Affinage

CTSD

Cathepsin D · UniProt P07339

Round 2 corrected
Length
412 aa
Mass
44.6 kDa
Annotated
2026-04-28
77 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Cathepsin D (CTSD) is a lysosomal aspartic endoprotease that serves as a principal effector of lysosomal proteolysis, with critical roles in autophagic flux, regulated cell death, and substrate-specific cleavage events across multiple tissues. After mannose-6-phosphate receptor-mediated lysosomal targeting and maturation—controlled by N-glycosylation (notably at N263, via DDOST/STT3B), O-GlcNAcylation, and S-sulfhydration of the pro-form—mature CTSD degrades substrates including α-synuclein, prolactin (generating an antiangiogenic 16 kDa fragment that causes postpartum cardiomyopathy), HSP90α (suppressing β-catenin-driven cardiac hypertrophy), and ACADM (modulating ferroptosis) (PMID:3927292, PMID:35287553, PMID:17289576, PMID:39716927, PMID:39779966). Upon lysosomal membrane permeabilization, cytosolic CTSD—activated by ceramide via acid sphingomyelinase—triggers Bax-dependent, caspase-independent apoptosis through mitochondrial AIF release (PMID:10508159, PMID:12782632). Loss-of-function mutations in CTSD cause the lysosomal storage disorder CLN10 (neuronal ceroid lipofuscinosis), and enzyme replacement with recombinant pro-CTSD corrects lysosomal storage and autophagic dysfunction in CLN10 models (PMID:16386934, PMID:31282275).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1985 High

    Cloning and sequencing of human CTSD established it as an aspartyl protease with a pre-pro-mature domain architecture conserved with other members of the pepsin family, providing the molecular identity needed for all subsequent mechanistic work.

    Evidence cDNA cloning from hepatoma library with full-length sequencing and homology analysis

    PMID:3927292

    Open questions at the time
    • No enzymatic characterization of recombinant protein in this study
    • Cellular substrates unknown
    • Post-translational processing intermediates not resolved
  2. 1990 High

    Detection of enzymatically active CTSD in extracellular senile plaques of Alzheimer disease brains provided the first evidence that CTSD functions outside the lysosomal lumen in a disease context, raising the question of how it reaches extracellular compartments.

    Evidence Immunohistochemistry and in situ enzyme histochemistry with synthetic peptide substrates on AD brain tissue

    PMID:1692625

    Open questions at the time
    • No direct demonstration that CTSD cleaves amyloid precursor protein or Aβ
    • Mechanism of CTSD externalization not determined
    • Causal role versus bystander in plaque formation unresolved
  3. 1999 High

    The discovery that ceramide generated by acid sphingomyelinase directly binds and activates pro-CTSD autocatalytic processing revealed a lipid-based activation mechanism linking sphingolipid signaling to lysosomal protease activity in apoptotic pathways.

    Evidence Direct ceramide-CTSD binding assay, in vitro autocatalytic cleavage reconstitution, A-SMase knockout and rescue

    PMID:10508159

    Open questions at the time
    • Binding site on CTSD not mapped
    • In vivo significance of ceramide-CTSD axis in non-immune cells not tested
    • Structural basis for ceramide-induced autoactivation unknown
  4. 2003 High

    Demonstration that cytosolic CTSD (released from permeabilized lysosomes) activates Bax in a Bid-independent manner to trigger mitochondrial AIF release established CTSD as a proximal executor of caspase-independent apoptosis, resolving how lysosomal proteases intersect mitochondrial death pathways.

    Evidence siRNA knockdown and pepstatin A inhibition in human T lymphocytes with subcellular fractionation and epistasis analysis

    PMID:12782632

    Open questions at the time
    • Direct CTSD-Bax interaction not biochemically demonstrated
    • Whether CTSD cleaves Bax or acts via an intermediate is unresolved
    • Generalizability beyond T lymphocytes not shown in this study
  5. 2005 High

    Showing that a catalytically inactive CTSD mutant retains mitogenic activity in breast cancer cells revealed a protease-independent extracellular function, separating CTSD's intracellular pro-apoptotic role from a receptor-mediated proliferative role in the tumor microenvironment.

    Evidence Active-site mutagenesis, tumor xenografts, and proliferation assays across cancer, endothelial, and fibroblast cell types

    PMID:16046058

    Open questions at the time
    • The putative cell-surface receptor for secreted CTSD remains unidentified
    • Structural determinants of protease-independent signaling not mapped
    • In vivo relevance of proteolytic versus non-proteolytic functions not separated
  6. 2006 High

    Identification of a CTSD missense mutation (Met199Ile) causing neuronal ceroid lipofuscinosis (CLN10) with ~36% residual enzyme activity directly linked partial CTSD loss-of-function to lysosomal storage neurodegeneration, defining CTSD as the CLN10 disease gene.

