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

• In this study, we show that the lysosomal aspartyl-protease cathepsin-D (Ctsd) is of considerable importance for nonoxidative listericidal defense mechanisms [3].
• Cathepsin D-mediated proteolysis of apolipoprotein E: Possible role in Alzheimer's disease [5].
• The activity of cathepsin D increased during days 2 and 3 of food deprivation [6].

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

• Decreased secretion of Cathepsin D in breast cancer in vivo by tamoxifen: mediated by the mannose-6-phosphate/IGF-II receptor [12]?
• Pepstatin A, a cathepsin D inhibitor, had no effect as a single agent in mice with L1210 leukemia but displayed some antimetastatic activity in mice with Lewis lung carcinoma [13].
• Administration of PGE2 (0.10 microgram/g body weight) diminished the rise in in-vitro LDH discharge and the increase in "free" Cathepsin D activity which occur during diet-induced pancreatitis [14].
• 17 beta-Estradiol (E2) induces cathepsin D mRNA levels and intracellular levels of immunoreactive protein in MCF-7 human breast cancer cells [15].
• In contrast, more than 70% of phagosomes that contained Escherichia coli, polystyrene beads, or exponential phase (E) L. pneumophila matured to phagolysosomes, as judged by co-localization with LAMP-1, cathepsin D and fluorescent endosomal probes [16].

Biological context of Ctsd

• Transient transfection of Ctsd in wild-type cells was sufficient to revert these wild-type phagosomes back to microbicidal compartments [3].
• Cathepsin D also degraded native OVA into antigenic peptide, whereas microglia prepared from cathepsin D-deficient mice retained an ability for antigen presentation [17].
• Also, several individual synthetic HEL sequences corresponding to selected cathepsin D-released fragments were recognized by murine T cells in the context of all three major histocompatibility complex (MHC) haplotypes tested [18].
• Although the binding sites for IGF-II and cathepsin D are distinct, reciprocal interactions between the ligands have been observed [19].
• 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 [20].

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

• We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase [1].
• It follows that proteolysis by cathepsin D is likely to represent an early event in the death pathway triggered by TNFalpha and occurs within the endosomal-lysosomal compartment [26].
• We also found in CD 40-stimulated astrocytes an increase of a low-affinity IgE receptor CD 23, which is known to induce iNOS expression [27].
• Thus, the affinity of AP-1 for membranes and in vivo transport of cathepsin D were measured for MPR-negative cells re-expressing various CD-MPR mutants [28].

Other interactions of Ctsd

• Cathepsin D targeted by acid sphingomyelinase-derived ceramide [24].
• The characteristic distribution pattern of lysosomal enzymes, acid phosphatase, lysozyme, and cathepsin D, and AAT was altered in the AVY [29].
• The main cathepsin D and OPN expression was observed in activated macrophages/microglia at 3 and 7 days [20].
• Our data suggest that cathepsin D rather than cathepsin B may play a central role in the initial release of HEL fragments during endosomal/lysosomal processing [18].
• The mutant receptors retained the ability to recycle to the Golgi and bind cathepsin D. These results indicate that the cytoplasmic tail of the Man-6-P/IGF-II receptor contains two signals that contribute to Golgi sorting, presumably by interacting with the Golgi clathrin-coated pit adaptor proteins [30].

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].

References