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Gene Review

Ctsd  -  cathepsin D

Mus musculus

Synonyms: CD, CatD, Cathepsin D
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Disease relevance of Ctsd

  • Increased expression of cathepsin D in the skin has been reported in wound healing, psoriasis and skin tumors [1].
  • Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis [1].
  • Moreover, the chronic treatment of l-NAME or SMT completely suppressed hemorrhage-necrotic changes in the small intestine of CD-/- mice, resulting in normal growth of the body weight of the mice [2].
  • Cutting edge: a novel nonoxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth [3].
  • In the present study, we have attempted to elucidate the mechanism underlying the seizure of cathepsin D-deficient (CD-/-) mice that show a novel type of lysosomal storage disease with a phenotype resembling late infantile NCL [4].

Psychiatry related information on Ctsd


High impact information on Ctsd

  • By 18 h, 70% contained lysosomal-associated membrane protein 1 (LAMP-1) and 40% contained cathepsin D; 50% of the vacuoles could be labeled by endocytosis, and the pH of this population of vacuoles averaged 5 [7].
  • Syt II directly regulates lysosomal exocytosis, whereby overexpression of Syt II inhibited Ca2+-triggered release of the lysosomal processed form of cathepsin D, whereas suppression of Syt II expression markedly potentiated this release [8].
  • Histochemistry and immunofluorescence showed that the giant organelles in both beige and CHS fibroblasts were positive for cathepsin D, lysosome-associated membrane protein (LAMP) 1, LAMP 2, and a 120-kD lysosomal glycoprotein, all marker proteins for late endosomes and lysosomes [9].
  • In addition to aminopeptidases, there were significant increases in activities of chymotrypsinlike enzyme, cathepsin C, cathepsin D, several glycosidases and neutral ribonuclease in the muscles of dystrophic mice [10].
  • Time-course experiments performed on MCF-7 cells with or without colchicine showed that release of cathepsin D and collagenolytic activity was associated more closely with release of bone mineral and degradation of bone matrix than was the release of N-acetylglucosaminidase [11].

Chemical compound and disease context of Ctsd


Biological context of Ctsd


Anatomical context of Ctsd

  • We observed enhanced susceptibility to L. monocytogenes infection of fibroblasts and bone-marrow macrophages and increased intraphagosomal viability of bacteria in fibroblasts isolated from Ctsd-deficient mice compared with wild type [3].
  • Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair [1].
  • Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry [21].
  • A cathepsin D (CD) inhibitor was searched using mouse embryonic fibroblasts deficient for CD [22].
  • All structures identified as lysosomes in the various cell types were immunoreactive for cathepsin D. The present data thus reveal that isolated Hex A deficiency results in region- and cell-specific abnormalities in the epididymis but in no apparent abnormalities in the testis or efferent ducts [23].

Associations of Ctsd with chemical compounds

  • The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase [24].
  • Synthetic DNA fragments specifically inhibited CD activity in a dose-dependent manner, but not the activities of other serine or cysteine proteinases [22].
  • CatD was found to proteolyze both lipid-free recombinant full-length human apoE and lipidated human plasma full-length apoE (apoE4/dipalmitoylphosphatidylcholine-reconstituted discs) [5].
  • Cathepsin is considered to be important for vacuole formation and cell lysis, and pepstatin A, a cathepsin D inhibitor, partially inhibited vacuole formation in DIDS-treated, serum-deprived MCT cells, although caspase activation was not inhibited [25].
  • To assess the role of microglial nitric oxide (NO) in neuropathological changes in CD-/- mice, l-N(G)-nitro-arginine methylester (l-NAME), a competitive NOS inhibitor, or S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, was administered intraperitoneally for 13 consecutive days [2].

Regulatory relationships of Ctsd


Other interactions of Ctsd


Analytical, diagnostic and therapeutic context of Ctsd

  • Mice deficient for the major lysosomal aspartic proteinase cathepsin D, generated by gene targeting, develop normally during the first 2 weeks, stop thriving in the third week and die in a state of anorexia at day 26 +/- 1 [31].
  • By electron microscopy, autophagosome/autolysosome-like bodies containing part of the cytoplasm, granular osmiophilic deposits, and fingerprint profiles were demonstrated in the neuronal perikarya of CD-/- mouse brains after P20 [32].
  • This suggests that not only CD-/- but also CB-/-CL-/- mice could be useful animal models for neuronal ceroid-lipofuscinosis/Batten disease [33].
  • Based on infection experiments with mutant bacteria, in vitro degradation, and immunoprecipitation experiments, we suggest that a major target of cathepsin D is the main virulence factor listeriolysin O [3].
  • Molecular cloning of mouse cathepsin D [34].


