO:0005576 extracellular region 2 GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-9612973 Autophagy 2
Partners
CST3FPN1MCOLN1NLRP3OGTP11ZRANB1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 X-ray crystal structure of human liver cathepsin B refined to 2.15 Å revealed the structural basis for its dual endo- and exopeptidase activity: an 'occluding loop' containing His110 and His111 blocks primed subsites, anchoring the C-terminal carboxylate of substrates and explaining dipeptidyl carboxypeptidase activity; the active-site Cys29 and Glu245 in the S2 subsite favor basic P2 side chains; the occluding loop also prevents cystatin-like inhibitors from binding as they do to papain. X-ray crystallography (2.15 Å resolution), Patterson search and heavy atom replacement, structural comparison with papain/actinidin The EMBO journal High 1868826
1986 Cloning and sequencing of human and mouse preprocathepsin B cDNAs revealed a 339-amino-acid precursor comprising a 17-residue signal peptide, a 62-residue propeptide, 254 residues of mature cathepsin B, and a 6-residue C-terminal extension; the propeptide contains a conserved glycosylation site and single cysteine, and comparative analysis suggested multi-step processing with possible active intermediate forms. cDNA cloning from human hepatoma and kidney libraries, nucleotide sequencing, comparative sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 3463996
1991 Purified human cathepsin B cleaves pro-uPA (single-chain urokinase-type plasminogen activator) at the Lys158-Ile159 bond—the same site cleaved by plasmin and kallikrein—generating enzymatically active two-chain uPA; this activation is blocked by the CTSB-specific inhibitor E-64; cathepsin B can also activate receptor-bound pro-uPA on tumor cell surfaces, whereas cathepsin D cannot activate pro-uPA. In vitro enzymatic assay with purified human cathepsin B, N-terminal amino acid sequencing of cleavage products, inhibitor (E-64) blocking, receptor-binding assay on U937 cells The Journal of biological chemistry High 1900515
1992 Cathepsin B cleaves the cartilage proteoglycan aggrecan at a single Gly-Val bond within the interglobular domain, only three amino acids C-terminal to the metalloproteinase (stromelysin) cleavage site, generating distinct G1 and G2 fragments. In vitro protease digestion of purified aggrecan G1-G2 domain fragment, SDS-PAGE fragment analysis, comparison with MMP-2, MMP-7, MMP-9 cleavage patterns The Journal of biological chemistry High 1326552
1984 Cystatin C (gamma-trace) was identified as the tightest-binding protein inhibitor of cathepsin B discovered at the time, also potently inhibiting cathepsins H and L and the plant cysteine proteinases papain and ficin, establishing a physiological role for extracellular cystatins in regulating cathepsin B activity. Enzyme inhibition kinetics with purified proteins, determination of inhibition constants Biochemical and biophysical research communications High 6203523
2001 Cathepsin B (released from lysosomes during necrosis) cleaves PARP-1 to generate a ~50 kDa fragment distinct from the apoptotic 89 kDa caspase-3 fragment; this cleavage is not inhibited by the broad-spectrum caspase inhibitor zVAD-fmk and is reproduced by purified cathepsin B in vitro on affinity-purified bovine PARP-1. In vitro cleavage assay with purified lysosomal proteases (cathepsins B, D, G) on affinity-purified PARP-1; lysosomal-rich fractions from Jurkat cells; comparison with necrotic cell lysates Cell death and differentiation High 11536009
2005 Cathepsin B (and to a lesser extent cathepsin L) is required for endosomal proteolytic cleavage of Ebola virus glycoprotein GP1, a step essential for viral entry into host cells; selective protease inhibitors and protease-deficient cell lines confirmed that CatB mediates GP1 cleavage enabling membrane fusion, and CatB/CatL inhibitors reduce multiplication of infectious Ebola virus-Zaire in culture. Selective protease inhibitors, protease-deficient cell lines, VSV pseudotype entry assay, biochemical proteolysis assay of EboV GP, infectious EboV-Zaire multiplication assay Science High 15831716
