1. Gene Aliases

Ctsd, Cathepsin D, CLN10, CPSD, Ceroid-Lipofuscinosis, Neuronal 10, EC 3.4.23.5, Epididymis Secretory Sperm Binding Protein Li 130P, Cathepsin D (Lysosomal Aspartyl Protease), Lysosomal Aspartyl Peptidase, Lysosomal Aspartyl Protease, HEL-S-130P, EC 3.4.23

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=CTSD&keywords=ctsd].

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

autophagosome assembly [The formation of a double membrane-bounded structure, the autophagosome, that occurs when a specialized membrane sac, called the isolation membrane, starts to enclose a portion of the cytoplasm. GO:0000045]

epithelial tube branching involved in lung morphogenesis [The process in which a highly ordered sequence of patterning events generates the branched epithelial tubes of the lung, consisting of reiterated combinations of bud outgrowth, elongation, and dichotomous subdivision of terminal units. GO:0060441]

insulin catabolic process [The chemical reactions and pathways resulting in the breakdown of insulin. GO:1901143]

insulin receptor recycling [The process that results in the return of an insulin receptor to an active state at the plasma membrane. An active state is when the receptor is ready to receive an insulin signal. Internalized insulin receptors can be recycled to the plasma membrane or sorted to lysosomes for protein degradation. GO:0038020]

lipoprotein catabolic process [The chemical reactions and pathways resulting in the breakdown of any conjugated, water-soluble protein in which the covalently attached nonprotein group consists of a lipid or lipids. GO:0042159]

positive regulation of apoptotic process [Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process. This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is positively regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0043065]

protein catabolic process [The chemical reactions and pathways resulting in the breakdown of a protein by the destruction of the native, active configuration, with or without the hydrolysis of peptide bonds. This term refers to the breakdown of mature proteins. For cleavage events involved in generating a mature protein from a precursor, consider instead the term 'protein maturation ; GO:0051604' and its children. GO:0030163]

proteolysis [The hydrolysis of proteins into smaller polypeptides and/or amino acids by cleavage of their peptide bonds. This term was intentionally placed under 'protein metabolic process ; GO:0019538' rather than 'protein catabolic process ; GO:0030163' to cover all processes centered on breaking peptide bonds, including those involved in protein processing. GO:0006508]

regulation of establishment of protein localization [Any process that modulates the frequency, rate or extent of the directed movement of a protein to a specific location. GO:0070201]

response to nutrient levels [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus reflecting the presence, absence, or concentration of nutrients. GO:0031667]

MSigDB Signatures:

REACTOME_NEUTROPHIL_DEGRANULATION: Neutrophil degranulation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_NEUTROPHIL_DEGRANULATION.html]

REACTOME_INNATE_IMMUNE_SYSTEM: Innate Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INNATE_IMMUNE_SYSTEM.html]

HEBERT_MATRISOME_TNBC_BONE_BRAIN_LIVER_LUNG_METASTASTASES: Matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastastases compared to normal samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HEBERT_MATRISOME_TNBC_BONE_BRAIN_LIVER_LUNG_METASTASTASES.html]

REACTOME_ADAPTIVE_IMMUNE_SYSTEM: Adaptive Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ADAPTIVE_IMMUNE_SYSTEM.html]

KEGG_LYSOSOME: Lysosome [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_LYSOSOME.html]

REACTOME_COLLAGEN_DEGRADATION: Collagen degradation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_COLLAGEN_DEGRADATION.html]

HEBERT_MATRISOME_TNBC_BONE_BRAIN_LUNG_LIVER_METASTASTASES_TUMOR_CELL_DERIVED: Tumor cell-derived matrisome proteins found in significantly higher abundance in TNBC brain, bone, liver and lung metastastases compared to normal samples. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/HEBERT_MATRISOME_TNBC_BONE_BRAIN_LUNG_LIVER_METASTASTASES_TUMOR_CELL_DERIVED.html]

REACTOME_EXTRACELLULAR_MATRIX_ORGANIZATION: Extracellular matrix organization [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_EXTRACELLULAR_MATRIX_ORGANIZATION.html]

REACTOME_DEGRADATION_OF_THE_EXTRACELLULAR_MATRIX: Degradation of the extracellular matrix [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_DEGRADATION_OF_THE_EXTRACELLULAR_MATRIX.html]

REACTOME_SIGNALING_BY_RECEPTOR_TYROSINE_KINASES: Signaling by Receptor Tyrosine Kinases [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_RECEPTOR_TYROSINE_KINASES.html]

