Cathepsin D—Many functions of one aspartic protease

Beneš, Petr; Větvička, Václav; Fusek, Martin

doi:10.1016/j.critrevonc.2008.02.008

Cited by 532 publications

(508 citation statements)

References 207 publications

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“…Cat D is an abundant aspartic endopeptidase in lysosomes (38,39). The precursor form of Cat D is proteolytically processed to an intermediate during its transport from the Golgi to acidic endolysosomal compartments.…”

Section: Lc3-ii Resulting In An Increased Lc3-ii/lc3-i Ratiomentioning

confidence: 99%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, ␣-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-␤ peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.Alzheimer disease is characterized by the accumulation of extracellular amyloid plaques that contain aggregates of the amyloid ␤-peptide (A␤).5 A␤ is derived from the amyloid precursor protein by sequential proteolytic processing by ␤-and ␥-secretases (1, 2). The initial cleavage of amyloid precursor protein (APP) by ␤-secretase results in the secretion of the soluble ectodomain and the generation of a membrane-tethered C-terminal fragment (APP-CTF␤). Subsequently, APP-CTF␤ can be cleaved by ␥-secretase to liberate A␤ from cellular membranes (2). In an alternative pathway, APP can also be cleaved by ␣-secretase within the A␤ domain, thereby generating CTF␣. The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3-5).The metabolism of APP is also regulated by macroautophagy (herein referred to as autophagy), a lysosome-dependent degradative pathway for long lived proteins, organelles, and nutrient recycling (6, 7). Autophagy starts with the formation of double-membrane vesicles, the so-called autophagosomes, which further fuse with lysosomes to become autolysosomes for degradation of autophagosome contents by lysosomal hydrolases (8). Autophagy is an essential prosurvival pathway induced by a variety of stress factors, including nutrient deprivation, growth factor withdrawal, oxidative stress, infection, and hypoxia (9). These factors contribute to the etiology of multiple diseases such as cancer, stroke, heart disease, and infection (10). Eukaryotic cells have a basal autophagic activity under normal physiological conditions. Cells deficient in autophagy show diffuse abnormal protein accumulation and mitochondrial disorganization (11,12), suggesting that autophagy is important to maintain cellular homeostasis by eliminating protein aggregates and damaged organelles. Basal ...

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Section: Lc3-ii Resulting In An Increased Lc3-ii/lc3-i Ratiomentioning

confidence: 99%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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“…Mature cathepsin B is found as a single-chain form (29 kDa) and as a two-chain form (25 and 4 kDa) of active enzyme (34). Active cathepsin D is produced through two successive cleavages of preproenzyme, resulting in formation of a two-chain mature enzyme (14-kDa L chain and 34-kDa H chain) in lysosomes (33). Recently, cytoplasmic leakage of cathepsin B was associated with inflammasome activation (29).…”

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confidence: 99%

“…Cathepsin B and D are functionally closely related and are the most abundant in this protein family (31)(32)(33). Maturation of these proteases proceeds through several steps.…”

mentioning

confidence: 99%

Recognition of Cytoplasmic RNA Results in Cathepsin-Dependent Inflammasome Activation and Apoptosis in Human Macrophages

Rintahaka

Lietzén

Öhman

et al. 2011

The Journal of Immunology

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dsRNA is an important pathogen-associated molecular pattern that is primarily recognized by cytosolic pattern-recognition receptors of the innate-immune system during virus infection. This recognition results in the activation of inflammasome-associated caspase-1 and apoptosis of infected cells. In this study, we used high-throughput proteomics to identify secretome, the global pattern of secreted proteins, in human primary macrophages that had been activated through the cytoplasmic dsRNA-recognition pathway. The secretome analysis revealed cytoplasmic dsRNA-recognition pathway-induced secretion of several exosome-associated proteins, as well as basal and dsRNA-activated secretion of lysosomal protease cathepsins and cysteine protease inhibitors (cystatins). Inflammasome activation was almost completely abolished by cathepsin inhibitors in response to dsRNA stimulation, as well as encephalomyocarditis virus and vesicular stomatitis virus infections. Interestingly, Western blot analysis showed that the mature form of cathepsin D, but not cathepsin B, was secreted simultaneously with IL-18 and inflammasome components ASC and caspase-1 in cytoplasmic dsRNA-stimulated cells. Furthermore, small interfering RNA-mediated silencing experiments confirmed that cathepsin D has a role in inflammasome activation. Caspase-1 activation was followed by proteolytic processing of caspase-3, indicating that inflammasome activation precedes apoptosis in macrophages that had recognized cytoplasmic RNA. Like inflammasome activation, apoptosis triggered by dsRNA stimulation and virus infection was effectively blocked by cathepsin inhibition. In conclusion, our results emphasize the importance of cathepsins in the innate immune response to virus infection.

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“…By hydrolyzing intracellular proteins it participates in various physiological processes involved in maintaining tissue homeostasis, regulation of apoptosis, activation of hormones and growth factors (Benes et al, 2008), to mention a few. In insects, cathepsin D-like peptidases showed specialized functions like cellular remodelling during metamorphosis (Gui et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Is digestive cathepsin D the rule in decapod crustaceans?

Martinez-Alarcon

Saborowski

Rojo‐Arreola

et al. 2018

Comparative Biochemistry and Physiology Part B: Biochemistry an

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A B S T R A C TCathepsin D is an aspartic endopetidase with typical characteristics of lysosomal enzymes. Cathepsin D activity has been reported in the gastric fluid of clawed lobsters where it acts as an extracellular digestive enzyme. Here we investigate whether cathepsin D is unique in clawed lobsters or, instead, common in decapod crustaceans. Eleven species of decapods belonging to six infraorders were tested for cathepsin D activity in the midgut gland, the muscle tissue, the gills, and when technically possible, in the gastric fluid. Cathepsin D activity was present in the midgut gland of all 11 species and in the gastric fluid from the seven species from which samples could be taken. All sampled species showed higher activities in the midgut glands than in non-digestive organs and the activity was highest in the clawed lobster. Cathepsin D mRNA was obtained from tissue samples of midgut gland, muscle, and gills. Analyses of deduced amino acid sequence confirmed molecular features of lysosomal cathepsin D and revealed high similarity between the enzymes from Astacidea and Caridea on one side, and the enzymes from Penaeoidea, Anomura, and Brachyura on the other side. Our results support the presence of cathepsin D activity in the midgut glands and in the gastric fluids of several decapod species suggesting an extracellular function of this lysosomal enzyme. We discuss whether cathepsin D may derive from the lysosomal-like vacuoles of the midgut gland B-cells and is released into the gastric lumen upon secretion by these cells.

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Cathepsin D—Many functions of one aspartic protease

Cited by 532 publications

References 207 publications

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Recognition of Cytoplasmic RNA Results in Cathepsin-Dependent Inflammasome Activation and Apoptosis in Human Macrophages

Is digestive cathepsin D the rule in decapod crustaceans?

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