1991 In Alzheimer disease brains, cathepsin B (along with other lysosomal hydrolases) accumulates abnormally in neuronal perikarya and is found extracellularly in senile plaques, co-localizing with degenerating neuronal processes; in control brains cathepsin B is restricted to intracellular lysosomal compartments, establishing that lysosomal dysfunction and cathepsin B mis-localization occur in AD neurodegeneration. Immunocytochemistry, immunoelectron microscopy, and enzyme histochemistry in human post-mortem brain tissue from AD and control subjects Proceedings of the National Academy of Sciences of the United States of America High 1837142
2002 Cathepsin B is upregulated and enzymatically active in inflamed atherosclerotic lesions (but not in normal aorta or silent lesions) in apoE-knockout mice; cathepsin B activity was imaged in vivo within active atherosclerotic plaques using intravenously injectable near-infrared cathepsin B-activatable imaging beacons, confirming a role for cathepsin B proteolytic activity in vascular inflammation. In vivo near-infrared fluorescence tomographic imaging with cathepsin B-specific activatable probes, immunohistochemistry, Western blot in apoE-KO and apoE/eNOS double-KO mouse atherosclerosis models Circulation High 12057992
2011 Serum amyloid A (SAA) activates the NLRP3 inflammasome in macrophages through a cathepsin B-sensitive pathway (confirmed by cathepsin B inhibitor blocking IL-1β secretion) and via P2X7 receptor; SAA also induces cathepsin B secretion, identifying cathepsin B as a key effector in inflammasome-driven IL-1β maturation. Cathepsin B inhibitor treatment, siRNA knockdown of NLRP3 and ASC, ASC-KO macrophages, IL-1β ELISA, TLR2/4 blocking antibodies in human/mouse macrophages and THP-1 cells Journal of immunology High 21508263
2014 In transgenic mouse models of pancreatic and mammary carcinomas, cathepsin B in tumor cells and tumor-associated macrophages causally promotes tumor initiation, growth, angiogenesis, invasion, and metastasis; absence of cathepsin B enhances apoptosis; cathepsin B also associates with the tumor cell plasma membrane at elevated expression levels characteristic of cancer. Transgenic mouse models (MMTV-PyMT, RIP1-Tag2), genetic knockout of cathepsin B, tumor growth and metastasis assays, membrane fractionation Proteomics. Clinical applications High 24677670
2016 Under homeostatic conditions, cathepsin B cleaves the lysosomal calcium channel MCOLN1/TRPML1, which suppresses the transcription factor TFEB and reduces expression of lysosomal and autophagy-related genes, thereby controlling the number of lysosomes and autophagosomes in the cell; the cytosolic bacterium Francisella novicida exploits this CTSB activity to suppress lysosome/autophagosome availability and enhance its intracellular survival. CTSB knockout cells and mice, lysosome/autophagosome quantification, MCOLN1 cleavage assay, TFEB reporter assay, bacterial infection models Autophagy High 27786577
2016 Skeletal muscle-secreted cathepsin B (CTSB) acts as a myokine elevated by exercise (running); recombinant CTSB application enhances BDNF and doublecortin (DCX) expression in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11; in CTSB knockout mice, running fails to enhance adult hippocampal neurogenesis and spatial memory; plasma CTSB levels correlate with fitness and hippocampus-dependent memory in humans. CTSB KO mice, recombinant CTSB treatment of hippocampal progenitor cells, P11-dependency assay, hippocampal neurogenesis quantification, plasma CTSB measurement in mice/monkeys/humans, treadmill exercise protocol Cell metabolism High 27345423
