Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis

Hamilton, Garth; Colbert, Jeff D.; Schuettelkopf, A.W.; Watts, Colin

doi:10.1038/sj.emboj.7601979

Cited by 103 publications

(174 citation statements)

References 48 publications

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“…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]. The Eur.…”

mentioning

confidence: 86%

“…Cathepsin C may itself be regulated by cystatin F. Cystatins are a family of proteinaceous cysteine protease inhibitors, some of which bind very tightly to cathepsin active sites [64]. 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].…”

Section: Activation Of Granule Serine Proteasesmentioning

confidence: 99%

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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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confidence: 86%

Section: Activation Of Granule Serine Proteasesmentioning

confidence: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…Because of these preprogrammed effector functions, several control mechanisms probably are needed to prevent potential damage to the fetus. These mechanisms could involve inhibitory natural killer receptors such as NKG2A and KLRG1, regulation of IFN-γ expression by TWIST1, and control of granzyme A activity by cystatin 7 (also known as "cystatin F") (46,52,79). In addition, in comparison with Vγ9Vδ2 T cells in adults, Vγ9Vδ2 T cells in early life appear to have a higher threshold for activation by phosphoantigens such as HMB-PP and IPP, especially for the production of cytokines (this study and refs.…”

Section: Discussionmentioning

confidence: 99%

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

Dimova

Brouwer

Gosselin

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

187

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γδ T cells are unconventional T cells recognizing antigens via their γδ T-cell receptor (TCR) in a way that is fundamentally different from conventional αβ T cells. γδ T cells usually are divided into subsets according the type of Vγ and/or Vδ chain they express in their TCR. T cells expressing the TCR containing the γ-chain variable region 9 and the δ-chain variable region 2 (Vγ9Vδ2 T cells) are the predominant γδ T-cell subset in human adult peripheral blood. The current thought is that this predominance is the result of the postnatal expansion of cells expressing particular complementary-determining region 3 (CDR3) in response to encounters with microbes, especially those generating phosphoantigens derived from the 2-C-methyl-d-erythritol 4-phosphate pathway of isoprenoid synthesis. However, here we show that, rather than requiring postnatal microbial exposure, Vγ9Vδ2 T cells are the predominant blood subset in the second-trimester fetus, whereas Vδ1+ and Vδ3+ γδ T cells are present only at low frequencies at this gestational time. Fetal blood Vγ9Vδ2 T cells are phosphoantigen responsive and display very limited diversity in the CDR3 of the Vγ9 chain gene, where a germline-encoded sequence accounts for >50% of all sequences, in association with a prototypic CDR3δ2. Furthermore, these fetal blood Vγ9Vδ2 T cells are functionally preprogrammed (e.g., IFN-γ and granzymes-A/K), with properties of rapidly activatable innatelike T cells. Thus, enrichment for phosphoantigen-responsive effector T cells has occurred within the fetus before postnatal microbial exposure. These various characteristics have been linked in the mouse to the action of selecting elements and would establish a much stronger parallel between human and murine γδ T cells than is usually articulated.

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“…Dimer to monomer conversion is facilitated by proteolytic cleavage at the N-terminus (78), probably by cathepsin V (41). Proteolytic processing changes its inhibitory profile and, while full-length cystatin F inhibits legumain and cathepsins F, H, K, L, S and V (77), the N-terminal processing is essential for cathepsin C inhibition (78). In addition, intracellular localization of the dimeric and monomeric forms is different: the dimeric form is found primarily in endoplasmic reticulum and Golgi apparatus, while the monomeric form is found in lysosomes and is completely truncated at the N-terminus (78).…”

Section: Cystatins and The Immune Responsementioning

confidence: 99%

“…Proteolytic processing changes its inhibitory profile and, while full-length cystatin F inhibits legumain and cathepsins F, H, K, L, S and V (77), the N-terminal processing is essential for cathepsin C inhibition (78). In addition, intracellular localization of the dimeric and monomeric forms is different: the dimeric form is found primarily in endoplasmic reticulum and Golgi apparatus, while the monomeric form is found in lysosomes and is completely truncated at the N-terminus (78). Furthermore, the secreted dimeric cystatin F can be internalized by other cells through the mannose-6-phosphate receptor pathway and can thus function also in trans (76).…”

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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Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis

Cited by 103 publications

References 48 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

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

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