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FLASH GENE
Symbol CTSD contributors: mct - updated : 25-10-2017
HGNC name cathepsin D
HGNC id 2529
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
aspartyl protease domain
isoforms Precursor 52kD processed first into a 44 then a 32kD isoform
HOMOLOGY
interspecies ortholog to murine (80.4 pc)
intraspecies homolog to pepsinogen
Homologene
FAMILY
  • pepsin family of proteases
  • aspartic protease family
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION extracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,lysosome
    text
  • transport to the lysosomes being partially dependent upon sortilin
  • basic FUNCTION
  • involved in proteolytic degradation, cell invasion, and apoptosis
  • aspartic proteinase, bound to ceramide for proteolytic activity
  • cleaving procaspase 3, potentially recruited during apoptosis
  • involved in epidermal differentiation and major factor in the proteolysis of opsin
  • CTSD inhibitors block the formation of hyperphosphorylated tau fragments in hippocampus (lysosomal dysfunction)
  • play a key role in the homeostasis of neuronal structures
  • having a role in promoting cancer cell proliferation and invasion
  • playing an important role in intracellular cholesterol trafficking and ABCA1-mediated efflux
  • plays potentially an important role in the phagocytosis and lysosomal activation of macrophages/microglia during the central nervous system inflammation caused by trauma
  • predominant lysosomal protease, playing an important role in regulation of cellular apoptosis and mediating apoptosis induced by cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma
  • likely involved in beta-amyloidogenesis in Alzheimer disease (AD)
  • plays a significant role in the removal of AGE (advanced glycation end)-modified proteins
  • can likely function as an anti-apoptotic mediator by inducing autophagy under cellular stress
  • acts as an essential mediator to promote malignancy of benign prostatic epithelium
  • modulates the growth of fibroblasts by inhibiting LRP1 regulated intramembrane proteolysis (RIP) in the breast tumor microenvironment
  • acts as a transcriptional repressor, independently of its catalytic activity
  • acts as a nuclear transcriptional cofactor of TRPS1 to regulate ESR1+ breast cancer cells (BCC) proliferation and transformation in a non-proteolytic manner
  • CTSD enzymatic activity is a new factor affecting sensitivity of breast cancer cells to TNFSF10
  • importance of CTSD for the maintenance of metabolism in central nervous system neurons, with neuronal cell death of CTSD-deficient Purkinje Cells distinct from apoptosis
  • CELLULAR PROCESS cell life, differentiation
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • CST3 is a proteolytic target of cathepsin D (CTSD) and has a direct, causal impact on cell differentiation
  • CTSD is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis
  • MREG is likely required to maintain CTSD homeostasis in the RPE and likely plays a protective role in retinal health
  • critical regulatory role for that endogenous CTSD activity in dopaminergic cells in SNCA homeostasis which cannot be compensated for by increased CTSB
  • CTSD nuclear targeting is controlled by BAG6
  • also binds to full-length TRPS1
  • CTSD and NPC1 interaction with a new lysosomal function of NPC1 as a regulator of CTSD processing and activity
  • lysosomal enzyme cathepsin D (CTSD) mediates the proteolytic cleavage of PSAP precursor into saposins A-D
  • direct involvement of CLN3 in the regulation of CTSD activity
  • direct interaction between GRN and CTSD, and a combined reduction of GRN and CTSD synergistically reduced axonal outgrowth
  • cathepsin D is a protease that can activate VEGFC as well as VEGFD
  • cell & other
    REGULATION
    activated by by glycosaminoglycans (GAGs)
    repressed by regulated by ESR1, which is crucial for long-distance regulation of CTSD expression involving a looping mechanism
    ASSOCIATED DISORDERS
    corresponding disease(s) CLN10
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    reduced by approximately 50p100 in monocyte-derived macrophages of low HDL-C subjects, most significantly those with cholesterol efflux defects but without mutations in ABCA1
    constitutional     --over  
    significantly increased in the frontal cortex, in pyramidal and granule cells of the hippocampus, and in cerebellar neurons in autistic subjects as compared to controls
    tumoral     --over  
    in human breast carcinoma and many other tumor types
    constitutional       loss of function
    partial loss of CTSD activity is sufficient to cause a reduction in lysosomal function, which in turn leads to SNCA aggregation and propagation of the aggregates
    constitutional germinal mutation      
    increased lysosomal storage due to CTSD deficiency causes oxidative damage in brain pericytes, subsequently resulting in an increased vessel diameter, enhanced permeability of the BBB and the infiltration of peripheral blood mononuclear cells (PBMCs)
    constitutional     --low  
    reduced CTSD level is an important factor that may contribute to the pathogenesis of preeclampsia, possibly by inhibiting normal trophoblastic invasion
    Susceptibility
  • almost a mild risk factor for sporadic Alzheimer disease (AD)
  • Variant & Polymorphism SNP
  • (rs17571) of the cathepsin D gene associated with increased AD risk, in men but not in women
  • Candidate gene
    Marker
  • with eEF1s are promising markers for the detection of cellular senescence induced by a variety of treatments (
  • Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    upregulation of cathepsin D could be an additional therapeutic strategy to lessen alpha-synuclein burden in synucleinopathies
    cancer  
    inhibition of autophagy could be a novel strategy for the adjuvant chemotherapy of CTSD-expressing cancers
    ANIMAL & CELL MODELS
  • CtsD-deficient mice show severe visceral lesions like lymphopenia in addition to their central nervous system (CNS) phenotype of ceroid accumulation, microglia activation, and seizures