2022 Glucose metabolism in M2-like tumor-associated macrophages (TAMs) fuels the hexosamine biosynthetic pathway, leading to O-GlcNAcylation of cathepsin B at serine 210 by lysosome-localized OGT (O-GlcNAc transferase); this modification elevates mature cathepsin B levels in macrophages and promotes its secretion into the tumor microenvironment, thereby driving cancer metastasis and chemoresistance. Mass spectrometry identification of O-GlcNAcylation site (Ser210), OGT KO in macrophages, glycosylation site mutagenesis, co-immunoprecipitation, in vitro and in vivo metastasis assays, patient TAM correlation analysis Cancer cell High 36084651
1992 Human CTSB was definitively mapped to chromosome 8p22-p23.1 by three independent methods: PCR analysis of human-hamster somatic cell hybrids, FISH signal comparison in fibroblasts with chromosome 8 deletions, and fluorescence in situ hybridization to metaphase spreads with cathepsin B cosmid clones, resolving a prior ambiguity with a reported 13q14 location. PCR on somatic cell hybrid DNA, interphase FISH with chromosome 8 deletion fibroblasts, metaphase FISH with cosmid clones Human genetics High 1577456
2017 Tandem duplications of a 2.62 kb overlapping genomic region upstream of CTSB—containing an active keratinocyte enhancer—segregate with keratolytic winter erythema (KWE) in South African and Norwegian families; the duplication drives increased CTSB expression in keratinocytes of affected individuals, causing erythrokeratolysis, establishing CTSB overexpression as the cause of KWE. Targeted resequencing, SNP array, whole-genome sequencing, enhancer activity assays in keratinocyte cell lines, qPCR, immunohistochemistry of palmar epidermis, ChIA-PET chromatin interaction analysis American journal of human genetics High 28457472
2020 A gain-of-function missense mutation in CTSB, affecting a highly conserved residue, was found in a patient with autosomal dominant diffuse palmoplantar keratoderma; protein modelling predicted increased endopeptidase activity, and a cathepsin B enzymatic assay confirmed elevated proteolytic activity of the mutant, identifying the first gain-of-function CTSB variant. Whole exome sequencing, direct sequencing, protein modelling, cathepsin B enzymatic activity assay on patient-derived material Clinical and experimental dermatology Medium 32683719
2019 Cancer cell-secreted CST6 enters osteoclast precursors by endocytosis and suppresses cathepsin B (CTSB) activity; loss of CTSB activity leads to up-regulation of its hydrolytic substrate SPHK1, which then suppresses osteoclast maturation by inhibiting RANKL-induced p38 activation, defining a CST6-CTSB-SPHK1 signaling axis in osteoclastogenesis and bone metastasis. In vitro osteoclastogenesis assay, in vivo bone metastasis mouse model, CTSB activity assay, SPHK1 substrate identification, p38 signaling analysis, siRNA knockdown, recombinant CST6 protein treatment Theranostics Medium 34815788
2016 HDAC3 deficiency in macrophages increases cathepsin B (CTSB) expression via elevated histone acetylation at the CTSB locus; over-expressed CTSB causes lysosomal degradation of RIP1 (receptor-interacting serine-threonine kinase 1), reducing TNFα-mediated NF-κB activation and impairing inflammatory response to Pseudomonas aeruginosa infection. HDAC3 macrophage-specific KO mice, RNAseq, CHIPseq, Western blot, immunofluorescence, qRT-PCR, in vivo P. aeruginosa infection model, LPS intratracheal instillation Cell & bioscience Medium 35658939
2014 Cathepsin B promotes porcine preadipocyte differentiation by degrading fibronectin (Fn), a key extracellular matrix component and target gene of Wnt/β-catenin signaling; CTSB treatment relieved the anti-adipogenic effect of the Wnt/β-catenin activator LiCl, indicating that CTSB attenuates Wnt/β-catenin pathway activity through Fn degradation to facilitate adipogenesis. CTSB treatment of primary preadipocytes, fibronectin degradation assay, LiCl (Wnt activator) co-treatment, lipid accumulation staining, adipogenic gene expression analysis Molecular and cellular biochemistry Medium 24878992