    Evidence Genetic linkage, mutation sequencing, and cathepsin D enzyme activity assays in American Bulldog brain tissue

    PMID:16386934

    Open questions at the time
    • Human CLN10-causing mutations not characterized in this study
    • Threshold of CTSD activity required for neuronal survival not defined
    • Specific substrates whose failure to degrade causes NCL pathology not identified
  7. 2007 High

    The discovery that cardiac CTSD cleaves prolactin to generate a 16 kDa antiangiogenic fragment that drives postpartum cardiomyopathy identified a specific pathophysiological substrate and established CTSD as a key mediator of PPCM downstream of STAT3 loss.

    Evidence Cardiomyocyte-specific STAT3 KO mice, forced 16 kDa prolactin overexpression, bromocriptine rescue, and human patient serum analysis

    PMID:17289576

    Open questions at the time
    • Precise cleavage site on prolactin not mapped
    • Whether other cardiac proteases contribute to 16 kDa prolactin generation not excluded
    • Long-term efficacy of bromocriptine in human PPCM not established here
  8. 2008 Medium

    Mapping the ERα-dependent distal enhancer ~9 kb upstream of CTSD with chromatin looping to the promoter explained how estrogen drives CTSD overexpression in breast cancer, connecting transcriptional regulation to the known CTSD overexpression phenotype.

    Evidence ChIP, chromosome conformation capture, and bisulfite methylation analysis in MCF-7 cells

    PMID:19383337

    Open questions at the time
    • No genetic deletion of the enhancer to confirm necessity
    • Contribution of this enhancer relative to other regulatory elements not quantified
    • Looping mechanism not confirmed in non-breast cancer cell types
  9. 2019 High

    Successful enzyme replacement therapy with recombinant pro-CTSD in CLN10 mouse models—showing M6PR-dependent uptake, lysosomal maturation, and correction of storage pathology and autophagic flux—provided proof-of-concept that exogenous CTSD can functionally replace the endogenous enzyme in vivo.

    Evidence Recombinant pro-CTSD uptake/processing assays, systemic and intracranial ERT in CTSD-deficient mice with histopathology and lifespan analysis

    PMID:31282275

    Open questions at the time
    • Blood-brain barrier penetrance of systemic ERT limited
    • Long-term dosing and immunogenicity not fully assessed
    • Whether ERT fully rescues neurological phenotype unclear
  10. 2020 High

    Convergent studies established that CTSD is essential for autophagic flux and neuronal survival: CTSD knockdown causes lysosomal dysfunction and sensitivity to ischemic injury, while CTSD inhibition blocks autophagosome-lysosome fusion in glioblastoma cells, positioning CTSD as rate-limiting for late-stage autophagy.

    Evidence shRNA knockdown and lentiviral rescue in neurons with OGD/MCAO models; siRNA and pepstatin A in glioblastoma with LC3/p62 quantification

    PMID:32253787 PMID:32450052

    Open questions at the time
    • Molecular mechanism by which CTSD promotes autophagosome-lysosome fusion not identified
    • Whether CTSD acts on fusion machinery directly or via substrate clearance is unknown
    • Cell-type specificity of CTSD dependence in autophagy not systematically tested
  11. 2020 High

    Glycosylation at N233 in insect CTSD was shown to determine whether pro-CTSD is secreted (glycosylated) or retained intracellularly for autophagy-dependent maturation and caspase-3 activation, revealing a glycosylation-dependent sorting switch that governs the dual extracellular/intracellular functions of CTSD.

    Evidence Site-directed mutagenesis of N233, autophagy gene RNAi epistasis, and PNGase F treatment in Helicoverpa armigera midgut cells

    PMID:32324083

    Open questions at the time
    • Conservation of N233 glycosylation sorting switch in mammalian CTSD not demonstrated
    • Whether this mechanism operates in human cancer secretion of CTSD untested
    • Receptor for extracellular insect CTSD not identified
  12. 2022 High

    Recombinant CTSD treatment of iPSC-derived dopaminergic neurons from Parkinson disease patients (SNCA A53T) and CTSD-deficient mouse neurons reduced insoluble α-synuclein and restored endo-lysosomal function, establishing CTSD as the major lysosomal protease responsible for α-synuclein degradation.

