Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Dana Farber Cancer Institute and Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/2008; 26(1):389-420. DOI: 10.1146/annurev.immunol.26.021607.090404
Source: PubMed


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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Available from: Dipanjan Chowdhury, Aug 06, 2015
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    • "In contrast to what is suggested in relation with APC cells, a significant increase in the recruitment of cytotoxic cells, according to the expression levels of cytotoxic T and NK cell peptides granzyme (Chowdhury and Lieberman, 2008) and NK lysin (Andersson et al., 1995), in response to the expression of zfBD2 was detected in the muscle of fish injected with pMCV1.4-zfBD2 (Fig. 2C) compared to both control and pMCV1.4-injected "
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    • "Secretory lysosomes are polarized towards the immunological synapse, where they fuse with the plasma membrane releasing their cytotoxic contents [4]–[6]. The pore forming protein perforin then facilitates the entry of pro-apoptopic granzymes into the target cell cytoplasm resulting in cell death [2], [3]. "
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    ABSTRACT: Natural killer (NK) cell secretory lysosome exocytosis and cytotoxicity are impaired in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4), a disorder caused by mutations in the gene encoding the SNARE protein syntaxin 11. We show that syntaxin 11 binds to SNAP23 in NK cells and that this interaction is reduced by FHL-4 truncation and frameshift mutation proteins that delete all or part of the SNARE domain of syntaxin 11. In contrast the FHL-4 mutant proteins bound to the Sec-1/Munc18-like (SM) protein Munc18-2. We demonstrate that the C-terminal cysteine rich region of syntaxin 11, which is deleted in the FHL-4 mutants, is S-acylated. This posttranslational modification is required for the membrane association of syntaxin 11 and for its polarization to the immunological synapse in NK cells conjugated to target cells. Moreover, we show that Munc18-2 is recruited by syntaxin 11 to intracellular membranes in resting NK cells and to the immunological synapse in activated NK cells. This recruitment of Munc18-2 is abolished by deletion of the C-terminal cysteine rich region of syntaxin 11. These results suggest a pivotal role for S-acylation in the function of syntaxin 11 in NK cells.
    PLoS ONE 06/2014; 9(6):e98900. DOI:10.1371/journal.pone.0098900 · 3.23 Impact Factor
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    • "Splenocytes from each strain, harvested 8 days after Lm infection, were incubated with anti- CD3-coated Lm-infected RAW264.7 cells (Figure 3E). WT and Gzmb À/À splenocytes killed host cells and Lm equivalently, probably because the lack of GzmB is well compensated by other Gzms (Chowdhury and Lieberman, 2008). PFN-deficient splenocytes, even if they expressed GNLY, did not kill host cells or intracellular bacteria. "
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    ABSTRACT: When killer lymphocytes recognize infected cells, perforin delivers cytotoxic proteases (granzymes) into the target cell to trigger apoptosis. What happens to intracellular bacteria during this process is unclear. Human, but not rodent, cytotoxic granules also contain granulysin, an antimicrobial peptide. Here, we show that granulysin delivers granzymes into bacteria to kill diverse bacterial strains. In Escherichia coli, granzymes cleave electron transport chain complex I and oxidative stress defense proteins, generating reactive oxygen species (ROS) that rapidly kill bacteria. ROS scavengers and bacterial antioxidant protein overexpression inhibit bacterial death. Bacteria overexpressing a GzmB-uncleavable mutant of the complex I subunit nuoF or strains that lack complex I still die, but more slowly, suggesting that granzymes disrupt multiple vital bacterial pathways. Mice expressing transgenic granulysin are better able to clear Listeria monocytogenes. Thus killer cells play an unexpected role in bacterial defense.
    Cell 06/2014; 157(6):1309-1323. DOI:10.1016/j.cell.2014.03.062 · 32.24 Impact Factor
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