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

Abstract

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...

The role of cysteine peptidases in coronavirus cell entry and replication: The therapeutic potential of cathepsin inhibitors

“…The potent effect of cysteine peptidase inhibitors on CoV replication was already shown in the 1990s ( Table 2 ) when Colling and Grubb demonstrated the inhibition of CoV replication by cystatins C and D [ 139 , 140 ]. Cystatins are general inhibitors of cysteine peptidases (reviewed in [ 141 – 143 ]) and may inactivate either viral or host cysteine peptidases. Cystatin C potently affects HCoV-OC43 and HCoV-229E, inhibiting their replication by more than 99% at a concentration of 0.1 mM [ 140 ].…”

Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease

“…Because cell activation is a prerequisite for T cell differentiation, we assessed CD69 upregulation and IFN-γ production as phenotypic markers of these processes. We employed isolated CD3 + cells for the assessment of cell activation to avoid the indirect effects of non-T cells, 22 and the higher affinity of non-T cells for TLR9 ligands 23 (Fig. 2).…”

Parasite Cystatin: Immunomodulatory Molecule with Therapeutic Activity against Immune Mediated Disorders

“…Cystatins are naturally occurring intracellular cysteine protease inhibitors that are extensively expressed across all living organisms, from protozoa to mammals. Cystatins are mostly localized in the endosomes and lysosomes [ 32 ], however, they can also be found in the nucleus, cytosol, cell membrane, or secreted from the cells [ 33 ]. Cystatins participate in many vital physiologic processes and interfere in the immune processes (antigen processing and presentation, migration of immune cells, activation of toll-like receptors, and cytokines secretion), wound healing, bone remodeling, osteogenesis and reabsorption, proprotein processing, and disease progression (such as cancer and inflammation) [ 34 , 35 , 36 , 37 ].…”

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