Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-76fb5796d-x4r87 Total loading time: 0 Render date: 2024-04-25T15:41:20.328Z Has data issue: false hasContentIssue false

10 - Cytotoxic Granules House Potent Proapoptotic Toxins Critical for Antiviral Responses and Immune Homeostasis

from Part I - General Principles of Cell Death

Published online by Cambridge University Press:  07 September 2011

Douglas R. Green
By
Katherine Baran ,
Ilia Voskoboinik ,
Nigel J. Waterhouse ,
Vivien R. Sutton  and
Joseph A. Trapani
Edited by
John C. Reed
Douglas R. Green
Affiliation:
St. Jude Children's Research Hospital, Memphis, Tennessee
Katherine Baran
Affiliation:
Peter MacCallum Cancer Centre
Ilia Voskoboinik
Affiliation:
Peter MacCallum Cancer Centre
Nigel J. Waterhouse
Affiliation:
University of Queensland
Vivien R. Sutton
Affiliation:
Peter MacCallum Cancer Centre
Joseph A. Trapani
Affiliation:
Peter MacCallum Cancer Centre
John C. Reed
Affiliation:
Sanford-Burnham Medical Research Institute, La Jolla, California
Get access

Summary

General Introduction

Cytotoxic lymphocytes and apoptosis

The immune system of high-order organisms is a highly specialized compartment that eliminates transformed cells and cells infected with viruses or bacteria through a controlled process of cell-mediated cytotoxicity. The immune cells responsible for mediating cell death are collectively called cytotoxic lymphocytes (CLs) and are made up of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). CLs are distinguished primarily by their respective mechanism of antigen recognition. NK cells form part of the innate immune response, a generalized first line of defense. NK cells are generally CD3–CD56+ lymphocytes that recognize and respond to abnormal cells through an imbalance of facilitatory and inhibitory receptors (Bottino et al., 2004;Moretta et al., 2004). CTLs formpart of the adaptive immune response, a more specific response that is generated subsequent to and as a consequence of the innate response. These cells use their clonotypic T-cell receptors (TcRs) to recognize a peptide antigen presented on the major histocompatability complex (MHC) proteins on the surface of the target cell. CTLs can be identified on the basis of expression of CD3 and CD8 (CD3+CD8+) on their cell surface. In addition, some CD4+ T cells (typically T-helper cells) can have limited cytotoxic capacity

Type
Chapter
Information
Apoptosis
Physiology and Pathology
 , pp. 106 - 122
Publisher: Cambridge University Press
Print publication year: 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Abdelhaleem, M.M., Hameed, S., Klassen, D. and Greenberg, A.H. (1996) Leukophysin: an RNA helicase A-related molecule identified in cytotoxic T cell granules and vesicles. J Immunol, 156, 2026–35.
Alimonti, J.B., Shi, L., Baijal, P.K. and Greenberg, A.H. (2001) Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition. J Biol Chem, 276, 6974–82.
Anderson, D.H., Sawaya, M.R., Cascio, D., Ernst, W., Modlin, R., Krensky, A. and Eisenberg, D. (2003) Granulysin crystal structure and a structure-derived lytic mechanism. J Mol Biol, 325, 355–65.
Anderson, P., Nagler-Anderson, C., O’Brien, C., Levine, H., Watkins, S., Slayter, H.S., Blue, M.L. and Schlossman, S.F. (1990) A monoclonal antibody reactive with a 15-kDa cytoplasmic granule-associated protein defines a subpopulation of CD8+ T lymphocytes. J Immunol, 144, 574–82.
Andrade, F., Fellows, E., Jenne, D.E., Rosen, A. and Young, C.S. (2007) Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J, 26, 2148–57.
Andrade, F., Roy, S., Nicholson, D., Thornberry, N., Rosen, A. and Casciola-Rosen, L. (1998) Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity, 8, 451–60.
Arico, M. (1991) Cyclosporine therapy for refractory Langerhans cell histiocytosis. Blood, 78, 3107.
Barry, M., Heibein, J.A., Pinkoski, M.J., Lee, S.F., Moyer, R.W., Green, D.R. and Bleackley, R.C. (2000) Granzyme B shortcircuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol, 20, 3781–94.
Beresford, P.J., Xia, Z., Greenberg, A.H. and Lieberman, J. (1999) Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation. Immunity, 10, 585–94.
Beresford, P.J., Zhang, D., Oh, D.Y., Fan, Z., Greer, E.L., Russo, M.L., Jaju, M. and Lieberman, J. (2001) Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. J Biol Chem, 276, 43285–93.
Bird, C.H., Sun, J., Ung, K., Karambalis, D., Whisstock, J.C., Trapani, J.A. and Bird, P.I. (2005) Cationic sites on granzyme B contribute to cytotoxicity by promoting its uptake into target cells. Mol Cell Biol, 25, 7854–67.
Bossi, G. and Griffiths, G.M. (2005) CTL secretory lysosomes: biogenesis and secretion of a harmful organelle. Semin Immunol, 17, 87–94.
Bottino, C., Moretta, L., Pende, D., Vitale, M. and Moretta, A. (2004) Learning how to discriminate between friends and enemies, a lesson from natural killer cells. Mol Immunol, 41, 569–75.
Bou-Gharios, G., Moss, J., Olsen, I. and Partridge, T. (1988) Ultrastructural localization of a lysosomal enzyme in resin-embedded lymphocytes. Histochemistry, 89, 69–74.
