Inhibitory properties of cystatin F and its localization in U937 promonocyte cells

Langerholc, Tomaž; Zavašnik-Bergant, Valentina; Turk, Boris; Türk, Vito; Abrahamson, Magnus; Kos, Janko

doi:10.1111/j.1742-4658.2005.04594.x

Cited by 72 publications

(90 citation statements)

References 49 publications

(81 reference statements)

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“…Cystatin F has a unique cathepsin inhibition profile, with a clear preference for cathepsins F, K, L, and V (20,22). Interactions of cystatins with family C1 cysteine proteases are mediated by three regions, an N-terminal segment and the two hairpin loops L1 and L2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The inhibitor shares Ͻ35% sequence identity with other type II cystatins and possesses a unique extension of ϳ6 amino acids at its N terminus. Compared with other cystatins, the protein exhibits a distinct specificity profile, binding tightly to cathepsins F, K, L, and V, less tightly to cathepsins S and H, and not inhibiting cathepsins B, C, or X (20,22). Although cystatin F can inhibit AEP, its affinity is reduced compared with other AEP binding cystatins (11).…”

mentioning

confidence: 97%

“…Cystatin F is produced as a dimer (24) that is inactive as a cathepsin inhibitor. The dimer can be activated by chemical reduction, which is accompanied by a shift from dimeric to monomeric species (22).…”

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confidence: 99%

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Structural Basis of Reduction-dependent Activation of Human Cystatin F

Schüttelkopf

Hamilton

Watts

et al. 2006

Journal of Biological Chemistry

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Cystatins are important natural cysteine protease inhibitors targeting primarily papain-like cysteine proteases, including cathepsins and parasitic proteases like cruzipain, but also mammalian asparaginyl endopeptidase. Mammalian cystatin F, which is expressed almost exclusively in hematopoietic cells and accumulates in lysosome-like organelles, has been implicated in the regulation of antigen presentation and other immune processes. It is an unusual cystatin superfamily member with a redox-regulated activation mechanism and a restricted specificity profile. We describe the 2.1 Å crystal structure of human cystatin F in its dimeric "off" state. The two monomers interact in a fashion not seen before for cystatins or cystatin-like proteins that is crucially dependent on an unusual intermolecular disulfide bridge, suggesting how reduction leads to monomer formation and activation. Strikingly, core sugars for one of the two N-linked glycosylation sites of cystatin F are well ordered, and their conformation and interactions with the protein indicate that this unique feature of cystatin F may modulate its inhibitory properties, in particular its reduced affinity toward asparaginyl endopeptidase compared with other cystatins.

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Section: Resultsmentioning

confidence: 99%

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confidence: 97%

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Structural Basis of Reduction-dependent Activation of Human Cystatin F

Schüttelkopf

Hamilton

Watts

et al. 2006

Journal of Biological Chemistry

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“…We recently showed that cystatin F, which is principally found in immune cells, could inhibit cathepsin C [65]. Cystatin F is made initially as an inactive disulphide-linked dimer [66][67][68]. Reduction generates an inhibitor able to target some endopeptidases but we found that carbohydrate-driven lysosomal targeting [69] resulted in monomerisation and activation by proteolysis, which extended the protease target range to enzymes such as cathepsin C [65].…”

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confidence: 87%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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“…It is expressed as a disulphide linked dimer and targeted to the endosomal/lysosomal pathway through the mannose-6-phosphate sorting machinery (76), where it can regulate the activity of cysteine peptidases. However, cystatin F is not active as an inhibitor of cysteine cathepsins until it is converted to the monomeric form (77). Dimer to monomer conversion is facilitated by proteolytic cleavage at the N-terminus (78), probably by cathepsin V (41).…”

Section: Cystatins and The Immune Responsementioning

confidence: 99%

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

et al. 2017

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Cystatins comprise a superfamily of evolutionarily related proteins, present in all living organisms, from protozoa to mammals. They act as inhibitors of cysteine peptidases although they can also function independently of their inhibitory function. Cysteine cathepsins are implicated in various physiological and pathological processes. In the immune response they are involved in antigen processing and presentation, the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll-like receptor signalling. Cystatins are probably involved in the regulation of all these processes; importantly, cystatin F has a crucial role in the regulation of immune cell cytotoxicity. NK cells and CTLs exploit the granzyme/perforinAmong those peptidases involved in immune processes, many studies have been focused on a group of endosomal/lysosomal cysteine peptidases, the cysteine cathepsins, whose involvement in antigen processing and presentation, cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll like receptor (TLR) signalling have been demonstrated (3,4). In addition to cathepsins, another lysosomal cysteine peptidase, legumain or asparaginyl endopeptidase, has also been associated with the immune response, most notably with antigen presentation and TLR signalling (4, 5). The activities of cysteine cathepsins and legumain are regulated on different levels. Their expression, for example, is regulated at transcriptional or translational levels. They are synthesised as inactive precursors, activated only at the site of action, and compartmentalised into lysosomes or other organelles. Their activity can be regulated by oxidation of the active site cysteine or by endogenous protein inhibitors (6), the latter being presented in more detail. CYSTEINE CATHEPSINS AND LEGUMAIN AS REGULATORS OF THE IMMUNE RESPONSEIn humans, cysteine cathepsins comprise a group of 11 lysosomal peptidases (cathepsins B, C, F, H, K, L, O, S, V, X and W). They are members of the papain family, classified as clan CA (7). The expression pattern, levels, localization and specificities of cysteine cathepsins differ, contributing to their various physiological roles. Cathepsins B, H, L and C are expressed ubiquitously in cells and tissues, while expression of others is restricted to specific cell types. They are endopeptidases, with the exception of cathepsins B, C, H and X. Cathepsins B and X are carboxypeptidases, cleaving substrates at the C-terminal end, while cathepsins B and H are aminopeptidases, cleaving substrates at the N-terminal end. Interestingly, in addition to exopeptidase activity, cathepsins B and H also exhibit endopeptidase activity (7,8). Cathepsin B can act as an endo-or exopeptidase due to the position of the structural element, termed the occluding loop, while in cathepsin H the type of activity is determined by a minicha...

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Inhibitory properties of cystatin F and its localization in U937 promonocyte cells

Cited by 72 publications

References 49 publications

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Diverse regulatory roles for lysosomal proteases in the immune response

Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

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