Altered Storage of Proteases in Mast Cells from Mice Lacking Heparin: A Possible Role for Heparin Carboxypeptidase A Processing

Henningsson, Frida; Ledin, Johan; Lunderius, Carolina; Wilén, Maria; Hellman, Lars; Pejler, Gunnar

doi:10.1515/bc.2002.083

Cited by 42 publications

(49 citation statements)

References 51 publications

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“…C, effect of SG on granzyme B activity. Extracts were prepared from non-stimulated spleen cells (empty symbols) and from ConA-stimulated (3 days) spleen-derived CTLs predominantly highly sulfated GAGs of heparin type ([IdoUA-GlcNAc] n carbohydrate backbone) (36), whereas bone marrow-derived mast cells synthesize GAG chains of equally high charge density albeit of chondroitin sulfate type ([GlcUA-GalNAc] n carbohydrate backbone) (37). In contrast, SG produced by macrophages (38) and NK cells (17) contain chondroitin sulfate chains of much lower charge density.…”

Section: Discussionmentioning

confidence: 99%

Serglycin-deficient Cytotoxic T Lymphocytes Display Defective Secretory Granule Maturation and Granzyme B Storage

Grujić

Braga

Lukinius

et al. 2005

Journal of Biological Chemistry

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109

107

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Cytotoxic T lymphocytes eliminate infected and tumor cells mainly by perforin/granzyme-induced apoptosis. Earlier studies suggested that serglycin-proteoglycans form macromolecular complexes with granzymes and perforin in the cytotoxic granule. Serglycin-proteoglycans may also be involved in the delivery of the cytolytic machinery into target cells. We have developed a serglycin-deficient mouse strain, and here we studied the importance of serglycin-proteoglycans for various aspects of cytotoxic T lymphocyte function.35 SO 4 2؊ radiolabeling of serglycin-deficient cells demonstrated a dramatic reduction of incorporated label as compared with wild type cells, indicating that serglycin is by far the dominating proteoglycan species produced by the cytotoxic T lymphocyte. Moreover, lack of serglycin resulted in impaired ability of cytotoxic T lymphocytes to produce secretory granule of high electron density, although granule of lower electron density were produced both in wild type and serglycin-deficient cells. The serglycin deficiency did not affect the mRNA expression for granzyme A, granzyme B, or perforin. However, the storage of granzyme B, but not granzyme A, Fas ligand, or perforin, was severely defective in serglycin-deficient cells. Serglycin-deficient cells did not display defects in late cytotoxicity toward target cell lines. Taken together, these results point to a key role for serglycin in the storage of granzyme B and for secretory granule maturation but argue against a major role for serglycin in the apoptosis mediated by cytotoxic T lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Serglycin-deficient Cytotoxic T Lymphocytes Display Defective Secretory Granule Maturation and Granzyme B Storage

Grujić

Braga

Lukinius

et al. 2005

Journal of Biological Chemistry

Self Cite

109

107

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“…In line with such an explanation, it was recently shown that mast cell carboxypeptidase A expressed by bone marrow-derived mast cells is strictly dependent on heparin glycosaminoglycan for storage and processing, whereas mast cell tryptase can be stored and processed also in cells lacking heparin but containing chondroitin sulfate of equal charge density [35].…”

Section: Discussionmentioning

confidence: 87%

“…As can be seen in Table 1, PMA treatment resulted in a 50-80% increase in total proteoglycan synthesis. Further, treatment of the cells with HX-xyl, both in the presence or absence of PMA, resulted in a marked ( threefold) increase in the synthesis of 35 S-labelled macromolecules (Table 1). After HX-xyl treatment, the major part of the 35 S-labelled macromolecules expressed was recovered in the culture medium, regardless if PMA was present or not (Table 1).…”

Section: Xyloside and Proteoglycan Expressionmentioning

confidence: 97%

“…Further, treatment of the cells with HX-xyl, both in the presence or absence of PMA, resulted in a marked ( threefold) increase in the synthesis of 35 S-labelled macromolecules (Table 1). After HX-xyl treatment, the major part of the 35 S-labelled macromolecules expressed was recovered in the culture medium, regardless if PMA was present or not (Table 1). In contrast, control cells and cells treated with PMA retained a major portion of the 35 S-labelled macromolecules in the cell fraction (Table 1).…”