Browne, K.A., Blink, E., Sutton, V.R., Froelich, C.J., Jans, D.A. and Trapani, J.A. (1999) Cytosolic delivery of granzyme B by bacterial toxins: evidence that endosomal disruption, in addition to transmembrane pore formation, is an important function of perforin. Mol Cell Biol, 19, 8604–15.
Burkhardt, J.K., Hester, S. and Argon, Y. (1989) Two proteins targeted to the same lytic granule compartment undergo very different posttranslational processing. Proc Natl Acad Sci U S A, 86, 7128–32.
Burkhardt, J.K., Hester, S., Lapham, C.K. and Argon, Y. (1990) The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments. J Cell Biol, 111, 2327–40.
Bykovskaja, S.N., Rytenko, A.N., Rauschenbach, M.O. and Bykovsky, A.F. (1978) Ultrastructural alteration of cytolytic T lymphocytes following their interaction with target cells. I. Hypertrophy and change of orientation of the Golgi apparatus. Cell Immunol, 40, 164–74.
Casciola-Rosen, L., Garcia-Calvo, M., Bull, H.G., Becker, J.W., Hines, T., Thornberry, N.A. and Rosen, A. (2007) Mouse and human granzyme B have distinct tetrapeptide specificities and abilities to recruit the bid pathway. J Biol Chem, 282, 4545–52.
Chang, T.W. and Eisen, H.N. (1980) Effects of N alpha-tosyl-L-lysyl-chloromethylketone on the activity of cytotoxic T lymphocytes. J Immunol, 124, 1028–33.
Chowdhury, D., Beresford, P.J., Zhu, P., Zhang, D., Sung, J.S., Demple, B., Perrino, F.W. and Lieberman, J. (2006) The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Mol Cell, 23, 133–42.
Clayberger, C. and Krensky, A.M. (2003) Granulysin. Curr Opin Immunol, 15, 560–5.
Clementi, R., Locatelli, F., Dupre, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Arico, M. and Roncarolo, M.G. (2005) A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood, 105, 4424–8.
Cohen, J.J., Duke, R.C., Chervenak, R., Sellins, K.S. and Olson, L.K. (1985) DNA fragmentation in targets of CTL: an example of programmed cell death in the immune system. Adv Exp Med Biol, 184, 493–508.
Criado, M., Lindstrom, J.M., Anderson, C.G. and Dennert, G. (1985) Cytotoxic granules from killer cells: specificity of granules and insertion of channels of defined size into target membranes. J Immunol, 135, 4245–51.
Cullen, S.P., Adrain, C., Luthi, A.U., Duriez, P.J. and Martin, S.J. (2007) Human and murine granzyme B exhibit divergent substrate preferences. J Cell Biol, 176, 435–44.
Dang, T.X., Hotze, E.M., Rouiller, I., Tweten, R.K. and Wilson-Kubalek, E.M. (2005) Prepore to pore transition of a cholesterol-dependent cytolysin visualized by electron microscopy. J Struct Biol, 150, 100–108.
Darmon, A.J., Nicholson, D.W. and Bleackley, R.C. (1995) Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature, 377, 446–8.
Davis, J.E., Sutton, V.R., Smyth, M.J. and Trapani, J.A. (2000) Dependence of granzyme B-mediated cell death on a pathway regulated by Bcl-2 or its viral homolog, BHRF1. Cell Death Differ, 7, 973–83.
Deng, A., Chen, S., Li, Q., Lyu, S.C., Clayberger, C. and Krensky, A.M. (2005) Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J Immunol, 174, 5243–8.
Dennert, G. and Podack, E.R. (1983) Cytolysis by H-2-specific T killer cells. Assembly of tubular complexes on target membranes. J Exp Med, 157, 1483–95.
Dieli, F., Troye-Blomberg, M., Ivanyi, J., Fournie, J.J., Krensky, A.M., Bonneville, M., Peyrat, M.A., Caccamo, N., Sireci, G. and Salerno, A. (2001) Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vgamma9/Vdelta2 T lymphocytes. J Infect Dis, 184, 1082–5.
Dourmashkin, R.R., Deteix, P., Simone, C.B. and Henkart, P. (1980) Electron microscopic demonstration of lesions in target cell membranes associated with antibody-dependent cellular cytotoxicity. Clin Exp Immunol, 42, 554–60.
Duke, R.C., Persechini, P.M., Chang, S., Liu, C.C., Cohen, J.J. and Young, J.D. (1989) Purified perforin induces target cell lysis but not DNA fragmentation. J Exp Med, 170, 1451–6.
Dupuis, M., Schaerer, E., Krause, K.H. and Tschopp, J. (1993) The calcium-binding protein calreticulin is a major constituent of lytic granules in cytolytic T lymphocytes. J Exp Med, 177, 1–7.
Ebnet, K., Hausmann, M., Lehmann-Grube, F., Mullbacher, A., Kopf, M., Lamers, M. and Simon, M.M. (1995) Granzyme A-deficient mice retain potent cell-mediated cytotoxicity. EMBO J, 14, 4230–9.
Esser, M.T., Haverstick, D.M., Fuller, C.L., Gullo, C.A. and Braciale, V.L. (1998) Ca2+ signaling modulates cytolytic T lymphocyte effector functions. J Exp Med, 187, 1057–67.
Fan, Z., Beresford, P.J., Oh, D.Y., Zhang, D. and Lieberman, J. (2003a) Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell, 112, 659–72.
Fan, Z., Beresford, P.J., Zhang, D. and Lieberman, J. (2002) HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Mol Cell Biol, 22, 2810–20.