    Evidence rHsCTSD uptake and maturation assays in iPSC-derived neurons and ctsd-KO mouse neurons with SNCA solubility fractionation and autophagy flux measurement

    PMID:35287553

    Open questions at the time
    • Cleavage sites on α-synuclein not mapped
    • Whether CTSD can clear established Lewy body-like inclusions in vivo unknown
    • Contribution of other lysosomal proteases (e.g., cathepsin B/L) to α-synuclein clearance not excluded
  13. 2023 Medium

    Identification of O-GlcNAcylation as a post-translational modification required for CTSD maturation added a new regulatory layer, showing that perturbation of O-GlcNAc cycling (as by swainsonine) impairs conversion of pro-CTSD to mature active enzyme and consequently disrupts autophagy.

    Evidence Immunoprecipitation of O-GlcNAcylated CTSD, OGA/OGT inhibitor treatment, autophagy flux assays

    PMID:37442287

    Open questions at the time
    • Specific O-GlcNAcylation sites on CTSD not mapped
    • Whether O-GlcNAcylation affects CTSD folding, trafficking, or catalytic competence is unresolved
    • Single lab finding; independent confirmation needed
  14. 2024 Medium

    N-glycosylation at N263 by the DDOST/STT3B complex was shown to be required for CTSD protease activity, and glycosylated CTSD cleaves ACADM to modulate ferroptosis-related proteins (ACSL4, SLC7A11, GPX4), linking CTSD to ferroptosis regulation and colorectal cancer liver metastasis.

    Evidence N-glycoproteomics of matched CRC tissues, site-directed mutagenesis of N263, ACADM cleavage assays, ferroptosis marker analysis

    PMID:39716927

    Open questions at the time
    • Direct in vitro cleavage of ACADM by purified CTSD not demonstrated
    • How ACADM degradation mechanistically alters GPX4/SLC7A11 levels unclear
    • Whether N263 glycosylation is rate-limiting in non-cancer contexts unknown
  15. 2024 Medium

    Studies in Dictyostelium revealed that CTSD extracellular release depends on autophagy machinery (Atg1/Atg5), lysosomal exocytosis components (AP-3, LYST, mucolipin-1, WASH), and microfilaments, and that CLN5 protein secretion is regulated by extracellular CTSD levels, defining a trafficking pathway and functional link between two NCL disease proteins.

    Evidence Genetic KO of autophagy and trafficking genes in Dictyostelium, secretion assays, glycosylation analysis, Cln5-CtsD epistasis

    PMID:38272448

    Open questions at the time
    • Conservation of this secretory pathway in mammalian cells not confirmed
    • Molecular basis of Cln5-CtsD regulatory interaction not defined
    • Whether WASH complex role is direct or indirect unclear
  16. 2025 Medium

    Multiple studies expanded CTSD's mechanistic landscape: LRP6 facilitates CTSD-mediated HSP90α degradation to suppress β-catenin-driven cardiac hypertrophy; S-sulfhydration of pro-CTSD inhibits its maturation and downstream PANoptosis in traumatic brain injury; CTSD is positioned downstream of mTOR-MITF signaling for macrophage lysosomal homeostasis; and secreted glycosylated CTSD (regulated by KIF13B/STT3A) drives hepatocyte lipid accumulation via THBS1 interaction in MASLD.

    Evidence LRP6 co-IP/MS and cardiomyocyte-specific overexpression with TAC model; modified biotin switch for S-sulfhydration with AAV-shSnapin; myeloid SAMHD1 KO with rapamycin rescue; myeloid Kif13b KO with MASLD model

    PMID:39779966 PMID:40886983 PMID:41558604 PMID:41746601

    Open questions at the time
    • Direct in vitro cleavage of HSP90α by CTSD not shown
    • Specific cysteine residue(s) S-sulfhydrated on pro-CTSD not identified by mutagenesis
    • CTSD-THBS1 interaction interface not characterized
    • Each finding from a single laboratory

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity of the cell-surface receptor mediating protease-independent CTSD mitogenic signaling in cancer; the structural basis for ceramide-induced CTSD autoactivation; the precise mechanism by which cytosolic CTSD activates Bax; and whether CTSD-generated truncated α-synuclein species drive Parkinson disease pathology in vivo.
  • Putative CTSD cell-surface receptor unidentified after 20 years
  • No crystal structure of ceramide-bound CTSD
  • In vivo validation of astrocyte-to-neuron α-synuclein seeding via CTSD cleavage pending

