Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms

Colbert, Jeff D.; Matthews, S.; Kos, Janko; Watts, Colin

doi:10.1074/jbc.m111.253914

Cited by 34 publications

(39 citation statements)

References 45 publications

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“…However, the mechanism underlying legumain involvement in cytotoxicity is not known, though one possibility is through processing of either cathepsin L or H from their single chain to two chain forms (33). The fact that internalized exogenous cystatin F stabilizes cathepsin L protein levels and inhibits legumain in bone marrow-derived dendritic cells and macrophages supports this thesis (108).…”

Section: Regulation Of Cell Cytotoxicity By Cystatinssupporting

confidence: 48%

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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Section: Regulation Of Cell Cytotoxicity By Cystatinssupporting

confidence: 48%

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

et al. 2017

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“…It is also widely accepted that cysteine cathepsins are the primary proteases involved in a variety of pathological processes [36], [37]. CF has been identified as a major endogenous lysosomal cysteine protease inhibitor, and its potential target is cathepsins [38], [39]. The results of recent studies have suggesed that a proteolytic cleavage event is required to convert inactive CF into an active cathepsin inhibitor [12], [19].…”

Section: Discussionmentioning

confidence: 99%

“…For example, CF mRNA levels are significantly upregulated during the maturation and activation of immune cells from quiescent precursors [19], [40]. CF modulates the specific immune response through the inhibition of lysosomal cathepsin, which plays a role in immune cell activation, adhesion and transmigration [39], [41]. CF enhances the production of active pro-inflammatory molecules, increases the expression of inducible nitric oxide synthase and up-regulates nitric oxide production [42].…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2A Receptor Deficiency Up-Regulates Cystatin F Expression in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

et al. 2012

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In previous studies, we have shown that the inactivation of the adenosine A2A receptor exacerbates chronic cerebral hypoperfusion-induced white matter lesions (WMLs) by enhancing neuroinflammatory responses. However, the molecular mechanism underlying the effect of the adenosine A2A receptor remains unknown. Recent studies have demonstrated that cystatin F, a potent endogenous cysteine protease inhibitor, is selectively expressed in immune cells in association with inflammatory demyelination in central nervous system diseases. To understand the expression of cystatin F and its potential role in the effect of A2A receptor on WMLs induced through chronic cerebral hypoperfusion, we investigated cystatin F expression in the WMLs of A2A receptor gene knockout mice, the littermate wild-type mice and wild-type mice treated daily with the A2A receptor agonist CGS21680 or both CGS21680 and A2A receptor antagonist SCH58261 after chronic cerebral hypoperfusion. The results of quantitative-PCR and western blot analysis revealed that cystatin F mRNA and protein expression were significantly up-regulated in the WMLs after chronic cerebral hypoperfusion. In addition, cystatin F expression in the corpus callosum was significantly increased in A2A receptor gene knockout mice and markedly decreased in mice treated with CGS21680 on both the mRNA and protein levels. Additionally, SCH58261 counteracted the attenuation of cystatin F expression produced by CGS21680 after chronic cerebral hypoperfusion. Moreover, double immunofluorescence staining revealed that cystatin F was co-localized with the activated microglia marker CD11b. In conclusion, the cystatin F expression in the activated microglia is closely associated with the effect of the A2A receptors, which may be related to the neuroinflammatory responses occurring during the pathological process.

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“…Therefore, it is not clear under what circumstances cystatins meet their targets. In recent studies, it was shown that secreted type II cystatins can be internalized by immune or tumor cells, accumulating in endosomal/lysosomal vesicles ( 28 , 29 ). The vesicular localization of cystatins may result in affecting a number of cell functions.…”

Section: Endogenous and Exogenous Inhibitors Of Cysteine Cathepsinsmentioning

confidence: 99%

Cysteine Cathepsins as Regulators of the Cytotoxicity of NK and T Cells

et al. 2014

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Cysteine cathepsins are lysosomal peptidases involved at different levels in the processes of the innate and adaptive immune responses. Some, such as cathepsins B, L, and H are expressed constitutively in most immune cells. In cells of innate immunity they play a role in cell adhesion and phagocytosis. Other cysteine cathepsins are expressed more specifically. Cathepsin X promotes dendritic cell maturation, adhesion of macrophages, and migration of T cells. Cathepsin S is implicated in major histocompatibility complex class II antigen presentation, whereas cathepsin C, expressed in cytotoxic T lymphocytes and natural killer (NK) cells, is involved in processing pro-granzymes into proteolytically active forms, which trigger cell death in their target cells. The activity of cysteine cathepsins is controlled by endogenous cystatins, cysteine protease inhibitors. Of these, cystatin F is the only cystatin that is localized in endosomal/lysosomal vesicles. After proteolytic removal of its N-terminal peptide, cystatin F becomes a potent inhibitor of cathepsin C with the potential to regulate pro-granzyme processing and cell cytotoxicity. This review is focused on the role of cysteine cathepsins and their inhibitors in the molecular mechanisms leading to the cytotoxic activity of T lymphocytes and NK cells in order to address new possibilities for regulation of their function in pathological processes.

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Internalization of Exogenous Cystatin F Supresses Cysteine Proteases and Induces the Accumulation of Single-chain Cathepsin L by Multiple Mechanisms

Cited by 34 publications

References 45 publications

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

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

Adenosine A2A Receptor Deficiency Up-Regulates Cystatin F Expression in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

Cysteine Cathepsins as Regulators of the Cytotoxicity of NK and T Cells

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