Fan, Z., Beresford, P.J., Zhang, D., Xu, Z., Novina, C.D., Yoshida, A., Pommier, Y. and Lieberman, J. (2003b) Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nat Immunol, 4, 145–53.
Fellows, E., Gil-Parrado, S., Jenne, D.E. and Kurschus, F.C. (2007) Natural killer cell-derived human granzyme H induces an alternative, caspase-independent cell-death program. Blood, 110, 544–52.
Fernandes-Alnemri, T., Armstrong, R.C., Krebs, J., Srinivasula, S.M., Wang, L., Bullrich, F., Fritz, L.C., Trapani, J.A., Tomaselli, K.J., Litwack, G. and Alnemri, E.S. (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc Natl Acad Sci U S A, 93, 7464–9.
Froelich, C.J., Hanna, W.L., Poirier, G.G., Duriez, P.J., D’Amours, D., Salvesen, G.S., Alnemri, E.S., Earnshaw, W.C. and Shah, G.M. (1996a) Granzyme B/perforin-mediated apoptosis of Jurkat cells results in cleavage of poly(ADP-ribose) polymerase to the 89-kDa apoptotic fragment and less abundant 64-kDa fragment. Biochem Biophys Res Commun, 227, 658–65.
Froelich, C.J., Orth, K., Turbov, J., Seth, P., Gottlieb, R., Babior, B., Shah, G.M., Bleackley, R.C., Dixit, V.M. and Hanna, W. (1996b) New paradigm for lymphocyte granule-mediated cytotoxicity. Target cells bind and internalize granzyme B, but an endosomolytic agent is necessary for cytosolic delivery and subsequent apoptosis. J Biol Chem, 271, 29073–9.
Grakoui, A., Bromley, S.K., Sumen, C., Davis, M.M., Shaw, A.S., Allen, P.M. and Dustin, M.L. (1999) The immunological synapse: a molecular machine controlling T cell activation. Science, 285, 221–7.
Gray, L.S., Gnarra, J.R. and Engelhard, V.H. (1987) Demonstration of a calcium influx in cytolytic T lymphocytes in response to target cell binding. J Immunol, 138, 63–9.
Griffiths, G.M. and Isaaz, S. (1993) Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. J Cell Biol, 120, 885–96.
Grossman, W.J., Revell, P.A., Lu, Z.H., Johnson, H., Bredemeyer, A.J. and Ley, T.J. (2003) The orphan granzymes of humans and mice. Curr Opin Immunol, 15, 544–52.
Hadders, M.A., Beringer, D.X. and Gros, P. (2007) Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science, 317, 1552–4.
Han, J., Goldstein, L.A., Gastman, B.R., Rabinovitz, A. and Rabinowich, H. (2005) Disruption of Mcl-1. Bim complex in granzyme B-mediated mitochondrial apoptosis. J Biol Chem, 280, 16383–92.
Hargrove, M.E., Wang, J. and Ting, C.C. (1993) Regulation by glutathione of the activation and differentiation of IL-4-dependent activated killer cells. Cell Immunol, 149, 433–43.
Hayes, M.P., Berrebi, G.A. and Henkart, P.A. (1989) Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A. J Exp Med, 170, 933–46.
Heibein, J.A., Goping, I.S., Barry, M., Pinkoski, M.J., Shore, G.C., Green, D.R. and Bleackley, R.C. (2000) Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax. J Exp Med, 192, 1391–402.
Henkart, P.A., Berrebi, G.A., Takayama, H., Munger, W.E. and Sitkovsky, M.V. (1987) Biochemical and functional properties of serine esterases in acidic cytoplasmic granules of cytotoxic T lymphocytes. J Immunol, 139, 2398–405.
Heusel, J.W., Wesselschmidt, R.L., Shresta, S., Russell, J.H. and Ley, T.J. (1994) Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells. Cell, 76, 977–87.
Jans, D.A., Briggs, L.J., Jans, P., Froelich, C.J., Parasivam, G., Kumar, S., Sutton, V.R. and Trapani, J.A. (1998) Nuclear targeting of the serine protease granzyme A (fragmentin-1). J Cell Sci, 111 (Pt 17), 2645–54.
Johnson, H., Scorrano, L., Korsmeyer, S.J. and Ley, T.J. (2003) Cell death induced by granzyme C. Blood, 101, 3093–101.
Jongstra, J., Schall, T.J., Dyer, B.J., Clayberger, C., Jorgensen, J., Davis, M.M. and Krensky, A.M. (1987) The isolation and sequence of a novel gene from a human functional T cell line. J Exp Med, 165, 601–14.
Kagi, D., Ledermann, B., Burki, K., Seiler, P., Odermatt, B., Olsen, K.J., Podack, E.R., Zinkernagel, R.M. and Hengartner, H. (1994) Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature, 369, 31–7.
Kagi, D., Odermatt, B. and Mak, T.W. (1999) Homeostatic regulation of CD8+ T cells by perforin. Eur J Immunol, 29, 3262–72.
Kagi, D., Odermatt, B., Seiler, P., Zinkernagel, R.M., Mak, T.W. and Hengartner, H. (1997) Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med, 186, 989–97.
Kaiserman, D., Bird, C.H., Sun, J., Matthews, A., Ung, K., Whisstock, J.C., Thompson, P.E., Trapani, J.A. and Bird, P.I. (2006) The major human and mouse granzymes are structurally and functionally divergent. J Cell Biol, 175, 619–30.