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 6
Localization
GO:0005764 lysosome 8 GO:0005576 extracellular region 4 GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 7 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4
Partners
ACADMASAH1BAXCLN5HSP90AA1LRP6SNCATHBS1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 Human cathepsin D (CTSD) was cloned and sequenced from a hepatoma cDNA library. The cDNA predicts a 412-amino acid protein with a 20-aa pre-segment and 44-aa prosegment; the mature protein shows high sequence homology to other aspartyl proteases, establishing CTSD as a member of the aspartyl protease family with a conserved three-dimensional structure. cDNA cloning, nucleotide sequencing, amino acid sequence analysis Proceedings of the National Academy of Sciences of the United States of America High 3927292
1990 Enzymatically active cathepsin D (and cathepsin B) localizes to senile plaques in Alzheimer disease brains, accumulating in extracellular lysosomal dense bodies and lipofuscin granules derived from degenerating neurons, implicating CTSD as a candidate protease for amyloid precursor protein processing in plaques. Immunohistochemistry with anti-cathepsin D antisera, in situ enzyme histochemistry with synthetic peptide substrates, ultrastructural immunolocalization Proceedings of the National Academy of Sciences of the United States of America High 1692625
1999 Ceramide generated by acid sphingomyelinase directly binds to and activates cathepsin D, triggering autocatalytic proteolysis of the 52 kDa pre-pro-CTSD to produce enzymatically active 48/32 kDa isoforms. Acid sphingomyelinase-deficient cells have decreased CTSD activity, restored by A-SMase transfection, identifying CTSD as a ceramide target in endosomal apoptotic signaling. Direct ceramide-CTSD binding assay, in vitro autocatalytic cleavage assay, A-SMase knockout and reconstitution, biochemical fractionation The EMBO journal High 10508159
2003 In activated human T lymphocytes, cathepsin D (CTSD) translocates from lysosomes to the cytosol upon apoptotic stimulation and triggers Bax conformational change and relocation to mitochondria in a Bid-independent manner, leading to selective AIF release and early caspase-independent apoptosis. Pepstatin A and siRNA-mediated CTSD silencing inhibited these events, placing CTSD upstream of Bax in this pathway. Pepstatin A inhibitor treatment, siRNA knockdown of CTSD/Bax/AIF, subcellular fractionation, immunofluorescence localization, cell death assays The Journal of biological chemistry High 12782632
2005 CTSD (cath-D) is overexpressed and hypersecretated by breast cancer cells, stimulating tumorigenicity, metastasis, cancer cell proliferation, fibroblast outgrowth, and angiogenesis. A catalytically inactive mutant cath-D retains mitogenic activity for cancer, endothelial, and fibroblastic cells, indicating an extracellular mode of action involving an unidentified cell-surface receptor. During apoptosis, mature lysosomal CTSD translocates to the cytosol and its proteolytic activity participates in the apoptotic cascade. Catalytic-site mutagenesis, overexpression, tumor xenograft models, cell proliferation assays, apoptosis assays Cancer letters High 16046058
2006 A CTSD gene mutation (G to A, Met199Ile) in American Bulldogs causes neuronal ceroid lipofuscinosis (NCL) with ~36% residual cathepsin D enzymatic activity compared to controls, while 15 other lysosomal enzyme activities were unchanged or increased. This directly established that partial loss of CTSD catalytic activity is sufficient to cause NCL-like neurodegeneration. Genetic linkage analysis, mutation identification, cathepsin D enzyme activity assay in brain tissue, electron microscopy of storage material Molecular genetics and metabolism High 16386934
2007 Cardiac cathepsin D cleaves prolactin at its N-terminus to generate an antiangiogenic and proapoptotic 16 kDa fragment that mediates postpartum cardiomyopathy (PPCM). STAT3 deletion in cardiomyocytes enhanced cardiac CTSD expression and activity; forced cardiac generation of 16 kDa prolactin impaired the cardiac capillary network and recapitulated PPCM. Bromocriptine (prolactin secretion inhibitor) prevented PPCM. Cardiomyocyte-specific STAT3 knockout mice, CTSD activity assays, forced cardiac overexpression of 16 kDa prolactin, bromocriptine treatment, cardiac function assessment, patient serum analysis Cell High 17289576
2008 Estrogen receptor alpha (ERα) activates CTSD expression through a distal enhancer element located ~9 kbp upstream of the CTSD transcription start site. ChIP experiments showed estrogen-dependent recruitment of ERα and phosphorylated RNA Pol II to this enhancer, with chromatin looping connecting the distal enhancer to the CTSD promoter. Transient CpG methylation at both the promoter and the distal enhancer was observed during estrogen stimulation. Chromatin immunoprecipitation (ChIP), chromosome conformation capture (looping assay), bisulfite methylation analysis, reporter assays in MCF-7 cells Molecular oncology Medium 19383337
2019 Recombinant human pro-CTSD produced in a mammalian system is efficiently endocytosed via mannose-6-phosphate receptors, trafficked to lysosomes, and processed to the mature active form. In CTSD-deficient mouse models of CLN10 disease, systemic and intracranial administration of rhCTSD corrects lysosomal hypertrophy, storage accumulation, and impaired autophagic flux in viscera and CNS, establishing enzyme replacement as feasible for this lysosomal storage disorder. Recombinant protein uptake assays, lysosomal targeting/processing assays, CLN10 mouse model ERT, autophagic flux measurement, histopathology, lifespan analysis Autophagy High 31282275
2020 In Helicoverpa armigera (lepidopteran model), autophagy triggers CTSD maturation and relocalization inside midgut cells, where mature CTSD activates caspase-3 and promotes apoptosis. Glycosylation at asparagine-233 determines pro-CTSD secretion rather than intracellular retention. Steroid hormone 20-hydroxyecdysone (20E) promotes CTSD expression. This establishes that differential glycosylation and autophagy-regulated maturation control the dual pro-proliferative (extracellular) versus pro-apoptotic (intracellular) functions of CTSD. RNAi knockdown of autophagy genes, site-directed mutagenesis of N233, glycosylation analysis (PNGase F treatment), caspase-3 activity assays, immunofluorescence, hormone treatment experiments Autophagy High 32324083
2020 CTSD knockdown in neurons causes lysosomal dysfunction. Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity and renders neurons resistant to oxygen-glucose deprivation (OGD)-mediated lysosomal dysfunction and cell death in a stroke model, demonstrating that CTSD-dependent lysosomal proteolytic activity is required for neuronal survival during ischemia. shRNA-mediated CTSD knockdown, lentiviral CTSD overexpression, OGD neuronal model, MCAO stroke model, lysosomal function assays, cell death assays Autophagy High 32450052
2020 CTSD inhibition in radioresistant glioblastoma cells blocks autophagosome-lysosome fusion, increasing autophagosome accumulation while decreasing autolysosome formation, and sensitizes cells to ionizing radiation. CTSD protein levels positively correlate with the autophagy marker LC3-II/I and negatively with p62, positioning CTSD as a regulator of autophagic flux at the autophagosome-lysosome fusion step. siRNA knockdown, pepstatin A inhibition, Western blot for LC3 and p62, immunofluorescence for autophagosome/autolysosome quantification, clonogenic survival assay after irradiation Molecular carcinogenesis Medium 32253787
2022 Recombinant human pro-CTSD (rHsCTSD) is endocytosed by neuronal cells, delivered to lysosomes, and matured into active protease. In iPSC-derived dopaminergic neurons from Parkinson disease patients (SNCA A53T mutation) and in ctsd-deficient mouse neurons, rHsCTSD treatment reduces insoluble SNCA/α-synuclein conformers and restores endo-lysosome and autophagy function, establishing CTSD as the major lysosomal protease responsible for SNCA degradation. Recombinant protein uptake and maturation assays, iPSC-derived dopaminergic neurons, ctsd-KO mouse primary neurons, SNCA solubility fractionation, autophagy flux assays Autophagy High 35287553
2023 Swainsonine toxin reduces O-GlcNAcylation of CTSD, which impairs its maturation to the active form (m-CTSD). Increasing O-GlcNAcylation (with OGA inhibitor TMG) promotes autophagy, while decreasing it (with OGT inhibitor OSMI) inhibits autophagy. Immunoprecipitation confirmed direct O-GlcNAcylation of CTSD, establishing O-GlcNAcylation as a post-translational modification required for proper CTSD maturation and lysosomal function. Proteomics sequencing, immunoprecipitation of O-GlcNAcylated CTSD, OGA/OGT inhibitor treatment, autophagy flux assays, Western blot for mature/pro-CTSD forms Chemico-biological interactions Medium 37442287
2024 N-glycosylation at residue N263 of CTSD, mediated by the glycosyltransferase complex DDOST/STT3B, is required for CTSD protease activity. Glycosylated CTSD lyses ACADM, which in turn regulates ferroptosis-related proteins (ACSL4, SLC7A11, GPX4) to promote invasion and liver metastasis of colorectal cancer cells. N-glycoproteomics of matched primary and metastatic CRC tissues, site-specific glycosylation mutagenesis, ACADM cleavage assays, ferroptosis marker analysis, invasion/metastasis assays Advanced science Medium 39716927
