CTSD

CTSD Background

Cathepsin D (CTSD) is an aspartic endoprotease synthesized in the rough endoplasmic reticulum as inactive pre-pro-cathepsin D. The pre-pro-cathepsin D is cleaved and glycosylated to form 52 kDa pro-cathepsin D containing two N-linked oligosaccharides modified with mannose 6-phosphate (M6P) residues ^[1]. The pro-cathepsin D is targeted to intracellular vesicular structures, including lysosomes, endosomes, and phagosomes, both by M6P receptor (M6PR)-dependent and-independent pathways ^[2][3]. Upon entering the acidic endosomal and lysosomal compartment, the low pH induces its dissociation from M6PR and subsequent removal of its phosphate group. Proteolytic cleavage of the 44-amino acid propeptide at the N-terminus yields a 48 kDa single-chain intermediate active enzyme ^[4], which further undergoes autocatalysis after processing by cysteine proteases to generate mature CTSD (48 kDa). The mature CTSD consists of a heavy chain (34 kDa) and a light chain (14 kDa) ^[5]. CTSD activity is optimal at acidic pH. When stimulated by apoptotic signals, the lysosomal membrane becomes selectively permeabilized, leading to the release of mature CTSD into the cytosol. CTSD-induced mitochondrial dysfunction results in the release of cytochrome c from mitochondria, followed by activation of caspase-9 and caspase-3 ^[6][7]. Alternatively, CTSD may activate Bax via the Bid-independent pathway, resulting in the release of apoptosis-inducing factor (AIF) and caspase-independent apoptosis ^[8]. Pepstatin A (PepA), a pharmacological inhibitor of cathepsin D, is shown to block mitochondrial cytochrome c release and caspase activation in cardiomyocytes and fibroblasts ^[9][10]. In addition to apoptosis, CTSD also participates in numerous physiological processes, including cell proliferation ^[11], senescence ^[12], and tissue homeostasis ^{[13]. CTSD is also involved in various pathological processes such as cancer development as well as metastasis [14], atherosclerosis [15], and Alzheimer's disease [16].}

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[13] Saftig P, Hetman M, et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells [J]. EMBO J 1995, 14: 3599-3608.
[14] Hu L, Roth JM, Brooks P, Luty J, Karpatkin S (2008) Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis [J]. Cancer Res 68: 4666-4673.
[15] Hakala JK, Oksjoki R, et al. Lysosomal enzymes are released from cultured human macrophages, hydrolyze LDL in vitro, and are present extracellularly in human atherosclerotic lesions [J]. Arterioscler Thromb Vasc Biol 2003, 23: 1430-1436.
[16] Urbanelli L, Emiliani C, et al. Cathepsin D expression is decreased in Alzheimer's disease fibroblasts [J]. Neurobiol Aging 2008, 29: 12-22.