Kamal, A. and Goldstein, L.S. (2000) Connecting vesicle transport to the cytoskeleton. Curr Opin Cell Biol, 12, 503–508.
Kaspar, A.A., Okada, S., Kumar, J., Poulain, F.R., Drouvalakis, K.A., Kelekar, A., Hanson, D.A., Kluck, R.M., Hitoshi, Y., Johnson, D.E., Froelich, C.J., Thompson, C.B., Newmeyer, D.D., Anel, A., Clayberger, C. and Krensky, A.M. (2001) A distinct pathway of cell-mediated apoptosis initiated by granulysin. J Immunol, 167, 350–6.
Kataoka, T., Takaku, K., Magae, J., Shinohara, N., Takayama, H., Kondo, S. and Nagai, K. (1994) Acidification is essential for maintaining the structure and function of lytic granules of CTL. Effect of concanamycin A, an inhibitor of vacuolar type H(+)-ATPase, on CTL-mediated cytotoxicity. J Immunol, 153, 3938–47.
Kedersha, N.L., Gupta, M., Li, W., Miller, I. and Anderson, P. (1999) RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules. J Cell Biol, 147, 1431–42.
Keefe, D., Shi, L., Feske, S., Massol, R., Navarro, F., Kirchhausen, T. and Lieberman, J. (2005) Perforin triggers a plasma membrane-repair response that facilitates CTL induction of apoptosis. Immunity, 23, 249–62.
Kelly, J.M., Waterhouse, N.J., Cretney, E., Browne, K.A., Ellis, S., Trapani, J.A. and Smyth, M.J. (2004) Granzyme M mediates a novel form of perforin-dependent cell death. J Biol Chem, 279, 22236–42.
Kishi, A., Takamori, Y., Ogawa, K., Takano, S., Tomita, S., Tanigawa, M., Niman, M., Kishida, T. and Fujita, S. (2002) Differential expression of granulysin and perforin by NK cells in cancer patients and correlation of impaired granulysin expression with progression of cancer. Cancer Immunol Immunother, 50, 604–14.
Kojima, Y., Kawasaki-Koyanagi, A., Sueyoshi, N., Kanai, A., Yagita, H. and Okumura, K. (2002) Localization of Fas ligand in cytoplasmic granules of CD8+ cytotoxic T lymphocytes and natural killer cells: participation of Fas ligand in granule exocytosis model of cytotoxicity. Biochem Biophys Res Commun, 296, 328–36.
Kraut, J. (1977) Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem, 46, 331–58.
Kraut, R.P., Bose, D., Cragoe, E.J., Jr. and Greenberg, A.H. (1990) The influence of calcium, sodium, and the Na+/Ca2+ antiport on susceptibility to cytolysin/perforin-mediated cytolysis. J Immunol, 144, 3498–3505.
Krensky, A.M. (2000) Granulysin: a novel antimicrobial peptide of cytolytic T lymphocytes and natural killer cells. Biochem Pharmacol, 59, 317–20.
Kupfer, A. and Dennert, G. (1984) Reorientation of the microtubule-organizing center and the Golgi apparatus in cloned cytotoxic lymphocytes triggered by binding to lysable target cells. J Immunol, 133, 2762–6.
Kupfer, A., Dennert, G. and Singer, S.J. (1985) The reorientation of the Golgi apparatus and the microtubule-organizing center in the cytotoxic effector cell is a prerequisite in the lysis of bound target cells. J Mol Cell Immunol, 2, 37–49.
Kwon, B.S., Wakulchik, M., Liu, C.C., Persechini, P.M., Trapani, J.A., Haq, A.K., Kim, Y. and Young, J.D. (1989) The structure of the mouse lymphocyte pore-forming protein perforin. Biochem Biophys Res Commun, 158, 1–10.
Li, N., Ragheb, K., Lawler, G., Sturgis, J., Rajwa, B., Melendez, J.A. and Robinson, J.P. (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem, 278, 8516–25.
Lowin, B., Hahne, M., Mattmann, C. and Tschopp, J. (1994) Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature, 370, 650–2.
Lowrey, D.M., Aebischer, T., Olsen, K., Lichtenheld, M., Rupp, F., Hengartner, H. and Podack, E.R. (1989) Cloning, analysis, and expression of murine perforin 1 cDNA, a component of cytolytic T-cell granules with homology to complement component C9. Proc Natl Acad Sci U S A, 86, 247–51.
Lu, H., Hou, Q., Zhao, T., Zhang, H., Zhang, Q., Wu, L. and Fan, Z. (2006) Granzyme M directly cleaves inhibitor of caspase-activated DNase (CAD) to unleash CAD leading to DNA fragmentation. J Immunol, 177, 1171–8.
MacDermott, R.P., Schmidt, R.E., Caulfield, J.P., Hein, A., Bartley, G.T., Ritz, J., Schlossman, S.F., Austen, K.F. and Stevens, R.L. (1985) Proteoglycans in cell-mediated cytotoxicity. Identification, localization, and exocytosis of a chondroitin sulfate proteoglycan from human cloned natural killer cells during target cell lysis. J Exp Med, 162, 1771–87.
MacDonald, G., Shi, L., Vande Velde, C., Lieberman, J. and Greenberg, A.H. (1999) Mitochondria-dependent and -independent regulation of granzyme B-induced apoptosis. J Exp Med, 189, 131–44.
