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      Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma

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          Abstract

          The cytotoxic granzyme B (GrB)/perforin pathway has been traditionally viewed as a primary mechanism that is used by cytotoxic lymphocytes to eliminate allogeneic, virally infected and/or transformed cells. Although originally proposed to have intracellular and extracellular functions, upon the discovery that perforin, in combination with GrB, could induce apoptosis, other potential functions for this protease were, for the most part, disregarded. As there are 5 granzymes in humans and 11 granzymes in mice, many studies used perforin knockout mice as an initial screen to evaluate the role of granzymes in disease. However, in recent years, emerging clinical and biochemical evidence has shown that the latter approach may have overlooked a critical perforin-independent, pathogenic role for these proteases in disease. This review focuses on GrB, the most characterized of the granzyme family, in disease. Long known to be a pro-apoptotic protease expressed by cytotoxic lymphocytes and natural killer cells, it is now accepted that GrB can be expressed in other cell types of immune and nonimmune origin. To the latter, an emerging immune-independent role for GrB has been forwarded due to recent discoveries that GrB may be expressed in nonimmune cells such as smooth muscle cells, keratinocytes, and chondrocytes in certain disease states. Given that GrB retains its activity in the blood, can cleave extracellular matrix, and its levels are often elevated in chronic inflammatory diseases, this protease may be an important contributor to certain pathologies. The implications of sustained elevations of intracellular and extracellular GrB in chronic vascular, dermatological, and neurological diseases, among others, are developing. This review examines, for the first time, the multiple roles of GrB in disease pathogenesis.

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          Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.

          We report here the purification of the third protein factor, Apaf-3, that participates in caspase-3 activation in vitro. Apaf-3 was identified as a member of the caspase family, caspase-9. Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation. Activated caspase-9 in turn cleaves and activates caspase-3. Depletion of caspase-9 from S-100 extracts diminished caspase-3 activation. Mutation of the active site of caspase-9 attenuated the activation of caspase-3 and cellular apoptotic response in vivo, indicating that caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP.
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            Type 1 diabetes: new perspectives on disease pathogenesis and treatment.

            As our knowledge of type 1 (insulin-dependent) diabetes increases, so does our appreciation for the pathogenic complexity of this disease and the challenges associated with its treatment. Many new concepts about the pathogenesis of this disorder have arisen. The role of genetics versus environment in disease formation has been questioned, and the basis on which type 1 diabetes is characterised and diagnosed is the subject of much debate. Additionally, the care and treatment of patients with type 1 diabetes has seen a rapid evolution; with genetically engineered insulins, glucose monitoring devices, and algorithms all contributing to a decrease in disease-related complications. We focus this seminar on these changing views, and offer a new perspective on our understanding of the pathogenesis of type 1 diabetes and on principles for therapeutic management of patients with this disorder.
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              Death by a thousand cuts: granzyme pathways of programmed cell death.

              The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.
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                Author and article information

                Contributors
                dgranville@mrl.ubc.ca
                Journal
                Lab Invest
                Lab. Invest
                Laboratory Investigation; a Journal of Technical Methods and Pathology
                Nature Publishing Group US (New York )
                0023-6837
                1530-0307
                21 September 2009
                2009
                : 89
                : 11
                : 1195-1220
                Affiliations
                [1 ]GRID grid.416553.0, ISNI 0000 0000 8589 2327, UBC James Hogg Research Laboratory, Providence Heart and Lung Institute at St. Paul's Hospital, ; Vancouver, BC Canada
                [2 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Department of Pathology and Laboratory Medicine, , University of British Columbia, ; Vancouver, BC Canada
                Article
                BFlabinvest200991
                10.1038/labinvest.2009.91
                7102238
                19770840
                d86af522-491c-4981-af44-852a712f94ca
                © United States and Canadian Academy of Pathology, Inc. 2009

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 23 May 2009
                : 13 July 2009
                : 29 July 2009
                Categories
                Article
                Custom metadata
                © United States & Canadian Academy of Pathology 2009

                Pathology
                apoptosis,chronic disease,extracellular matrix,granzyme b,immunity,inflammation
                Pathology
                apoptosis, chronic disease, extracellular matrix, granzyme b, immunity, inflammation

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