2022 CTSB degrades ferroportin (FPN), the main iron export protein in macrophages; oxidized LDL (ox-LDL) upregulates macrophage CTSB, which negatively regulates FPN protein levels by promoting its degradation, disrupting iron homeostasis and inducing ferroptosis, thereby promoting atherosclerotic plaque progression. Co-immunoprecipitation (CTSB-FPN interaction), CTSB knockdown and pharmacological inhibition, FPN protein stability assay, ferroptosis markers in macrophages, in vivo ApoE-KO and HFD rat AS models, single-cell transcriptome analysis of human AS tissue Molecular and cellular biochemistry Medium 39960586
2023 Lysosomal membrane permeabilization (LMP) releases cathepsin B into the cytoplasm where it activates the NLRP3 inflammasome, leading to caspase-1-dependent pyroptosis (GSDMD-N cleavage, IL-1β/IL-18 release); in sepsis-induced acute kidney injury (LPS-treated HK-2 cells), CTSB activity is elevated, CTSB inhibition with CA074 reverses LMP-induced mitochondrial membrane potential loss and apoptosis via the mitochondrial pathway. CTSB activity assay, CA074 inhibitor, JC-1 mitochondrial membrane potential, Annexin V/PI apoptosis staining, acridine orange lysosomal staining, Western blot, CCK8, CLP mouse model, DIA proteomics Frontiers in immunology Medium 36713420
2019 In arsenic-induced liver fibrosis, NaAsO2 upregulates autophagy flux, which promotes cytoplasmic cathepsin B (CTSB) release from lysosomes; cytoplasmic CTSB activates the NLRP3 inflammasome, driving hepatic stellate cell (HSC) activation; inhibition of autophagy decreases cytoplasmic CTSB and attenuates NLRP3 inflammasome activation and HSC activation. Autophagy inhibitor (chloroquine), CTSB activity assay, NLRP3 inhibitor, immunofluorescence, Western blot in HSC-t6 cells and primary rat HSCs, in vivo NaAsO2-treated rat model Chemosphere Medium 31669990
2025 ZRANB1 mediates K33-linked deubiquitination of CTSB, stabilizing CTSB protein expression; MINPP1 modulates this deubiquitination to regulate CTSB levels and downstream ferroptosis in HBV-positive hepatocellular carcinoma cells; the MINPP1-ZRANB1-CTSB axis is active only in HBV-positive HCC cells and promotes ferroptosis via a glycolytic bypass mechanism. Immunoprecipitation, immunofluorescence, ubiquitin modification analysis (K33-linkage), CTSB expression/stability assays, in vivo xenograft experiments Biology direct Medium 41035046
2025 ETS1 transcription factor is expressed in septoclasts (cartilage-resorbing cells at the chondro-osseous junction) and promotes transcription of Ctsb and Mmp13 during differentiation of septoclasts from pericytes; ETS1 siRNA knockdown in primary septoclast cultures significantly reduced Ctsb and Mmp13 expression. RNA-seq of isolated septoclast and pericyte populations, ETS1 siRNA knockdown in primary septoclast cultures, immunofluorescence localization Cell and tissue research Medium 40387924
2025 OGT-mediated O-GlcNAcylation of cathepsin B in prefrontal astrocytes promotes CTSB maturation; reduced O-GlcNAcylation (via OGT downregulation by BXHPD treatment) lowers ROS, attenuates lysosomal membrane permeabilization and cytoplasmic CTSB leakage, and suppresses NLRP3 inflammasome activation, improving depressive-like behaviors in a corticosterone mouse model. CO-IP for OGT-CTSB interaction, O-GlcNAcylation analysis, Western blot, immunofluorescence (OGT/S100β and CTSB/LAMP1 colocalization), DHE staining for ROS, Aldh1l1-Cre/ERT2 astrocyte-specific mice, behavioral tests Journal of ethnopharmacology Medium 41391522
2025 METTL3 upregulates CTSB expression in chondrocytes by promoting m6A methylation of CTSB mRNA, as confirmed by m6A RNA immunoprecipitation and dual-luciferase reporter assays; METTL3 silencing protects against IL-1β-induced chondrocyte apoptosis, inflammation, oxidative stress, and ferroptosis, effects that are rescued by CTSB overexpression, establishing a METTL3-m6A-CTSB regulatory axis in osteoarthritis. m6A RNA immunoprecipitation (MeRIP), dual-luciferase reporter assay, METTL3 and CTSB siRNA knockdown, Western blot, flow cytometry, TUNEL, ELISA, ROS/MDA/Fe2+ assays in human chondrocytes Journal of orthopaedic surgery and research Medium 41466292