  1. Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. Egberts, F., Heinrich, M., Jensen, J.M., Winoto-Morbach, S., Pfeiffer, S., Wickel, M., Schunck, M., Steude, J., Saftig, P., Proksch, E., Schütze, S. J. Cell. Sci. (2004) [Pubmed]
  2. Involvement of nitric oxide released from microglia-macrophages in pathological changes of cathepsin D-deficient mice. Nakanishi, H., Zhang, J., Koike, M., Nishioku, T., Okamoto, Y., Kominami, E., von Figura, K., Peters, C., Yamamoto, K., Saftig, P., Uchiyama, Y. J. Neurosci. (2001) [Pubmed]
  3. Cutting edge: a novel nonoxidative phagosomal mechanism exerted by cathepsin-D controls Listeria monocytogenes intracellular growth. del Cerro-Vadillo, E., Madrazo-Toca, F., Carrasco-Marín, E., Fernandez-Prieto, L., Beck, C., Leyva-Cobián, F., Saftig, P., Alvarez-Dominguez, C. J. Immunol. (2006) [Pubmed]
  4. Proteolytic degradation of glutamate decarboxylase mediates disinhibition of hippocampal CA3 pyramidal cells in cathepsin D-deficient mice. Shimizu, T., Hayashi, Y., Yamasaki, R., Yamada, J., Zhang, J., Ukai, K., Koike, M., Mine, K., von Figura, K., Peters, C., Saftig, P., Fukuda, T., Uchiyama, Y., Nakanishi, H. J. Neurochem. (2005) [Pubmed]
  5. Cathepsin D-mediated proteolysis of apolipoprotein E: Possible role in Alzheimer's disease. Zhou, W., Scott, S.A., Shelton, S.B., Crutcher, K.A. Neuroscience (2006) [Pubmed]
  6. Combined effects of fasting and vinblastine treatment on serum insulin level, the size of autophagic-lysosomal compartment, protein content and lysosomal enzyme activities of liver and exocrine pancreatic cells of the mouse. Kovács, A.L., László, L., Fellinger, E., Jakab, A., Orosz, A., Réz, G., Kovács, J. Comp. Biochem. Physiol., B (1989) [Pubmed]
  7. Legionella pneumophila replication vacuoles mature into acidic, endocytic organelles. Sturgill-Koszycki, S., Swanson, M.S. J. Exp. Med. (2000) [Pubmed]
  8. Synaptotagmin II negatively regulates Ca2+-triggered exocytosis of lysosomes in mast cells. Baram, D., Adachi, R., Medalia, O., Tuvim, M., Dickey, B.F., Mekori, Y.A., Sagi-Eisenberg, R. J. Exp. Med. (1999) [Pubmed]
  9. The giant organelles in beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes. Burkhardt, J.K., Wiebel, F.A., Hester, S., Argon, Y. J. Exp. Med. (1993) [Pubmed]
  10. Various enzyme activities in muscle and other organs of dystrophic mice. Aoyagi, T., Wada, T., Kojima, F., Nagai, M., Umezawa, H. J. Clin. Invest. (1981) [Pubmed]
  11. Effects of inhibition of microtubule assembly on bone mineral release and enzyme release by human breast cancer cells. Eilon, G., Mundy, G.R. J. Clin. Invest. (1981) [Pubmed]
  12. Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: mediated by the mannose-6-phosphate/IGF-II receptor? Dabrosin, C., Johansson, A.C., Ollinger, K. Breast Cancer Res. Treat. (2004) [Pubmed]
  13. Antimetastatic activity of adriamycin in combinations with proteinase inhibitors in mice. Leto, G., Tumminello, F.M., Gebbia, N., Woynarowska, B., Bernacki, R.J. Anticancer Res. (1990) [Pubmed]
  14. Protective effects of PGE2 on diet-induced acute pancreatitis in mice. Manabe, T., Steer, M.L. Gastroenterology (1980) [Pubmed]
  15. Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. Krishnan, V., Porter, W., Santostefano, M., Wang, X., Safe, S. Mol. Cell. Biol. (1995) [Pubmed]
  16. Evidence that Dot-dependent and -independent factors isolate the Legionella pneumophila phagosome from the endocytic network in mouse macrophages. Joshi, A.D., Sturgill-Koszycki, S., Swanson, M.S. Cell. Microbiol. (2001) [Pubmed]
  17. Involvement of cathepsin E in exogenous antigen processing in primary cultured murine microglia. Nishioku, T., Hashimoto, K., Yamashita, K., Liou, S.Y., Kagamiishi, Y., Maegawa, H., Katsube, N., Peters, C., von Figura, K., Saftig, P., Katunuma, N., Yamamoto, K., Nakanishi, H. J. Biol. Chem. (2002) [Pubmed]
  18. Cathepsin D, but not cathepsin B, releases T cell stimulatory fragments from lysozyme that are functional in the context of multiple murine class II MHC molecules. van Noort, J.M., Jacobs, M.J. Eur. J. Immunol. (1994) [Pubmed]
