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Apoptosis Induced by Granzyme B-Glycosaminoglycan Complexes: Implications for Granule-Mediated Apoptosis In Vivo Open Access (recommended)

Descriptions

Resource type(s)
Journal Article
Keyword
Apoptosis
Granzyme
Rights
Attribution 3.0 United States

Creator
Galvin, John P
Froelich, Christopher J
Wang, Baikun
Spaeny-Dekking, Liesbeth H. A.
Seth, Prem K
Hack, C. EriK
Abstract
Lymphocyte granule-mediated apoptosis occurs by perforin-mediated intracellular delivery of granule-associated serine proteases (granzymes). A granule-associated proteoglycan, namely serglycin, that contains chondroitin 4-sulfate (CS) glycosaminoglycans is present in the granules of cytotoxic cells. Serglycin acts as scaffold for packaging the positively charged granzymes and probably chaperones the proteases secreted extracellularly. To learn how the interaction of granzyme B (GrB) with serglycin might influence the apoptotic potential of this proteases, we have evaluated a model system where desalted CS is combined with isolated human granzyme. CS-GrB complexes were very stable, remaining undissociated in salt concentrations upwards to 500 mM (pH 7.4). On the basis of a capture enzyme immunoassay that accurately detects GrB, equivalent amounts of active free and CS-GrB, delivered by perforin or adenovirus, efficiently induced apoptosis in Jurkat cells and produced a similar time-dependent increase in caspase-3-like activity. CS-GrB processed isolated caspases-3 and -7 less efficiently than free granzyme. However, when added to cytosolic extracts, rates of processing were nearly equivalent for the two forms, suggesting cationic GrB may nonspecifically bind cytosolic proteins, leading to reduce proteolytic activity. Finally, GrB was found to be exocytosed from lymphocyte-activated killer cells as a neutral, high macromolecular weight complex, which possessed apoptotic activity. Collectively, the results indicate that neutral, high m.w. GrB has the capacity to induce cell death and will be useful to study the mechanism of cytotoxic cell-mediated apoptosis in vitro.
Original Bibliographic Citation
Galvin JP, Spaeny-Dekking LH, Wang B, Seth P, Hack CE, Froelich CJ. (1999) Apoptosis Induced by Granzyme B-Glycosaminoglycan Complexes: Implications for Granule-Mediated Apoptosis In Vivo. J Immunol 162(9):5345-5350.
Publisher
American Association of Immunologists, Inc.
DigitalHub. Galter Health Sciences Library
Date Created
1999
Original Identifier
(PMID)10228010
Language
English
Subject: MESH
Apoptosis
Granzymes
Glycosaminoglycans
DOI
10.18131/G3C881
ARK
ark:/c8131/g3c881

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