Section: Xyloside and Proteoglycan Expressionmentioning

confidence: 97%

“…In contrast, control cells and cells treated with PMA retained a major portion of the 35 S-labelled macromolecules in the cell fraction (Table 1). 35 S-labelled macromolecules recovered from the medium fractions were analyzed by gel chromatography to discriminate between intact proteoglycans and free glycosaminoglycan chains. Further, samples were analyzed both before and after treatment with alkali (NaOH), a treatment that is known to release glycosaminoglycans from their respective protein cores.…”

Section: Xyloside and Proteoglycan Expressionmentioning

confidence: 99%

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Secretion of macrophage urokinase plasminogen activator is dependent on proteoglycans

Pejler

Winberg

Vuong

et al. 2003

European Journal of Biochemistry

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The importance of proteoglycans for secretion of proteolytic enzymes was studied in the murine macrophage cell line J774. Untreated or 4b-phorbol 12-myristate 13-acetate (PMA)-stimulated macrophages were treated with hexyl-b-D-thioxyloside to interfere with the attachment of glycosaminoglycan chains to their respective protein cores. Activation of the J774 macrophages with PMA resulted in increased secretion of trypsin-like serine proteinase activity. This activity was completely inhibited by plasminogen activator inhibitor 1 and by amiloride, identifying the activity as urokinase plasminogen activator (uPA). Treatment of both the unstimulated or PMA-stimulated macrophages with xyloside resulted in decreased uPA activity and Western blotting analysis revealed an almost complete absence of secreted uPA protein after xyloside treatment of either control-or PMA-treated cells. Zymography analyses with gels containing both gelatin and plasminogen confirmed these findings. The xyloside treatment did not reduce the mRNA levels for uPA, indicating that the effect was at the post-translational level. Treatment of the macrophages with xylosides did also reduce the levels of secreted matrix metalloproteinase 9. Taken together, these findings indicate a role for proteoglycans in the secretion of uPA and MMP-9.Keywords: proteoglycan; xyloside; matrix metalloproteinase; urokinase; secretion.The capacity to secrete various compounds is an important property of cells in the monocytoid-macrophage lineage, in addition to the phagocytic and antigen presenting functions [1]. The secretory repertoire includes such molecules as tumor necrosis factor-a, lipoprotein lipase, proteoglycans, leukotrienes, and various proteases [2]. The proteoglycans expressed by monocytes and macrophages have been characterized to some extent. The major product seems to be serglycin, as shown by N-terminal sequencing of proteoglycans released from the cultured monocytic cell lines U937 and THP-1 [2,3]. Moreover, it has been shown that activated murine and human macrophages express syndecan-4 [4] and syndecan-2 [5], respectively, on the cell surface.The release of serglycin from monocytes and macrophages is the subject of regulation by inflammatory signaling molecules such as interferon-c, transforming growth factor-b, and platelet derived growth factor [2,6]. It is therefore likely that the secretion of proteoglycans in these cells is linked to inflammatory reactions and that its function(s) may be linked to the binding, transport and regulation of other secretory products. Indeed, recent data indicate that mice lacking functional heparin chains attached to their serglycin proteoglycans show severe defects in their capacities to store mast cell proteases in the secretory granules [7,8], clearly demonstrating the importance of intact proteoglycans for normal storage of proteases in these cells. Serglycin proteoglycans have also been implicated in the regulation of mast cell protease activities [9][10][11].The biological functions of proteoglycans from acti...

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Serglycin proteoglycan: Regulating the storage and activities of hematopoietic proteases

2009

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Serglycin (SG), like all other proteoglycans, consists of a protein "core" to which sulfated and thereby negatively charged polysaccharide chains of glycosaminoglycan type are attached. The recent generation of mice lacking a functional SG gene has revealed a number of biological functions of SG. In particular, it has been shown that SG has a key role in promoting the storage and in regulating the activities of a number of proteases expressed in hematopoietic cell types, most notably various mast cell proteases. In this review, we summarize the recent development in our understanding of the biological function of SG, in particular by focusing on the novel insight provided through analysis of the SG-deficient mouse strain.

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Altered Storage of Proteases in Mast Cells from Mice Lacking Heparin: A Possible Role for Heparin Carboxypeptidase A Processing

Cited by 42 publications

References 51 publications

Serglycin-deficient Cytotoxic T Lymphocytes Display Defective Secretory Granule Maturation and Granzyme B Storage

Serglycin-deficient Cytotoxic T Lymphocytes Display Defective Secretory Granule Maturation and Granzyme B Storage

Secretion of macrophage urokinase plasminogen activator is dependent on proteoglycans

Serglycin proteoglycan: Regulating the storage and activities of hematopoietic proteases

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