  19. Modulation of cathepsin D routing by IGF-II involves IGF-II binding to IGF-II/M6P receptor in MCF-7 breast cancer cells. Faridi, J.S., Mohan, S., De León, D.D. Growth Factors (2004) [Pubmed]
  20. Gene expression profiling of cathepsin D, metallothioneins-1 and -2, osteopontin, and tenascin-C in a mouse spinal cord injury model by cDNA microarray analysis. Hashimoto, M., Koda, M., Ino, H., Yoshinaga, K., Murata, A., Yamazaki, M., Kojima, K., Chiba, K., Mori, C., Moriya, H. Acta Neuropathol. (2005) [Pubmed]
  21. Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation. Li, W., Yuan, X.M., Olsson, A.G., Brunk, U.T. Arterioscler. Thromb. Vasc. Biol. (1998) [Pubmed]
  22. Cathepsin D is specifically inhibited by deoxyribonucleic acids. Shibata, M., Koike, M., Waguri, S., Zhang, G., Koga, T., Uchiyama, Y. FEBS Lett. (2002) [Pubmed]
  23. II. Characterization and development of the regional- and cellular-specific abnormalities in the epididymis of mice with beta-hexosaminidase A deficiency. Adamali, H.I., Somani, I.H., Huang, J.Q., Gravel, R.A., Trasler, J.M., Hermo, L. J. Androl. (1999) [Pubmed]
  24. Cathepsin D targeted by acid sphingomyelinase-derived ceramide. Heinrich, M., Wickel, M., Schneider-Brachert, W., Sandberg, C., Gahr, J., Schwandner, R., Weber, T., Saftig, P., Peters, C., Brunner, J., Krönke, M., Schütze, S. EMBO J. (1999) [Pubmed]
  25. Anion-exchange blocker enhances cytoplasmic vacuole formation and cell death in serum-deprived mouse kidney epithelial cells in mice. Araki, T., Hayashi, M., Saruta, T. Cell Biol. Int. (2006) [Pubmed]
  26. Endosomal-lysosomal proteolysis mediates death signalling by TNFalpha, not by etoposide, in L929 fibrosarcoma cells: evidence for an active role of cathepsin D. Démoz, M., Castino, R., Cesaro, P., Baccino, F.M., Bonelli, G., Isidoro, C. Biol. Chem. (2002) [Pubmed]
  27. Loss of dopaminergic neurons by the induction of inducible nitric oxide synthase and cyclooxygenase-2 via CD 40: relevance to Parkinson's disease. Okuno, T., Nakatsuji, Y., Kumanogoh, A., Moriya, M., Ichinose, H., Sumi, H., Fujimura, H., Kikutani, H., Sakoda, S. J. Neurosci. Res. (2005) [Pubmed]
  28. A casein kinase II phosphorylation site in the cytoplasmic domain of the cation-dependent mannose 6-phosphate receptor determines the high affinity interaction of the AP-1 Golgi assembly proteins with membranes. Mauxion, F., Le Borgne, R., Munier-Lehmann, H., Hoflack, B. J. Biol. Chem. (1996) [Pubmed]
  29. Induction of avascular yolk sac due to reduction of basic fibroblast growth factor by retinoic acid in mice. Yasuda, Y., Nishi, N., Takahashi, J.A., Konishi, H., Ohara, I., Fujita, H., Ohta, M., Itoh, N., Hatanaka, M., Tanimura, T. Dev. Biol. (1992) [Pubmed]
  30. The cytoplasmic tail of the mannose 6-phosphate/insulin-like growth factor-II receptor has two signals for lysosomal enzyme sorting in the Golgi. Johnson, K.F., Kornfeld, S. J. Cell Biol. (1992) [Pubmed]
  31. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. Saftig, P., Hetman, M., Schmahl, W., Weber, K., Heine, L., Mossmann, H., Köster, A., Hess, B., Evers, M., von Figura, K. EMBO J. (1995) [Pubmed]
  32. Cathepsin D deficiency induces lysosomal storage with ceroid lipofuscin in mouse CNS neurons. Koike, M., Nakanishi, H., Saftig, P., Ezaki, J., Isahara, K., Ohsawa, Y., Schulz-Schaeffer, W., Watanabe, T., Waguri, S., Kametaka, S., Shibata, M., Yamamoto, K., Kominami, E., Peters, C., von Figura, K., Uchiyama, Y. J. Neurosci. (2000) [Pubmed]
  33. Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease). Koike, M., Shibata, M., Waguri, S., Yoshimura, K., Tanida, I., Kominami, E., Gotow, T., Peters, C., von Figura, K., Mizushima, N., Saftig, P., Uchiyama, Y. Am. J. Pathol. (2005) [Pubmed]
  34. Molecular cloning of mouse cathepsin D. Grusby, M.J., Mitchell, S.C., Glimcher, L.H. Nucleic Acids Res. (1990) [Pubmed]
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