Inactivation of human cystatin C and kininogen by human cathepsin D

Lenarčič, Brigita; Krašovec, Marta; Ritonja, Anka; Ólafsson, Ísleifur; Türk, Vito

doi:10.1016/0014-5793(91)80295-e

Cited by 91 publications

(54 citation statements)

References 26 publications

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“…Thus, cystatins may bind to cathepsin B and limit its extralysosomal functions. Interestingly, human genome does not encode aspartate-specific protease inhibitors, which could antagonize functions of cathepsin D (55); moreover, cathepsin D is able to inactivate cystatins (56,57). Importantly, we found that cathepsin D was secreted earlier than cathepsin B in dsRNAstimulated cells.…”

Section: Discussionmentioning

confidence: 85%

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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Section: Discussionmentioning

confidence: 85%

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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“…The ECM contains several specific protease inhibitors, including members of the family of tissue inhibitors of metalloprotease [56], plasminogen activator inhibitor [57,58]. cystatin and stefin families [59,60]. The balance between the relative level of proteases and their specific inhibitors dictates the degree of protease activity, and essentially ensures that uncontrolled proteolysis of the components of the basement membrane does not occur.…”

Section: The Integrinsmentioning

confidence: 99%

“…These proteases appear to form a proteolytic cascade that initially degrades the protease inhibitors, abolishing their effects, and subsequently degrades many components of the basement membrane. For example, cathepsin D actively degrades cystatin C, the major inhibitor of cathepsin B, resulting in the enhancement of the enzymatic activity of cathepsin B [59]. which itself activates UPA [68] and degrades collagen type IV, laminin and fibronectin [69].…”

Section: The Integrinsmentioning

confidence: 99%

Apoptosis, tumour invasion and prostate cancer

Tenniswood

1997

British Journal of Urology

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IntroductionCell death, or apoptosis, is not a single phenomenon but a series of morphologically and biochemically related processes [1,2]. Cell death of lymphocytes and other cells of reticulo-endothelial origin is dominated by changes in nuclear morphology [3], while apoptotic death of glandular epithelial cells, such as those of the prostate, requires profound cytoplasmic changes and alterations in the cell-cell and cell-substratum interactions [4]. The rodent prostate is a very useful model for the study of apoptosis induced by hormone withdrawal, The gland is an arborhed network of ducts, with several cell types that display anatomical and biochemical heterogeneity and substantially different sensitivities to androgen ablation. nor the basal cells that are also localized to the proximal region, appear to require androgens for survival. The prostate begins to regress about 12 h after castration, when the level of Sct-DHT falls below that needed to inhibit involution [lo]. The reduction in prostate size that occurs over the next 3-6 days is primarily due to the selective loss of the secretory luminal epithelial cells in the distal and intermediate regions, resulting in the complete obliteration of many of the ducts while maintaining the proximal segments of the ducts after castration. The process of apoptosis in the prostate can be broken down into several stages (Fig. 1). During the precondensation stage, many of the genes that are necessary for cell death are induced de now, or recruited from other functions in the gland. The length of the precondensation stage appears to vary from cell to cell and probably reflects the microheterogeneity in the hormone or growth factor environment. The precondensation phase is followed by cytoplasmic condensation which involves the loss of the interactions between the dying cell and its neighbours as the extra-cellular matrix (ECM) is degraded and the cytoplasmic volume decreases. During nuclear condensation, the activation of one or more endonucleases results in the fragmentation of the DNA and its marginalization to the nuclear periphery, Producing the hyperchromatic, pyknotic nucleus characteristic of apoptotic cells. As the initiation of apoptosis in glandular tissues is stochastic, it is difficult to separate clearly cytoplasmic and nuclear condensation temporally in vivo, but in isolated cells from other tissues (e.g. granulosal cells), nuclear condensation is clearly initiated after cytoplasmic condensation. During the fragmentation phase the apoptotic cell is subdivided into several apoptotic bodies which are subsequently phagocytosed by the neighbouring epithelial cells or macrophages and degraded by the lysosomal enzymes, activated either in the host cell or in the apoptotic body [l 11. Remarkably, this latter process occurs with no leakage of the intracelMar components into the extracellular space, ensuring that the complement cascade system is not activated and that there is no inflammatory response. This feature distinguishes apoptosis from necrosis. In the pr...

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“…The mechanisms controlling the intracellular inhibition of cysteine proteinases in endosomes and lysosomes with cystatin C entering the endosomal -lysosomal pathway by endocytotic uptake may include dimerisation (Ekiel and Abrahamson, 1996;Merz et al, 1997), proteolytic fragmentation by cathepsin D (Lenarčič et al, 1991) or neutrophilic granulocyte elastase (Abrahamson et al, 1991). Some of these mechanisms may operate already in the pericellular microenvironment and may restrict the inhibitory function of the secreted cystatin C against the proteolytic activity of cell surface associated and/or secreted enzymes (Křepela et al, 1998).…”

mentioning

confidence: 99%

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

et al. 2004

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To determine the role of the cysteine proteinase inhibitor cystatin C in the invasive behavior of squamous cell carcinoma of the head and neck (SCCHN), Cystatin C protein level was measured in 82 pairs of primary tumour tissue and adjacent noncancerous mucosa, using the enzyme-linked immunosorbent assay. The median level of cystatin C in tumour tissue was 1.18 times lower than that in corresponding mucosa (P ¼ 0.031). In normal mucosa samples, the cystatin C level was influenced by the site of sampling: it was lower in nonlaryngeal tissue samples (oral cavity, oro-or hypopharynx) than in laryngeal samples (P ¼ 0.004). The tumour cystatin C level correlated inversely with pN-stage (P ¼ 0.047), whereas a trend of lower cystatin C levels was observed in the group with extranodal tumour extension compared to those with no extranodal spread (P ¼ 0.069). In univariate analysis, the patients with low tumour cystatin C levels exhibited poor disease-free survival (DFS, P ¼ 0.013) and disease-specific survival (DSS, P ¼ 0.013). In multivariate analysis, the most powerful predictor of survival was pN-stage (DFS: P ¼ 0.040, HR 2.78; DSS: P ¼ 0.011, HR 4.36,), followed by the cystatin C level (DFS: P ¼ 0.043, HR 0.22; DSS: P ¼ 0.067, HR 0.25). When comparing the prognostic strength of cystatin C to that of stefin A, another cysteine proteinase inhibitor, which emerged as the most significant prognosticator for survival in our previous study analysing the same cohort of patients, stefin A proved to be significantly more reliable predictor for both DFS and DSS than cystatin C. Our results indicate that cystatin C is implicated in the invasive behavior of SCCHN, and that there are variations in regulation of proteolytic pathways under nonmalignant conditions, inherent to individual subsites inside the upper aerodigestive tract. The correlation between high cystatin C levels and improved survival concurs with the concept of the protective role of high levels of cysteine proteinase inhibitors in tissue homogenates that has been previously suggested by the survival results in breast and lung carcinoma as well as SCCHN.

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Inactivation of human cystatin C and kininogen by human cathepsin D

Cited by 91 publications

References 26 publications

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

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

Apoptosis, tumour invasion and prostate cancer

Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis

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