Martin, S.J., Amarante-Mendes, G.P., Shi, L., Chuang, T.H., Casiano, C.A., O’Brien, G.A., Fitzgerald, P., Tan, E.M., Bokoch, G.M., Greenberg, A.H. and Green, D.R. (1996) The cytotoxic cell protease granzyme B initiates apoptosis in a cell-free system by proteolytic processing and activation of the ICE/CED-3 family protease, CPP32, via a novel two-step mechanism. EMBO J, 15, 2407–16.
Martinvalet, D., Dykxhoorn, D.M., Ferrini, R. and Lieberman, J. (2008) Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell, 133, 681–92.
Martinvalet, D., Zhu, P. and Lieberman, J. (2005) Granzyme A induces caspase-independent mitochondrial damage, a required first step for apoptosis. Immunity, 22, 355–70.
Masson, D., Nabholz, M., Estrade, C. and Tschopp, J. (1986) Granules of cytolytic T-lymphocytes contain two serine esterases. EMBO J, 5, 1595–1600.
Masson, D., Peters, P.J., Geuze, H.J., Borst, J. and Tschopp, J. (1990) Interaction of chondroitin sulfate with perforin and granzymes of cytolytic T-cells is dependent on pH. Biochemistry, 29, 11229–35.
Masson, D. and Tschopp, J. (1985) Isolation of a lytic, pore-forming protein (perforin) from cytolytic T-lymphocytes. J Biol Chem, 260, 9069–72.
Masson, D. and Tschopp, J. (1987) A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell, 49, 679–85.
Matloubian, M., Suresh, M., Glass, A., Galvan, M., Chow, K., Whitmire, J.K., Walsh, C.M., Clark, W.R. and Ahmed, R. (1999) A role for perforin in downregulating T-cell responses during chronic viral infection. J Virol, 73, 2527–36.
McGuire, M.J., Lipsky, P.E. and Thiele, D.L. (1993) Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. J Biol Chem, 268, 2458–67.
Mehta, P.A., Davies, S.M., Kumar, A., Devidas, M., Lee, S., Zamzow, T., Elliott, J., Villanueva, J., Pullen, J., Zewge, Y. and Filipovich, A. (2006) Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia, 20, 1539–41.
Menager, M.M., Menasche, G., Romao, M., Knapnougel, P., Ho, C.H., Garfa, M., Raposo, G., Feldmann, J., Fischer, A. and de Saint Basile, G. (2007) Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13–4. Nat Immunol, 8, 257–67.
Metkar, S.S., Wang, B., Ebbs, M.L., Kim, J.H., Lee, Y.J., Raja, S.M. and Froelich, C.J. (2003) Granzyme B activates procaspase-3 which signals a mitochondrial amplification loop for maximal apoptosis. J Cell Biol, 160, 875–85.
Monks, C.R., Freiberg, B.A., Kupfer, H., Sciaky, N. and Kupfer, A. (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature, 395, 82–6.
Moretta, L., Bottino, C., Pende, D., Vitale, M., Mingari, M.C. and Moretta, A. (2004) Different checkpoints in human NK-cell activation. Trends Immunol, 25, 670–6.
Motyka, B., Korbutt, G., Pinkoski, M.J., Heibein, J.A., Caputo, A., Hobman, M., Barry, M., Shostak, I., Sawchuk, T., Holmes, C.F., Gauldie, J. and Bleackley, R.C. (2000) Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell, 103, 491–500.
Mullbacher, A., Waring, P., Tha Hla, R., Tran, T., Chin, S., Stehle, T., Museteanu, C. and Simon, M.M. (1999) Granzymes are the essential downstream effector molecules for the control of primary virus infections by cytolytic leukocytes. Proc Natl Acad Sci U S A, 96, 13950–5.
Munford, R.S., Sheppard, P.O. and O’Hara, P.J. (1995) Saposin-like proteins (SAPLIP) carry out diverse functions on a common backbone structure. J Lipid Res, 36, 1653–63.
Murphy, M.E., Moult, J., Bleackley, R.C., Gershenfeld, H., Weissman, I.L. and James, M.N. (1988) Comparative molecular model building of two serine proteinases from cytotoxic T lymphocytes. Proteins, 4, 190–204.
Okada, S., Li, Q., Whitin, J.C., Clayberger, C. and Krensky, A.M. (2003) Intracellular mediators of granulysin-induced cell death. J Immunol, 171, 2556–62.
Olsen, I., Bou-Gharios, G. and Abraham, D. (1990) The activation of resting lymphocytes is accompanied by the biogenesis of lysosomal organelles. Eur J Immunol, 20, 2161–70.
Orye, E., Plum, J. and De Smedt, M. (1984) Beta-glucuronidase activity in human T and B lymphocytes and the Tmu and T gamma subpopulations. Histochemistry, 81, 287–290.
Pao, L.I., Sumaria, N., Kelly, J.M., van Dommelen, S., Cretney, E., Wallace, M.E., Anthony, D.A., Uldrich, A.P., Godfrey, D.I., Papadimitriou, J.M., Mullbacher, A., Degli-Esposti, M.A. and Smyth, M.J. (2005) Functional analysis of granzyme M and its role in immunity to infection. J Immunol, 175, 3235–43.
Pardo, J., Perez-Galan, P., Gamen, S., Marzo, I., Monleon, I., Kaspar, A.A., Susin, S.A., Kroemer, G., Krensky, A.M., Naval, J. and Anel, A. (2001) A role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis. J Immunol, 167, 1222–9.