2024 CLN5 (Cln5) and CTSD (CtsD) are both released extracellularly via signal peptide-dependent secretion and autophagy-linked pathways in Dictyostelium discoideum. CtsD release requires autophagy proteins Atg1 and Atg5, lysosomal exocytosis machinery (AP-3, LYST, mucopilin-1, WASH), and microfilaments. Extracellular CtsD is glycosylated, and Cln5 release is regulated by the amount of extracellular CtsD, identifying a regulatory relationship between these two CLN disease proteins. Dictyostelium genetic KO models for autophagy and trafficking genes, secretion assays, glycosylation analysis, epistasis experiments between Cln5 and CtsD Traffic Medium 38272448
2025 LRP6 interacts with HSP90α and CTSD in cardiomyocytes under mechanical stress (identified by mass spectrometry co-IP). LRP6 facilitates CTSD-mediated degradation of HSP90α, which suppresses β-catenin activation and reduces cardiac hypertrophy after pressure overload. Treatment with pepstatin A (CTSD inhibitor) or recombinant HSP90α abolished the cardioprotective effect of LRP6, placing CTSD in the LRP6/HSP90α/β-catenin axis. Mass spectrometry after LRP6 co-immunoprecipitation, cardiomyocyte-specific LRP6 overexpression mice, transverse aortic constriction model, pepstatin A treatment, HSP90α recombinant protein rescue, echocardiography Acta pharmacologica Sinica Medium 39779966
2025 SAMHD1 deficiency in macrophages enhances MITF nuclear translocation, which suppresses CTSD expression downstream of mTOR signaling, impairing lysosomal autophagy flux and promoting inflammation in ulcerative colitis. Pharmacological mTOR inhibition (rapamycin) restores MITF-CTSD signaling and lysosomal function, placing CTSD downstream of the mTOR-MITF axis in macrophage lysosomal homeostasis. Myeloid-specific SAMHD1 knockout mice, scRNA-seq, MITF nuclear translocation assays, CTSD expression analysis, lysosomal flux assays, rapamycin treatment, colitis model International journal of biological macromolecules Medium 40886983
2025 In mTBI, Snapin binds CBS, disrupting H2S metabolic homeostasis. Reduced H2S limits S-sulfhydration of pro-CTSD at a specific cysteine residue, promoting its maturation into active CTSD and inducing PANoptosis. Pepstatin A (CTSD inhibitor) and NaHS (H2S donor) both confer neuroprotection, establishing S-sulfhydration of pro-CTSD as a regulatory PTM controlling its maturation and downstream apoptotic/pyroptotic/necroptotic signaling. Conditional Snapin knockdown (AAV-shSnapin), modified biotin switch assay for S-sulfhydration, co-immunoprecipitation of Snapin-CBS, H2S measurement with ion-selective electrode, pepstatin A and NaHS treatment, PANoptosis protein analysis, behavioral tests Journal of advanced research Medium 41558604
2026 KIF13B in macrophages controls proteasome-dependent degradation of the glycosyltransferase STT3A. Kif13b deficiency allows STT3A accumulation, which enhances CTSD glycosylation and secretion, promoting lipid accumulation and inflammation in the liver during MASLD. Secreted CTSD exerts its detrimental effect through interaction with the hepatocyte membrane protein THBS1, defining the KIF13B/STT3A/CTSD/THBS1 axis in macrophage-hepatocyte crosstalk. Myeloid Kif13b knockout mice, diet-induced MASLD model, CTSD glycosylation assays, CTSD secretion measurement, CTSD-THBS1 interaction studies, proteasome activity assays Hepatology Medium 41746601
2025 Astrocytic cathepsin D (CtsD) cleaves α-synuclein pre-formed fibrils into C-terminally truncated, seeding-competent species within lysosomes. These truncated species are transferred to neurons where they promote Lewy neurite-like aggregate growth. α-Syn PFF exposure disrupts lysosomal membrane integrity in astrocytes and upregulates CtsD, creating a feed-forward amplification of α-syn pathogenicity. Neuron-astrocyte co-culture, α-syn PFF treatment, CtsD inhibition/KO in astrocytes, mass spectrometry characterization of cleaved α-syn species, seeding assays in neurons, lysosomal membrane integrity assays bioRxivpreprint Medium bio_10.1101_2025.10.03.680233
2025 Deletion of CtsD in mice dramatically decreases bone mass with reduced osteoblast numbers and increased osteoclast numbers. In osteoblasts, CtsD inactivation attenuates differentiation and downregulates LC3B with decreased p62, p-Akt, and p-GSK3β. In osteoclasts, CtsD inactivation increases differentiation with decreased LC3B but elevated p62, demonstrating that CtsD-mediated autophagy plays opposing roles in osteoblasts versus osteoclasts to regulate bone homeostasis. CtsD conditional knockout mice, microCT bone analysis, histomorphometry, siRNA knockdown in MC3T3E1 and RAW264.7 cells, LC3B/p62/Akt/GSK3β Western blot, osteoblast and osteoclast differentiation assays bioRxivpreprint Medium bio_10.1101_2025.04.09.645406

