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FLASH GENE
Symbol CTSD contributors: mct - updated : 25-10-2017
HGNC name cathepsin D
HGNC id 2529
Corresponding disease
CLN10 ceroid-lipofuscinosis, neuronal, 10
Location 11p15.5      Physical location : 1.773.984 - 1.785.222
Synonym name
  • cathepsin D (lysosomal aspartyl protease)
  • lysosomal aspartyl protease
  • ceroid-lipofuscinosis, neuronal 10
  • epididymis secretory sperm binding protein Li 130P
  • Synonym symbol(s) CPSD, RPELAP, B2A4, MGC2311, CLN10, HEL-S-130P
    EC.number 3.4.23.5
    DNA
    TYPE anonymous DNA segment
    STRUCTURE 11.24 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (TATA box)
    text structure TATA-box controlled transcription start site (TSS) potentially estrogen regulated
    MAPPING cloned Y linked N status confirmed
    Map see INS ,PTH PTH
    Physical map
    RPLP2 5q31 ribosomal protein, large P2 TTS-2.2 11p15.5 transport-secretion protein 2.2 MGC45840 11p15.5 hypothetical protein MGC45840 CD151 11p15.5 CD151 antigen POLR2L 11p15 polymerase (RNA) II (DNA directed) polypeptide L, 7.6kDa TM4SF7 11p15.5 transmembrane 4 superfamily member 7 MGC3234 11p15.5 hypothetical protein MGC3234 AP2A2 11p15.5 adaptor-related protein complex 2, alpha 2 subunit MUC6 11p15.5 mucin 6, gastric LOC387738 11 similar to secreted gel-forming mucin LOC338731 11p15.5 hypothetical LOC338731 LOC387739 11 LOC387739 LOC387740 11 similar to Mucin 2 precursor (Intestinal mucin 2) MUC5B 11p15.5 mucin 5, subtype B, tracheobronchial TOLLIP 11p15.5 toll interacting protein STK29 11p15.5 serine/threonine kinase 29 HCCA2 11p15.5 HCCA2 protein DUSP8 11p15.5 dual specificity phosphatase 8 LOC387741 11 hypothetical gene supported by AK124823 LOC387742 11 hypothetical gene supported by AK124823 CTSD 11p15.5 cathepsin D (lysosomal aspartyl protease) LOC255701 11p15.5 similar to large subunit ribosomal protein L36a LOC390029 11 similar to A-X actin SYT8 11p15.5 synaptotagmin VIII TNNI2 11p15.5 troponin I, skeletal, fast LSP1 11p15.5 lymphocyte-specific protein 1 TNNT3 11p15.5 troponin T3, skeletal, fast MRPL23 11p15.5 mitochondrial ribosomal protein L23 LOC387743 11 LOC387743 H19 11p15.5 H19, imprinted maternally expressed untranslated mRNA IGF2 11p15.5 insulin-like growth factor 2 (somatomedin A) IGF2AS 11p15.5 insulin-like growth factor 2, antisense INS 11p15.5 insulin TH 11p15.5 tyrosine hydroxylase ASCL2 11p15.5 achaete-scute complex-like 2 (Drosophila) C11orf21 11p15.5 chromosome 11 open reading frame 21 PHEMX 11p15.5 pan-hematopoietic expression CD81 11p15.5 CD81 antigen (target of antiproliferative antibody 1) TSSC4 11p15.5 tumor suppressing subtransferable candidate 4 TRPM5 11p15.5 transient receptor potential cation channel, subfamily M, member 5 KCNQ1 11p15.5 potassium voltage-gated channel, KQT-like subfamily, member 1
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 2205 48 412 - 1999 10508159
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     pharynx   highly
     salivary gland   highly
    Nervousbrain   predominantly Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier/liningretinal pigment epithelium (RPE)  
    Nervouscentral  highly Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skin/Tegumentkeratinocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    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
  • 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