2024 Cathepsin B promotes microglial efferocytosis of apoptotic neurons during brain development; CTSB is enriched in microglia in high-neuronal-turnover brain regions; myeloid-specific CTSB knockdown in zebrafish led to dysmorphic microglia containing undigested dead cells and accumulation of apoptotic cells, phenocopied by global Ctsb KO in mice; live imaging revealed deficits in phagolysosomal fusion and acidification, identifying a role in lysosomal digestion rather than initial phagocytic uptake. Zebrafish myeloid-specific CTSB knockdown, global Ctsb-KO mice, live fluorescence imaging of phagolysosomal fusion and acidification, apoptosis markers (TUNEL), confocal imaging of brain regions, behavioral assessment bioRxivpreprint Medium
2025 Beauvericin (BEA) acts as an uncompetitive inhibitor of cathepsin B; NMR analyses confirmed direct interaction between BEA and CTSB; enzyme kinetics established uncompetitive inhibition; molecular docking identified a putative BEA binding site in human CTSB distinct from the active site; BEA significantly suppresses CTSB activity in mouse BMDCs and human iDCs. Enzyme kinetics (uncompetitive inhibitor determination), NMR spectroscopy (direct binding), molecular docking, CTSB activity assay in BMDCs and THP-1-derived iDCs bioRxivpreprint Medium
2025 Elevated lysosomal cathepsin B levels and CTSB leakage to the cytoplasm trigger amyloidogenesis in mucopolysaccharidosis type IIIC and sialidosis mouse models; CTSB-deficient MPS IIIC mice (Hgsnat-P304L/Ctsb-/-) and mice chronically treated with brain-penetrating CTSB inhibitor E64 showed drastic reduction in neuronal Thioflavin-S-positive/APP-positive amyloid deposits and restored autophagy markers; E64 treatment rescued behavioral deficits. CTSB-deficient double-KO mice, chronic brain-penetrating E64 inhibitor treatment, Thioflavin-S staining, β-amyloid immunostaining, P62/LC3 autophagy markers, behavioral testing (hyperactivity, anxiety), immunofluorescence of cortical neurons bioRxivpreprint Medium
2024 Extralysosomal cathepsin B in progressive multiple sclerosis brains cleaves the C-terminal domain of TAF1, a core component of the general transcription factor TFIID; loss of C-terminal TAF1 disrupts RNAPII promoter-proximal pausing at oligodendroglial myelination genes; mice lacking the C-terminal TAF1 domain exhibit MS-like brain transcriptomic signature, CNS-resident inflammation, progressive demyelination, and motor disability. Detection of TAF1 C-terminal underexpression in MS brain tissue, identification of CTSB-mediated endoproteolysis of TAF1, generation of Taf1Δ38 mice, transcriptomic analysis, immunofluorescence, behavioral assessment bioRxivpreprint Low
2025 Cathepsin B (CTSB) cleaves the lysosomal nitrate transporter Sialin to generate a proteolytic fragment called Sialin2 that localizes to mitochondria and acts as a nitrate sensor; Sialin2 scaffolds LKB1-AMPK complexes to drive mitochondrial biogenesis and metabolic adaptation. Cryo-EM structure of Sialin2, microscale thermophoresis (MST) nitrate-binding assay, fractionation showing CTSB-dependent generation of Sialin2, AMPK complex co-immunoprecipitation, sCiSiNiS biosensor for real-time nitrate signaling bioRxivpreprint Low

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
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
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
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
2005 Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science (New York, N.Y.) 694 15831716
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
1991 The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity. The EMBO journal 536 1868826
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1996 Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity 448 8612130