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
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
2012 A census of human soluble protein complexes. Cell 689 22939629
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
2007 A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 645 17289576
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
1990 Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proceedings of the National Academy of Sciences of the United States of America 409 1692625
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2004 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. The Biochemical journal 372 14744259
2003 Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. The Journal of biological chemistry 354 12782632
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
2000 BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proceedings of the National Academy of Sciences of the United States of America 340 10931940
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1985 Cloning and sequence analysis of cDNA for human cathepsin D. Proceedings of the National Academy of Sciences of the United States of America 337 3927292
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1999 Cathepsin D targeted by acid sphingomyelinase-derived ceramide. The EMBO journal 294 10508159
2017 KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 270 28199306
2005 Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. Cancer letters 265 16046058
2000 Tyrosine phosphorylation of CpsD negatively regulates capsular polysaccharide biosynthesis in streptococcus pneumoniae. Molecular microbiology 177 10760144
2020 Autophagy triggers CTSD (cathepsin D) maturation and localization inside cells to promote apoptosis. Autophagy 124 32324083
2003 Positive correlation between tyrosine phosphorylation of CpsD and capsular polysaccharide production in Streptococcus pneumoniae. Journal of bacteriology 116 14526017
2004 The effect that mutations in the conserved capsular polysaccharide biosynthesis genes cpsA, cpsB, and cpsD have on virulence of Streptococcus pneumoniae. The Journal of infectious diseases 105 15122528
1993 Identification of cpsD, a gene essential for type III capsule expression in group B streptococci. Molecular microbiology 105 8355611
2006 A mutation in the cathepsin D gene (CTSD) in American Bulldogs with neuronal ceroid lipofuscinosis. Molecular genetics and metabolism 104 16386934
2020 Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective. Autophagy 101 32450052
2019 Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis. Autophagy 82 31282275
2003 Mutational analysis of the carboxy-terminal (YGX)4 repeat domain of CpsD, an autophosphorylating tyrosine kinase required for capsule biosynthesis in Streptococcus pneumoniae. Journal of bacteriology 70 12730159
2022 Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models. Autophagy 63 35287553
2008 Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta neuropathologica 55 18762956
2015 Autophosphorylation of the Bacterial Tyrosine-Kinase CpsD Connects Capsule Synthesis with the Cell Cycle in Streptococcus pneumoniae. PLoS genetics 52 26378458
2020 Inhibition of Cathepsin D (CTSD) enhances radiosensitivity of glioblastoma cells by attenuating autophagy. Molecular carcinogenesis 44 32253787
2023 TMT-based quantitative proteomics revealed protective efficacy of Icariside II against airway inflammation and remodeling via inhibiting LAMP2, CTSD and CTSS expression in OVA-induced chronic asthma mice. Phytomedicine : international journal of phytotherapy and phytopharmacology 43 37451150
2008 E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements. Molecular oncology 36 19383337
1999 Analysis of the 5' portion of the type 19A capsule locus identifies two classes of cpsC, cpsD, and cpsE genes in Streptococcus pneumoniae. Journal of bacteriology 34 10348877
2010 The insulin-like growth factor 2 (IGF2) gene intron3-g.3072G>A polymorphism is not the only Sus scrofa chromosome 2p mutation affecting meat production and carcass traits in pigs: evidence from the effects of a cathepsin D (CTSD) gene polymorphism. Journal of animal science 30 20382874
2006 Interaction of CTSD and A2M polymorphisms in the risk for Alzheimer's disease. Journal of the neurological sciences 29 16784755