Pardo, J., Wallich, R., Martin, P., Urban, C., Rongvaux, A., Flavell, R.A., Mullbacher, A., Borner, C. and Simon, M.M. (2008) Granzyme B-induced cell death exerted by ex vivo CTL: discriminating requirements for cell death and some of its signs. Cell Death Differ, 15, 567–79.
Pasternack, M.S., Verret, C.R., Liu, M.A. and Eisen, H.N. (1986) Serine esterase in cytolytic T lymphocytes. Nature, 322, 740–3.
Pena, S.V. and Krensky, A.M. (1997) Granulysin, a new human cytolytic granule-associated protein with possible involvement in cell-mediated cytotoxicity. Semin Immunol, 9, 117–25.
Persechini, P.M., Liu, C.C., Jiang, S. and Young, J.D. (1989) The lymphocyte pore-forming protein perforin is associated with granules by a pH-dependent mechanism. Immunol Lett, 22, 23–7.
Peters, P.J., Borst, J., Oorschot, V., Fukuda, M., Krahenbuhl, O., Tschopp, J., Slot, J.W. and Geuze, H.J. (1991) Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. J Exp Med, 173, 1099–1109.
Pham, C.T. and Ley, T.J. (1999) Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci U S A, 96, 8627–32.
Pham, C.T., MacIvor, D.M., Hug, B.A., Heusel, J.W. and Ley, T.J. (1996) Long-range disruption of gene expression by a selectable marker cassette. Proc Natl Acad Sci U S A, 93, 13090–5.
Podack, E.R. and Konigsberg, P.J. (1984) Cytolytic T cell granules. Isolation, structural, biochemical, and functional characterization. J Exp Med, 160, 695–710.
Podack, E.R. and Kupfer, A. (1991) T-cell effector functions: mechanisms for delivery of cytotoxicity and help. Annu Rev Cell Biol, 7, 479–504.
Podack, E.R., Young, J.D. and Cohn, Z.A. (1985) Isolation and biochemical and functional characterization of perforin 1 from cytolytic T-cell granules. Proc Natl Acad Sci U S A, 82, 8629–33.
Raja, S.M., Metkar, S.S., Honing, S., Wang, B., Russin, W.A., Pipalia, N.H., Menaa, C., Belting, M., Cao, X., Dressel, R. and Froelich, C.J. (2005) A novel mechanism for protein delivery: granzyme B undergoes electrostatic exchange from serglycin to target cells. J Biol Chem, 280, 20752–61.
Redelman, D. and Hudig, D. (1980) The mechanism of cell-mediated cytotoxicity. I. Killing by murine cytotoxic T lymphocytes requires cell surface thiols and activated proteases. J Immunol, 124, 870–8.
Revell, P.A., Grossman, W.J., Thomas, D.A., Cao, X., Behl, R., Ratner, J.A., Lu, Z.H. and Ley, T.J. (2005) Granzyme B and the downstream granzymes C and/or F are important for cytotoxic lymphocyte functions. J Immunol, 174, 2124–31.
Romero, V. and Andrade, F. (2008) Non-apoptotic functions of granzymes. Tissue Antigens, 71, 409–16.
Rosado, C.J., Buckle, A.M., Law, R.H., Butcher, R.E., Kan, W.T., Bird, C.H., Ung, K., Browne, K.A., Baran, K., Bashtannyk-Puhalovich, T.A., Faux, N.G., Wong, W., Porter, C.J., Pike, R.N., Ellisdon, A.M., Pearce, M.C., Bottomley, S.P., Emsley, J., Smith, A.I., Rossjohn, J., Hartland, E.L, Voskoboinik, I., Trapani, J.A., Bird, P.I., Dunstone, M.A. and Whisstock, J.C. (2007) A common fold mediates vertebrate defense and bacterial attack. Science, 317, 1548–51.
Rosado, C.J., Kondos, S., Bull, T.E., Kuiper, M.J., Law, R.H.P., Buckle, A.M., Voskoboinik, I., Bird, P.I., Trapani, J.A., Whisstock, J.C. and Dunstone, M.A. (2008) The MACPF/CDC family of pore forming toxins. Cellular Microbiology, 10, 1765–74.
Sarin, A., Haddad, E.K. and Henkart, P.A. (1998) Caspase dependence of target cell damage induced by cytotoxic lymphocytes. J Immunol, 161, 2810–16.
Sedelies, K.A., Ciccone, A., Clarke, C.J., Oliaro, J., Sutton, V.R., Scott, F.L., Silke, J., Susanto, O., Green, D.R., Johnstone, R.W., Bird, P.I., Trapani, J.A. and Waterhouse, N.J. (2008) Blocking granule-mediated death by primary human NK cells requires both protection of mitochondria and inhibition of caspase activity. Cell Death Differ, 15, 708–17.
Sekiya, M., Ohwada, A., Katae, M., Dambara, T., Nagaoka, I. and Fukuchi, Y. (2002) Adenovirus vector-mediated transfer of 9 kDa granulysin induces DNA fragmentation in HuD antigen-expressing small cell lung cancer murine model cells. Respirology, 7, 29–35.
Sharif-Askari, E., Alam, A., Rheaume, E., Beresford, P.J., Scotto, C., Sharma, K., Lee, D., DeWolf, W.E., Nuttall, M.E., Lieberman, J. and Sekaly, R.P. (2001) Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation. Embo J, 20, 3101–13.
Shi, L., Kam, C.M., Powers, J.C., Aebersold, R. and Greenberg, A.H. (1992) Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions. J Exp Med, 176, 1521–9.