REACTOME_SIGNALING_BY_NUCLEAR_RECEPTORS: Signaling by Nuclear Receptors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_NUCLEAR_RECEPTORS.html]

REACTOME_SIGNALING_BY_INSULIN_RECEPTOR: Signaling by Insulin receptor [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_SIGNALING_BY_INSULIN_RECEPTOR.html]

REACTOME_ESR_MEDIATED_SIGNALING: ESR-mediated signaling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ESR_MEDIATED_SIGNALING.html]

NABA_MATRISOME_ASSOCIATED: Ensemble of genes encoding ECM-associated proteins including ECM-affiliated proteins, ECM regulators and secreted factors [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_MATRISOME_ASSOCIATED.html]

REACTOME_INSULIN_RECEPTOR_RECYCLING: Insulin receptor recycling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INSULIN_RECEPTOR_RECYCLING.html]

KEGG_MEDICUS_REFERENCE_NUCLEAR_INITIATED_ESTROGEN_SIGNALING_PATHWAY: Pathway Definition from KEGG: E2 -> ((ESR1/2)+(NCOA1/2/3)) => (BCL2,EBAG9,KRT19,CTSD,TFF1,PGR) [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MEDICUS_REFERENCE_NUCLEAR_INITIATED_ESTROGEN_SIGNALING_PATHWAY.html]

NABA_MATRISOME: Ensemble of genes encoding extracellular matrix and extracellular matrix-associated proteins [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/NABA_MATRISOME.html]

REACTOME_MHC_CLASS_II_ANTIGEN_PRESENTATION: MHC class II antigen presentation [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_MHC_CLASS_II_ANTIGEN_PRESENTATION.html]

7. Gene Descriptions

NCBI Gene Summary: This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

GeneCards Summary: CTSD (Cathepsin D) is a Protein Coding gene. Diseases associated with CTSD include Ceroid Lipofuscinosis, Neuronal, 10 and Neuronal Ceroid Lipofuscinosis. Among its related pathways are Peptide hormone metabolism and ESR-mediated signaling. Gene Ontology (GO) annotations related to this gene include aspartic-type endopeptidase activity. An important paralog of this gene is NAPSA.

UniProtKB/Swiss-Prot Summary: Acid protease active in intracellular protein breakdown. Plays a role in APP processing following cleavage and activation by ADAM30 which leads to APP degradation [PMID: 27333034]. Involved in the pathogenesis of several diseases such as breast cancer and possibly Alzheimer disease.

8. Cellular Location of Gene Product

Cytoplasmic expression with a granular in all tissues. Predicted location: Secreted, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000117984/subcellular]

9. Mechanistic Information

Summary

CTSD, encoding the enzyme Cathepsin D, is crucial in intracellular protein breakdown and is implicated in the pathogenesis of several diseases, including lung cancer [CS: 9]. In the context of lung toxicity and diseases, the dysregulation of CTSD can be understood through its functional roles and the specific cellular responses to lung stressors [CS: 8]. For example, in response to cigarette smoke exposure, there is an upregulation of Cathepsin D mRNA in mice lungs, primarily expressed in macrophages [CS: 7]. This increase in CTSD expression may be a cellular response to the increased need for protein breakdown and turnover caused by smoke-induced damage [CS: 8]. The proteolytic activity of Cathepsin D could help in degrading damaged or misfolded proteins, a common consequence of oxidative stress from smoke, thereby aiding in cellular repair and maintenance [CS: 8].

In the case of lung cancer, different patterns of CTSD expression are observed [CS: 9]. For instance, in human lung cancer tumors, CTSD mRNA is often downregulated compared to adjacent normal tissue, suggesting a role in cancer progression [CS: 8]. This could be attributed to the enzyme's role in protein degradation and activation of growth factors [CS: 7]. Downregulation in cancer cells may be a mechanism to reduce the breakdown of proteins that are beneficial for tumor growth and survival [CS: 8]. On the other hand, in small cell lung cancer (SCLC), higher expression of CTSD correlates with better overall survival, indicating a complex role in cancer biology [CS: 7]. This higher expression in the low-risk group could be facilitating the removal of damaged proteins and preventing the accumulation of harmful products, which is critical in maintaining cellular health and combating cancer progression [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000117984/tissue]

Cell type enchanced: distal enterocytes, hofbauer cells, macrophages, proximal enterocytes (cell type enhanced) [https://www.proteinatlas.org/ENSG00000117984/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: