The role of cystatins in cells of the immune system

Kopitar-Jerala, Nataša

doi:10.1016/j.febslet.2006.10.055

Cited by 118 publications

(95 citation statements)

References 87 publications

(98 reference statements)

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“…However, our data indicate that FheCL1 is resistant to this proteolytic degradation, which is consistent with our earlier findings showing that the mature enzyme is highly resistant to proteolytic degradation by endopeptidases (33). We have also shown that FheCL1 can degrade cystatins/serpins such as SCCA1 and SCCA2 (34) and therefore this may protect the enzyme from inhibition by cystatins within the lysosome that are known to regulate the activity of resident endolysosomal cathepsins (35).…”

Section: Discussionsupporting

confidence: 92%

Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3

Donnelly

O’Neill

Stack

et al. 2010

Journal of Biological Chemistry

123

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Helminth pathogens prepare a Th2 type immunological environment in their hosts to ensure their longevity. They achieve this by secreting molecules that not only actively drive type 2 responses but also suppress type 1 responses. Here, we show that the major cysteine proteases secreted from the helminth pathogens Fasciola hepatica (FheCL1) and Schistosoma mansoni (SmCB1) protect mice from the lethal effects of lipopolysaccharide by preventing the release of inflammatory mediators, nitric oxide, interleukin-6, tumor necrosis factor ␣, and interleukin-12, from macrophages. The proteases specifically block the MyD88-independent TRIF-dependent signaling pathway of Toll-like receptor (TLR)4 and TLR3. Microscopical and flow cytometric studies, however, show that alteration of macrophage function by cysteine protease is not mediated by cleavage of components of the TLR4 complex on the cell surface but occurs by degradation of TLR3 within the endosome. This is the first study to describe a parasite molecule that degrades this receptor and pinpoints a novel mechanism by which helminth parasites modulate the innate immune responses of their hosts to suppress the development of Th1 responses.To establish successful chronic infections, helminth parasites induce potent Th2 immune responses, which can only occur when Th1 cytokines are suppressed (1). To create this anti-inflammatory environment helminths secrete molecules that prevent dendritic cells and macrophages responding to Toll-like receptor (TLR) 2 Th1-stimulating ligands such as LPS and CpG (2-5). It has been proposed that helminth-secreted molecules themselves signal through TLRs, activating a different pattern of kinases compared with LPS, resulting in the extracellular signal-regulated kinase dependent inhibition of interleukin (IL)-12 production (reviewed in Ref. 6). The molecular nature of these Th1-suppressing components, however, remains largely unknown.Enzyme activity ascribable to the papain family of cysteine proteases (clan CA, family C1), such as cathepsin L and B, has been identified as a major component of the secretions of almost all helminth parasites of humans, livestock, and companion animals (7,8). These proteases are pivotal to the parasitic lifestyle by mediating fundamental processes such as host invasion, acquisition of nutrients, and the migration through host tissues (reviewed in Ref. 9). They can also have a systemic effect on the immune responses of their hosts by cleaving immunoglobulins and preventing antibody-mediated immune effector function, which protects the parasites from immune elimination (10, 11). We have shown that the predominant secreted product of the human and animal helminth pathogen Fasciola hepatica, a cathepsin L1 cysteine protease (FheCL1), suppressed the onset of protective Th1 immune responses in mice to infections with the respiratory microbe Bordetella pertussis, making them more susceptible to disease. In addition, injection of the cysteine protease immediately prior to immunization of mice with a B. pertussis whole...

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Section: Discussionsupporting

confidence: 92%

Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3

Donnelly

O’Neill

Stack

et al. 2010

Journal of Biological Chemistry

123

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“…Cathepsins are involved in processing and presentation of antigens, and are also involved in several pathological conditions such as inflammation and cancer. Cystatins can also induce synthesis of tumor necrosis factor and interleukin 10, and stimulate nitric oxide production (17).…”

Section: Discussionmentioning

confidence: 99%

Proteomics of exhaled breath: methodological nuances and pitfalls

Kurova¹,

Анаев²,

Kononikhin³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Background: The analysis of exhaled breath condensate (EBC) can be an alternative to traditional endoscopic sampling of lower respiratory tract secretions. This is a simple non-invasive method of diagnosing respiratory diseases, in particular, respiratory inflammatory processes. Methods: Samples were collected with a special device-condenser (ECoScreen, VIASYS Healthcare, Germany), then treated with trypsin according to the proteomics protocol for standard protein mixtures and analyzed by nanoflow high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) with a 7-Tesla Finnigan LTQ-FT mass spectrometer (Thermo Electron, Germany). Mascot software (Matrixscience) was used for screening the database NCBInr for proteins corresponding to the peptide maps that were obtained. Results: EBCs from 17 young healthy non-smoking donors were collected. Different methods for concentrating protein were compared in order to optimize EBC preparations for proteomic analysis. The procedure that was chosen allowed identification of proteins exhaled by healthy people. The major proteins in the condensates were cytoskeletal keratins. Another 12 proteins were identified in EBC from healthy non-smokers. Some keratins were found in the ambient air and may be considered exogenous components of exhaled air. Conclusions: Knowledge of the normal proteome of exhaled breath allows one to look for biomarkers of different disease states in EBC. Proteins in ambient air can be identified in the respiratory tract and should be excluded from the analysis of the proteome of EBC. The results obtained allowed us to choose the most effective procedure of sample preparation when working with samples containing very low protein concentrations. Clin Chem Lab Med 2009;47:706-12.

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“…The cystatins are naturally occurring cysteine proteinase inhibitors (see Kopitar-Jerala, 2006). We identified and cloned a cystatin from S. domuncula.…”

Section: Discussionmentioning

confidence: 99%

“…the cystatins and the stefins [see http://merops.sanger.ac.uk (Rawlings et al, 2004)]. These molecules are subdivided into (i) type 1 cystatins, cystatin/stefins A and B; these are polypeptides of ~98 amino acid residues that possess neither disulphide bonds nor carbohydrate side chains, and are located mainly intracellularly; (ii) type 2 cystatins C, D, E/M, F, S, SN, and SA; these are characterized by conserved disulphide bridges; and (iii) type 3 cystatins, the kininogens (Kopitar-Jerala, 2006). For the analysis of the proteinase specificity in the sponge spicules, type 1 sponge cystatin was cloned and the recombinant protein prepared.…”

Section: Sponge Cysteine Proteinase Inhibitor: Cystatinmentioning

confidence: 99%

Identification of a silicatein(-related) protease in the giant spicules of the deep-sea hexactinellidMonorhaphis chuni

Müller

Boreiko

Schloßmacher

et al. 2008

Journal of Experimental Biology

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SUMMARYSilicateins, members of the cathepsin L family, are enzymes that have been shown to be involved in the biosynthesis/condensation of biosilica in spicules from Demospongiae (phylum Porifera), e.g. Tethya aurantium and Suberites domuncula. The class Hexactinellida also forms spicules from this inorganic material. This class of sponges includes species that form the largest biogenic silica structures on earth. The giant basal spicules from the hexactinellids Monorhaphis chuni and Monorhaphis intermedia can reach lengths of up to 3·m and diameters of 10·mm. The giant spicules as well as the tauactines consist of a biosilica shell that surrounds the axial canal, which harbours the axial filament, in regular concentric, lamellar layers, suggesting an appositional growth of the spicules. The lamellae contain 27·kDa proteins, which undergo post-translational modification (phosphorylation), while total spicule extracts contain additional 70·kDa proteins. The 27·kDa proteins cross-reacted with anti-silicatein antibodies. The extracts of spicules from the hexactinellid Monorhaphis displayed proteolytic activity like the silicateins from the demosponge S. domuncula. Since the proteolytic activity in spicule extracts from both classes of sponge could be sensitively inhibited by E-64 (a specific cysteine proteinase inhibitor), we used a labelled E-64 sample as a probe to identify the protein that bound to this inhibitor on a blot. The experiments revealed that the labelled E-64 selectively recognized the 27·kDa protein. Our data strongly suggest that silicatein(-related) molecules are also present in Hexactinellida. These new results are considered to also be of impact for applied biotechnological studies.

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The role of cystatins in cells of the immune system

Cited by 118 publications

References 87 publications

Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3

Helminth Cysteine Proteases Inhibit TRIF-dependent Activation of Macrophages via Degradation of TLR3

Proteomics of exhaled breath: methodological nuances and pitfalls

Identification of a silicatein(-related) protease in the giant spicules of the deep-sea hexactinellidMonorhaphis chuni

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