2016 Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function. Cell metabolism 445 27345423
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
1991 Cathepsin B efficiently activates the soluble and the tumor cell receptor-bound form of the proenzyme urokinase-type plasminogen activator (Pro-uPA). The Journal of biological chemistry 301 1900515
1986 Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs. Proceedings of the National Academy of Sciences of the United States of America 287 3463996
2014 Cathepsin B: multiple roles in cancer. Proteomics. Clinical applications 285 24677670
2001 Characterization of the necrotic cleavage of poly(ADP-ribose) polymerase (PARP-1): implication of lysosomal proteases. Cell death and differentiation 285 11536009
1984 The place of human gamma-trace (cystatin C) amongst the cysteine proteinase inhibitors. Biochemical and biophysical research communications 282 6203523
2022 Increased glucose metabolism in TAMs fuels O-GlcNAcylation of lysosomal Cathepsin B to promote cancer metastasis and chemoresistance. Cancer cell 272 36084651
2002 In vivo imaging of proteolytic activity in atherosclerosis. Circulation 267 12057992
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
1992 The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. The Journal of biological chemistry 251 1326552
2009 Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). Journal of proteome research 237 19199708
2011 Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. Journal of immunology (Baltimore, Md. : 1950) 233 21508263
2016 Regulation of lysosomal dynamics and autophagy by CTSB/cathepsin B. Autophagy 170 27786577
2021 CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis. Theranostics 57 34815788
2023 Apigenin Alleviated High-Fat-Diet-Induced Hepatic Pyroptosis by Mitophagy-ROS-CTSB-NLRP3 Pathway in Mice and AML12 Cells. Journal of agricultural and food chemistry 55 37141464
2011 Profiling trait anxiety: transcriptome analysis reveals cathepsin B (Ctsb) as a novel candidate gene for emotionality in mice. PloS one 50 21897848
2023 CTSB promotes sepsis-induced acute kidney injury through activating mitochondrial apoptosis pathway. Frontiers in immunology 48 36713420
2019 miR-140 targeting CTSB signaling suppresses the mesenchymal transition and enhances temozolomide cytotoxicity in glioblastoma multiforme. Pharmacological research 38 31398406
1992 Confirmation of the human cathepsin B gene (CTSB) assignment to chromosome 8. Human genetics 36 1577456
2019 Autophagic-CTSB-inflammasome axis modulates hepatic stellate cells activation in arsenic-induced liver fibrosis. Chemosphere 35 31669990
2017 Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families. American journal of human genetics 28 28457472
2020 Protective Role of Astrocyte-Derived Exosomal microRNA-361 in Cerebral Ischemic-Reperfusion Injury by Regulating the AMPK/mTOR Signaling Pathway and Targeting CTSB. Neuropsychiatric disease and treatment 25 32801720
2020 Cilostazol alleviate nicotine induced cardiomyocytes hypertrophy through modulation of autophagy by CTSB/ROS/p38MAPK/JNK feedback loop. International journal of biological sciences 24 32398966
2018 mir-637 inhibits the proliferation of cholangiocarcinoma cell QBC939 through interfering CTSB expression. European review for medical and pharmacological sciences 23 29565483
2002 Investigation of candidate genes for meat quality in dry-cured ham production: the porcine cathepsin B (CTSB) and cystatin B (CSTB) genes. Animal genetics 20 12047225
2021 Significances of viable synergistic autophagy-associated cathepsin B and cathepsin D (CTSB/CTSD) as potential biomarkers for sudden cardiac death. BMC cardiovascular disorders 18 33964876
2022 Histone deacetylase 3 facilitates TNFα-mediated NF-κB activation through suppressing CTSB induced RIP1 degradation and is required for host defense against bacterial infection. Cell & bioscience 17 35658939
