Leukocystatin, A New Class II Cystatin Expressed Selectively by Hematopoietic Cells

Halfon, Sherin; Ford, J. E.; Foster, Jessica; Dowling, L A; Lucian, Linda; Sterling, Marissa; Xu, Yuming; Weiss, Mary C.; Ikeda, Mami; Liggett, Debra; Helms, Allison; Caux, Christophe; Lebecque, Serge; Hannum, Chuck; Menon, Satish; McClanahan, Terrill K.; Gorman, Daniel M.; Zurawski, Gérard

doi:10.1074/jbc.273.26.16400

Cited by 99 publications

(96 citation statements)

References 36 publications

(38 reference statements)

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“…Although cystatin F can inhibit AEP, its affinity is reduced compared with other AEP binding cystatins (11). The expression of cystatin F is limited to hematopoietic cells, with the highest expression levels being observed in monocytes, dendritic cells, and certain types of T-cells (19,20). Furthermore, it has been shown that cystatin F mRNA becomes up-regulated during dendritic cell maturation (23).…”

mentioning

confidence: 99%

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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mentioning

confidence: 99%

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Schüttelkopf

Hamilton

Watts

et al. 2006

Journal of Biological Chemistry

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“…However, in cytotoxic cells the most prominent role in the regulation of cathepsin activity is attributed to cystatin F (Figure 1). Its preferential expression in immune cells and its endosomal/lysosomal localization already imply an important role in the immune response (73,76). In addition, cystatin F was found co-localized with granzyme A, perforin and Lamp-1 in human CD8+ T blasts, its overexpression in mouse CTLs led to decreased activity of cathepsin C (78).…”

Section: Regulation Of Cell Cytotoxicity By Cystatinsmentioning

confidence: 99%

“…Cystatin F is expressed primarily in cells of the immune system, such as dendritic cells, T cells and NK cells (72)(73)(74). While other type II cystatins are mainly secreted, the intracellular levels of cystatin F are unusually high, implying an important intracellular role (75).…”

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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“…In general, cathepsins need to be activated in the acid environment of lysosomes and are sensitively regulated as their release in the extracellular space can be destructive for cells (Halfon et al 1998). However, CTSS is stable and active at neutral and acid pH (Kirschke et al 1989).…”

Section: Introductionmentioning

confidence: 99%

“…CST7 is limited in its expression to cells of the immune system, e.g. natural killer (NK) cells and dendritic cells, and therefore potentially involved in the process of embryo implantation (Halfon et al 1998, Nathanson et al 2002.…”

Section: Introductionmentioning

confidence: 99%

The embryo's cystatin C and F expression functions as a protective mechanism against the maternal proteinase cathepsin S in mice

Baston-Buest

Schanz²,

Buest³

et al. 2010

Reproduction

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A successful implantation of a mammalian embryo into the maternal endometrium depends on a highly synchronized fetal-maternal dialogue involving chemokines, growth factors, and matrix-modifying enzymes. A growing body of evidence suggests an important role for proteinases playing a role in matrix degeneration and enhancing the embryo's invasive capacity and influencing the mother's immunological status in favor of the conceptus. This study focused on the expression of cathepsin S (CTSS) and its inhibitors in the murine fetal-maternal interface as well as the detection of the cellular sources of either proteinase and inhibitors. Nested RT-PCR for detection of embryonic mRNAs, immunohistochemistry of maternal and fetal tissues in B6C3F1 mice, and FACS analysis for determination of immunocompetent cell population were applied. This study shows that the cysteine proteinase CTSS is upregulated in the stroma of the implantation site, and that pregnancy induces an influx of CTSS-positive uterine natural killer cells. Compared to maternal tissues, the CTSS inhibitors cystatin F and C, but not the proteinase itself, are expressed in blastocysts. In conclusion, CTSS underlies a hormonal regulation in the maternal tissue and therewith most likely supports the embryonic implantation. The invading embryo regulates the depth of its own invasion through the expression of the cathepsin inhibitors and furthermore, interleukin-6 to activate CTSS in maternal tissues. Additionally, the observed decrease in CD3C cells leads to the hypothesis that cells of the cytotoxic T-cell group are downregulated in the decidua to support the implantation and ensure the survival of the embryo.

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Leukocystatin, A New Class II Cystatin Expressed Selectively by Hematopoietic Cells

Cited by 99 publications

References 36 publications

Structural Basis of Reduction-dependent Activation of Human Cystatin F

Structural Basis of Reduction-dependent Activation of Human Cystatin F

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

The embryo's cystatin C and F expression functions as a protective mechanism against the maternal proteinase cathepsin S in mice

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