Shi, L., Mai, S., Israels, S., Browne, K., Trapani, J.A. and Greenberg, A.H. (1997) Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization. J Exp Med, 185, 855–66.
Shinkai, Y., Takio, K. and Okumura, K. (1988) Homology of perforin to the ninth component of complement (C9). Nature, 334, 525–7.
Shiver, J.W. and Henkart, P.A. (1991) A noncytotoxic mast cell tumor line exhibits potent IgE-dependent cytotoxicity after transfection with the cytolysin/perforin gene. Cell, 64, 1175–81.
Slade, D.J., Lovelace, L.L., Chruszcz, M., Minor, W., Lebioda, L. and Sodetz, J.M. (2008) Crystal structure of the MACPF domain of human complement protein C8 alpha in complex with the C8 gamma subunit. J Mol Biol, 379, 331–42.
Smyth, M.J., Kelly, J.M., Sutton, V.R., Davis, J.E., Browne, K.A., Sayers, T.J. and Trapani, J.A. (2001) Unlocking the secrets of cytotoxic granule proteins. J Leukoc Biol, 70, 18–29.
Smyth, M.J., Thia, K.Y., Street, S.E., MacGregor, D., Godfrey, D.I. and Trapani, J.A. (2000) Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med, 192, 755–60.
Stenger, S., Hanson, D.A., Teitelbaum, R., Dewan, P., Niazi, K.R., Froelich, C.J., Ganz, T., Thoma-Uszynski, S., Melian, A., Bogdan, C., Porcelli, S.A., Bloom, B.R., Krensky, A.M. and Modlin, R.L. (1998) An antimicrobial activity of cytolytic T cells mediated by granulysin. Science, 282, 121–5.
Stepp, S.E., Dufourcq-Lagelouse, R., Le Deist, F., Bhawan, S., Certain, S., Mathew, P.A., Henter, J.I., Bennett, M., Fischer, A., de Saint Basile, G. and Kumar, V. (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science, 286, 1957–9.
Stevens, R.L., Kamada, M.M. and Serafin, W.E. (1989) Structure and function of the family of proteoglycans that reside in the secretory granules of natural killer cells and other effector cells of the immune response. Curr Top Microbiol Immunol, 140, 93–108.
Stevens, R.L., Otsu, K., Weis, J.H., Tantravahi, R.V., Austen, K.F., Henkart, P.A., Galli, M.C. and Reynolds, C.W. (1987) Co-sedimentation of chondroitin sulfate A glycosaminoglycans and proteoglycans with the cytolytic secretory granules of rat large granular lymphocyte (LGL) tumor cells, and identification of a mRNA in normal and transformed LGL that encodes proteoglycans. J Immunol, 139, 863–8.
Stinchcombe, J., Bossi, G. and Griffiths, G.M. (2004) Linking albinism and immunity: the secrets of secretory lysosomes. Science, 305, 55–9.
Stinchcombe, J.C., Bossi, G., Booth, S. and Griffiths, G.M. (2001) The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity, 15, 751–61.
Stinchcombe, J.C. and Griffiths, G.M. (2003) The role of the secretory immunological synapse in killing by CD8+ CTL. Semin Immunol, 15, 301–5.
Stinchcombe, J.C. and Griffiths, G.M. (2007) Secretory mechanisms in cell-mediated cytotoxicity. Annu Rev Cell Dev Biol, 23, 495–17.
Stinchcombe, J.C., Majorovits, E., Bossi, G., Fuller, S. and Griffiths, G.M. (2006) Centrosome polarization delivers secretory granules to the immunological synapse. Nature, 443, 462–5.
Sutton, V.R., Davis, J.E., Cancilla, M., Johnstone, R.W., Ruefli, A.A., Sedelies, K., Browne, K.A. and Trapani, J.A. (2000) Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J Exp Med, 192, 1403–14.
Sutton, V.R., Vaux, D.L. and Trapani, J.A. (1997) Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes. J Immunol, 158, 5783–90.
Sutton, V.R., Waterhouse, N.J., Browne, K.A., Sedelies, K., Ciccone, A., Anthony, D., Koskinen, A., Mullbacher, A. and Trapani, J.A. (2007) Residual active granzyme B in cathepsin C-null lymphocytes is sufficient for perforin-dependent target cell apoptosis. J Cell Biol, 176, 425–33.
Sutton, V.R., Wowk, M.E., Cancilla, M. and Trapani, J.A. (2003) Caspase activation by granzyme B is indirect, and caspase autoprocessing requires the release of proapoptotic mitochondrial factors. Immunity, 18, 319–29.
Thia, K.Y. and Trapani, J.A. (2007) The granzyme B gene is highly polymorphic in wild mice but essentially invariant in common inbred laboratory strains. Tissue Antigens, 70, 198–204.
Thomas, D.A., Du, C., Xu, M., Wang, X. and Ley, T.J. (2000) DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis. Immunity, 12, 621–32.
Tilley, S.J., Orlova, E.V., Gilbert, R.J., Andrew, P.W. and Saibil, H.R. (2005) Structural basis of pore formation by the bacterial toxin pneumolysin. Cell, 121, 247–56.
Trapani, J.A. (1998) Dual mechanisms of apoptosis induction by cytotoxic lymphocytes. Int Rev Cytol, 182, 111–92.
Trapani, J.A. (2001) Granzymes: a family of lymphocyte granule serine proteases. Genome Biol, 2, REVIEWS3014.