2021 CTSB Knockdown Inhibits Proliferation and Tumorigenesis in HL-60 Cells. International journal of medical sciences 17 33628106
2014 CTSB promotes porcine preadipocytes differentiation by degrading fibronectin and attenuating the Wnt/β-catenin signaling pathway. Molecular and cellular biochemistry 16 24878992
2023 CTSB Nuclear Translocation Facilitates DNA Damage and Lysosomal Stress to Promote Retinoblastoma Cell Death. Molecular biotechnology 13 38159170
2017 Divergent roles of three cytochrome c in CTSB-modulating coelomocyte apoptosis in Apostichopus japonicus. Developmental and comparative immunology 13 28549733
1999 Genome scanning detects amplification of the cathepsin B gene (CtsB) in transformed rat ovarian surface epithelial cells. Journal of the Society for Gynecologic Investigation 13 10065424
2024 Proanthocyanidins alleviate acute alcohol liver injury by inhibiting pyroptosis via inhibiting the ROS-MLKL-CTSB-NLRP3 pathway. Phytomedicine : international journal of phytotherapy and phytopharmacology 12 39612889
2023 Exosome-derived miR-142-5p from liver stem cells improves the progression of liver fibrosis by regulating macrophage polarization through CTSB. Environmental toxicology 11 37209404
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
2008 TCF7L2 gene polymorphisms do not predict susceptibility to diabetes in tropical calcific pancreatitis but may interact with SPINK1 and CTSB mutations in predicting diabetes. BMC medical genetics 11 18706099
1990 A TaqI DNA polymorphism in the human cathepsin B gene (CTSB). Nucleic acids research 11 1972569
2023 Integrative transcriptomic and network pharmacology analysis reveals the neuroprotective role of BYHWD through enhancing autophagy by inhibiting Ctsb in intracerebral hemorrhage mice. Chinese medicine 9 37957754
2022 CTSB+ macrophage repress memory immune hub in the liver metastasis site of colorectal cancer patient revealed by multi-omics analysis. Biochemical and biophysical research communications 9 35964553
2024 Melittin treatment suppressed malignant NSCLC progression through enhancing CTSB-mediated hyperautophagy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 8 39426282
2023 Elaidic acid induced hepatocyte pyroptosis via autophagy-CTSB-NLRP3 pathway. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 8 37748573
2017 TRAIL DR5-CTSB crosstalk participates in breast cancer autophagy initiated by SAHA. Cell death discovery 8 29018571
2024 hCeO2@ Cu5.4O nanoparticle alleviates inflammatory responses by regulating the CTSB-NLRP3 signaling pathway. Frontiers in immunology 7 38711511
2024 MiR-223 enhances lipophagy by suppressing CTSB in microglia following lysolecithin-induced demyelination in mice. Lipids in health and disease 7 38909243
2023 Circ_0020014 mediates CTSB expression and participates in IL-1β-prompted chondrocyte injury via interacting with miR-24-3p. Journal of orthopaedic surgery and research 7 37980493
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
2024 Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D. Annals of clinical and translational neurology 6 38837642
2023 Dapagliflozin Attenuates NLRP3/Caspase-1 Signaling Pathway-Mediated Pyroptosis of Vascular Smooth Muscle Cells by Downregulating CTSB. Alternative therapies in health and medicine 6 37384401
2023 Correlation Analysis of CTSB Promoter Polymorphism and Function in Patients with Dilated Cardiomyopathy. DNA and cell biology 5 36976816
2020 Mechanism of action of Panax notoginoside against lung cancer in mice based on response to CTSB gene. BMC complementary medicine and therapies 5 33238959
2011 Exclusion of CTSB and FDFT1 as positional and functional candidate genes for keratolytic winter erythema (KWE). Journal of dermatological science 5 21945151
2024 Shikonin from lithospermum erythrorhizon induces pyroptosis in trophoblast cells by activating the CTSB-NLRP3 inflammasome. Annals of medicine 4 39183455
