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FLASH GENE

Symbol

CTSD

contributors: mct - updated : 25-10-2017

HGNC name	cathepsin D
HGNC id	2529

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001909 9 - 2205 48 412 - 1999 10508159

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive esophagus       highly   pharynx       highly   salivary gland       highly Nervous brain       predominantly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial barrier/lining retinal pigment epithelium (RPE)     Nervous central     highly Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Skin/Tegument keratinocyte

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
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed neurology neurodegenerative Parkinson/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