Trapani, J.A., Jans, D.A., Jans, P.J., Smyth, M.J., Browne, K.A. and Sutton, V.R. (1998a) Efficient nuclear targeting of granzyme B and the nuclear consequences of apoptosis induced by granzyme B and perforin are caspase-dependent, but cell death is caspase-independent. J Biol Chem, 273, 27934–8.
Trapani, J.A., Jans, P., Smyth, M.J., Froelich, C.J., Williams, E.A., Sutton, V.R. and Jans, D.A. (1998b) Perforin-dependent nuclear entry of granzyme B precedes apoptosis, and is not a consequence of nuclear membrane dysfunction. Cell Death Differ, 5, 488–96.
Trapani, J.A., Sutton, V.R., Thia, K.Y., Li, Y.Q., Froelich, C.J., Jans, D.A., Sandrin, M.S. and Browne, K.A. (2003) A clathrin/dynamin- and mannose-6-phosphate receptor-independent pathway for granzyme B-induced cell death. J Cell Biol, 160, 223–33.
Tschopp, J. and Nabholz, M. (1990) Perforin-mediated target cell lysis by cytolytic T lymphocytes. Annu Rev Immunol, 8, 279–302.
Uellner, R., Zvelebil, M.J., Hopkins, J., Jones, J., MacDougall, L.K., Morgan, B.P., Podack, E., Waterfield, M.D. and Griffiths, G.M. (1997) Perforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain. EMBO J, 16, 7287–96.
Van Den Broek, M.E., Kagi, D., Ossendorp, F., Toes, R., Vamvakas, S., Lutz, W.K., Melief, C.J., Zinkernagel, R.M. and Hengartner, H. (1996) Decreased tumor surveillance in perforin-deficient mice. J Exp Med, 184, 1781–90.
Veugelers, K., Motyka, B., Frantz, C., Shostak, I., Sawchuk, T. and Bleackley, R.C. (2004) The granzyme B-serglycin complex from cytotoxic granules requires dynamin for endocytosis. Blood, 103, 3845–53.
Voskoboinik, I., Smyth, M.J. and Trapani, J.A. (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol, 6, 940–52.
Voskoboinik, I., Sutton, V.R., Ciccone, A., House, C.M., Chia, J., Darcy, P.K., Yagita, H. and Trapani, J.A. (2007) Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood, 110, 1184–90.
Voskoboinik, I., Thia, M.C., Fletcher, J., Ciccone, A., Browne, K., Smyth, M.J. and Trapani, J.A. (2005) Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491. J Biol Chem, 280, 8426–34.
Walch, M., Latinovic-Golic, S., Velic, A., Sundstrom, H., Dumrese, C., Wagner, C.A., Groscurth, P. and Ziegler, U. (2007) Perforin enhances the granulysin-induced lysis of Listeria innocua in human dendritic cells. BMC Immunol, 8, 14.
Wang, Z., Choice, E., Kaspar, A., Hanson, D., Okada, S., Lyu, S.C., Krensky, A.M. and Clayberger, C. (2000) Bactericidal and tumoricidal activities of synthetic peptides derived from granulysin. J Immunol, 165, 1486–90.
Waterhouse, N.J., Sedelies, K.A., Browne, K.A., Wowk, M.E., Newbold, A., Sutton, V.R., Clarke, C.J., Oliaro, J., Lindemann, R.K., Bird, P.I., Johnstone, R.W. and Trapani, J.A. (2005) A central role for Bid in granzyme B-induced apoptosis. J Biol Chem, 280, 4476–82.
Waterhouse, N.J., Sedelies, K.A. and Trapani, J.A. (2006a) Role of Bid-induced mitochondrial outer membrane permeabilization in granzyme B-induced apoptosis. Immunol Cell Biol, 84, 72–8.
Waterhouse, N.J., Sutton, V.R., Sedelies, K.A., Ciccone, A., Jenkins, M., Turner, S.J., Bird, P.I. and Trapani, J.A. (2006b) Cytotoxic T lymphocyte-induced killing in the absence of granzymes A and B is unique and distinct from both apoptosis and perforin-dependent lysis. J Cell Biol, 173, 133–44.
Waterhouse, N.J. and Trapani, J.A. (2007) H is for helper: granzyme H helps granzyme B kill adenovirus-infected cells. Trends Immunol, 28, 373–5.
Yannelli, J.R., Sullivan, J.A., Mandell, G.L. and Engelhard, V.H. (1986) Reorientation and fusion of cytotoxic T lymphocyte granules after interaction with target cells as determined by high resolution cinemicrography. J Immunol, 136, 377–82.
Young, J.D., Liu, C.C., Leong, L.G. and Cohn, Z.A. (1986) The pore-forming protein (perforin) of cytolytic T lymphocytes is immunologically related to the components of membrane attack complex of complement through cysteine-rich domains. J Exp Med, 164, 2077–82.
Zhang, D., Beresford, P.J., Greenberg, A.H. and Lieberman, J. (2001a) Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proc Natl Acad Sci U S A, 98, 5746–51.
Zhang, D., Pasternack, M.S., Beresford, P.J., Wagner, L., Greenberg, A.H. and Lieberman, J. (2001b) Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A. J Biol Chem, 276, 3683–90.
Zhao, T., Zhang, H., Guo, Y. and Fan, Z. (2007a) Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. J Biol Chem, 282, 12104–11.
Zhao, T., Zhang, H., Guo, Y., Zhang, Q., Hua, G., Lu, H., Hou, Q., Liu, H. and Fan, Z. (2007b) Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells. Cell Death Differ, 14, 489–99.

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×