2022 Coprophagy Prevention Decreases the Reproductive Performance and Granulosa Cell Apoptosis via Regulation of CTSB Gene in Rabbits. Frontiers in physiology 4 35923240
2022 Association of AXIN1 rs12921862 C/A and rs1805105 G/A and CTSB rs12898 G/A polymorphisms with papillary thyroid carcinoma: A case-control study. Journal of clinical laboratory analysis 4 36510340
2025 hCeO2@CA-074Me Nanoparticles Alleviate Inflammation and Improve Osteogenic Microenvironment by Regulating the CTSB-NLRP3 Signaling Pathway. International journal of nanomedicine 3 39802379
2025 The molecular mechanism by which CTSB degrades FPN to disrupt macrophage iron homeostasis and promote the progression of atherosclerosis. Molecular and cellular biochemistry 3 39960586
2024 3-Monochloropropane-1,2-diol esters induce HepG2 cells necroptosis via CTSB/TFAM/ROS pathway. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 3 38408632
2020 Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B. Clinical and experimental dermatology 3 32683719
2019 A single nucleotide polymorphism CTSB rs12898 is associated with primary hepatic cancer in a Chinese population. International journal of clinical and experimental pathology 3 31934146
2025 The SGLT2 inhibitor dapagliflozin suppresses endothelial cell pyroptosis mediated by the NF-κB/NLRP3 pathway through downregulation of CTSB. Biochemical pharmacology 2 40058708
2025 ETS1 promotes the expression of Ctsb and Mmp13 during the differentiation of septoclasts from pericytes. Cell and tissue research 2 40387924
2024 Danggui-Shaoyao-San protects against non-alcoholic steatohepatitis via modulation of hepatic APP protein, Lysosomal CTSB release, and NF-κB activation. Heliyon 2 39114010
2025 Transition of CELF2 PAS usage promotes recovery of refractory JDM through alternative splicing regulation of CTSB. Molecular therapy. Nucleic acids 1 40686855
2026 Nuciferine Prevents Obesity by Inhibiting Macrophage Inflammation Involving LGALS3, CTSB, and RBP4 Genes Based on an Integrative Analysis of Adipose Tissue Transcriptomics and Network Pharmacology. Current pharmaceutical design 0 41574531
2026 Integrative multi-omics implicates a CTSB/ITIH-ECM axis in autism spectrum disorder. Neurobiology of disease 0 42019823
2025 hCeO2@CA-074Me Nanoparticles Alleviate Inflammation and Improve Osteogenic Microenvironment by Regulating the CTSB-NLRP3 Signaling Pathway [Retraction]. International journal of nanomedicine 0 40027871
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
2025 Blood transcriptome analysis reveals CTSB and ATP6V0D1 expression in circulating monocytes as potential biomarkers of sepsis. Shock (Augusta, Ga.) 0 40961380
2025 Multi-omics genetic study revealing ferroptosis regulator CTSB driving prostate cancer progression by modulating the immune microenvironment. Naunyn-Schmiedeberg's archives of pharmacology 0 41020944
2025 MINPP1 promotes ferroptosis in HBV-related hepatocellular carcinoma by regulating CTSB K33-linked deubiquitination via ZRANB1. Biology direct 0 41035046
2025 Multi-omics analysis of ketogenic diet-mediated neural repair in spinal cord injury: Targeting of lysosomal autophagy through CTSB/LAMP2 regulation. The Journal of nutritional biochemistry 0 41115614
2025 CTSB mediates oxidative stress and intestinal epithelial barrier disruption in intestinal ischemia‑reperfusion injury. Molecular medicine reports 0 41235676
2025 Banxia Houpo Decoction reduces lysosomal leakage of prefrontal astrocytes through the OGT-CTSB-NLRP3 pathway to improve depressive-like behaviors. Journal of ethnopharmacology 0 41391522
2025 METTL3 promotes chondrocyte injury in osteoarthritis by increasing CTSB expression. Journal of orthopaedic surgery and research 0 41466292
2022 Protective Role of Astrocyte-Derived Exosomal microRNA-361 in Cerebral Ischemic-Reperfusion Injury by Regulating the AMPK/mTOR Signaling Pathway and Targeting CTSB [Retraction]. Neuropsychiatric disease and treatment 0 36353467