2001 No evidence for genetic association or linkage of the cathepsin D (CTSD) exon 2 polymorphism and Alzheimer disease. Annals of neurology 27 11198280
2007 Rapid detection and identification of the bacterium Pantoea stewartii in maize by TaqMan real-time PCR assay targeting the cpsD gene. Journal of applied microbiology 24 18179542
2019 Anxa2- and Ctsd-knockout CHO cell lines to diminish the risk of contamination with host cell proteins. Biotechnology progress 23 30972970
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
2020 Antiproliferative and Antimetastatic Effects of Praeruptorin C on Human Non-Small Cell Lung Cancer Through Inactivating ERK/CTSD Signalling Pathways. Molecules (Basel, Switzerland) 18 32244796
2006 Isolation, activity and immunological characterisation of a secreted aspartic protease, CtsD, from Aspergillus fumigatus. Protein expression and purification 16 17275325
2016 Txn1, Ctsd and Cdk4 are key proteins of combination therapy with taurine, epigallocatechin gallate and genistein against liver fibrosis in rats. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 27894668
2023 Swainsonine inhibits autophagic degradation and causes cytotoxicity by reducing CTSD O-GlcNAcylation. Chemico-biological interactions 14 37442287
2017 Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder. Neuropediatrics 14 29284168
2021 Rapid and Progressive Loss of Multiple Retinal Cell Types in Cathepsin D-Deficient Mice-An Animal Model of CLN10 Disease. Cells 13 33800998
2024 N-glycosylation Modification of CTSD Affects Liver Metastases in Colorectal Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 39716927
2024 Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD. Traffic (Copenhagen, Denmark) 8 38272448
2023 TUNEL-positive structures in activated microglia and SQSTM1/p62-positive structures in activated astrocytes in the neurodegenerative brain of a CLN10 mouse model. Glia 5 37571859
2008 Sequence identification, tissue distribution and polymorphism of the porcine cathepsin D (CTSD) gene. Animal biotechnology 5 18607787
2023 Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 37249374
2025 Low-density lipoprotein receptor-related protein 6 ameliorates cardiac hypertrophy by regulating CTSD/HSP90α signaling during pressure overload. Acta pharmacologica Sinica 3 39779966
2025 Plastic additive bisphenol S induces depression by promoting AZU1/CTSD proteins to mediate plasma-related proteins and metabolites: A comprehensive multi-omics analysis. Ecotoxicology and environmental safety 3 40694910
2025 SAMHD1 deficiency disrupts macrophage autophagy-lysosomal homeostasis and promotes inflammation via the mTOR-MITF-CTSD axis in ulcerative colitis. International journal of biological macromolecules 3 40886983
2021 Prenatal-onset of congenital neuronal ceroid lipofuscinosis with a novel CTSD mutation. Birth defects research 3 34491000
2024 Studies on the Role of MAP4K2, SPI1, and CTSD in Osteoporosis. Cell biochemistry and biophysics 2 39586961
2021 The c.863A>G (p.Glu288Gly) variant of the CTSD gene is not associated with CLN10 disease. Molecular genetics & genomic medicine 2 34331747
2024 CTSD upregulation as a key driver of spinal ligament abnormalities in spinal stenosis. Bone 1 38917962
2020 Clinical Prescription-Protein-Small Molecule-Disease Strategy (CPSD), A New Strategy for Chinese Medicine Development: A Case Study in Cardiovascular Diseases. Frontiers in pharmacology 1 32038243
2017 Absence of association of the Ala58Val (rs17571) CTSD gene variant with Parkinson's disease or amyotrophic lateral sclerosis in a Han Chinese population. Neuroscience letters 1 28917980
2026 Snapin mediates neuronal PANoptosis after mild traumatic brain injury via H2S-dependent S-sulfhydration of CTSD. Journal of advanced research 0 41558604
2026 Myeloid KIF13B suppresses the STT3A/CTSD/THBS1 axis to prevent MASH. Hepatology (Baltimore, Md.) 0 41746601
2026 hUMSCs-exo@Cyasterone protects the cell model of steroid-induced femur head necrosis by regulating N-glycosylation modification of CTSD-N258A. PloS one 0 41931502
2024 CTSD is the key therapeutic target of Jinshui Liujun decoction in treating chronic bronchitis. Natural product research 0 39463007
2024 A Novel Variant of the CTSD Gene Associated with Juvenile-onset Neuronal Ceroid Lipofuscinosis Type 10: A Case Report and Literature Review. Cerebellum (London, England) 0 39656415