Apoptosis and survival - Granzyme B signaling

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Granzyme B signaling

Granzyme B is abundant serine protease, which is responsible for rapid induction of caspase-dependent apoptosis, promoting caspase activation directly and indirectly, through proteolysis of the Bcl-2 family proteins [1], [2].

CD8+ T cells cytotoxicity is activated after cell infection, cancer transformation, and allogenic antigens presentation by MHC class I. NK cells are activated after recognition of allogenic or modified antigens on MHC class I-negative target cell surface [3], [4], [5]. This results in NK or CD8+ T cells polarization and maturation of cytotoxic granule inclusive Granzyme B and Perforin. Synaptotagmin VII [6], [7], Rab-27A and Unc-13 homolog D (Munc13-4) are essential regulators of cytotoxic granule maturation and fusion with the plasma membrane [8], [9], [10]. These granules are localized in contact with the target cells and contain also lysosome-resident proteins Lysosomal-associated membrane protein 1 and 2 (LAMP1 and LAMP2) and CD63 [11]. Perforin and Granzyme B release from cytotoxic granules into the immunological synapse formed between effector cells [12].

Perforin allows Granzyme B access to cytosolic and nuclear substrates [13], [14], [15]. In the cytoplasm human Granzyme B cleaves BH3 interacting domain death agonist (Bid) more efficiently than it cleaves caspases [1]. Proteolysis of Bid by Granzyme B results in the translocation of the C terminus of Bid (tBid) to mitochondria. In mitochondria outer membrane Granzyme B also cleaves anti-apoptotic Bcl-2 family protein Myeloid cell leukemia sequence 1 (Mcl-1) [16], [17]. Those interactions induce the release of mitochondrial Cytochrome c somatic (Cytochrome C) and Diablo homolog (Smac/Diablo) into the cytosol [2]. Cytochrome C is involved in the apoptosome pathway together with Apoptotic peptidase activating factor 1 (Apaf-1) and activated Caspase 9 [18], [19]. Release of mitochondrial Smac/Diablo represses the inhibitors of apoptosis in target cell, making caspases more readily activated directly by Granzyme B [19].

On the other hand, Granzyme B directly processes Caspase-8, and Caspase-10, and then activates Caspase-3, and Caspase-7. Caspase-3 is the central effector caspase within the Granzyme B-initiated caspase cascade. It completes maturation of Caspase-8 and Caspase-10 and activates Caspase-2, Caspase-6 and Caspase-9 [1].

Granzyme B directly cleaves caspase substrates, like nuclear Lamin B1 [20], Nuclear mitotic apparatus protein 1 (NUMA1) [2], [21], Poly (ADP-ribose) polymerase 1 (PARP-1) [22], [23], and cytoplasmic DNA fragmentation factor 45kDa alpha polypeptide (ICAD) [24], and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) [25]. Caspases also cleave Lamin A/C [15].

Cleavage of structural components of nucleoskeleton, Lamins and NUMA1, results in nuclear integrity disruption [20], [26]. Degradation of ICAD induces release of DNA fragmentation factor 40kDa beta polypeptide (DFF40 (CAD)) that degrades chromosomal DNA [24], [27]. Cleavage of PARP-1 promotes apoptosis by preventing DNA repair-induced survival [28]. Degradation of ROCK2 results in membrane blebbing [2], [25]. Granzyme B cleaves Tubulin alpha and induces microtubule polymerization and cytoskeletal collapse [29]. Proteolysis of Fibroblast growth factor receptor 1 (FGFR1) and transmembrane Notch homolog 1 translocation-associated (NOTCH1 (NEXT)) results in target cell isolation from survival signals from extracellular environment and enhances programmed cell death, apoptosis [22].

References:

  1. Adrain C, Murphy BM, Martin SJ
    Molecular ordering of the caspase activation cascade initiated by the cytotoxic T lymphocyte/natural killer (CTL/NK) protease granzyme B. The Journal of biological chemistry 2005 Feb 11;280(6):4663-73
  2. Bots M, Medema JP
    Granzymes at a glance. Journal of cell science 2006 Dec 15;119(Pt 24):5011-4
  3. Fassett MS, Davis DM, Valter MM, Cohen GB, Strominger JL
    Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Proceedings of the National Academy of Sciences of the United States of America 2001 Dec 4;98(25):14547-52
  4. Cullen SP, Martin SJ
    Mechanisms of granule-dependent killing. Cell death and differentiation 2008 Feb;15(2):251-62
  5. Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, Chávez R, Lascurain R
    Cell death mechanisms induced by cytotoxic lymphocytes. Cellular & molecular immunology 2009 Feb;6(1):15-25
  6. Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL
    The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 25;100(24):14151-6
  7. Fowler KT, Andrews NW, Huleatt JW
    Expression and function of synaptotagmin VII in CTLs. Journal of immunology (Baltimore, Md. : 1950) 2007 Feb 1;178(3):1498-504
  8. Shirakawa R, Higashi T, Tabuchi A, Yoshioka A, Nishioka H, Fukuda M, Kita T, Horiuchi H
    Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. The Journal of biological chemistry 2004 Mar 12;279(11):10730-7
  9. Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, van Loon A, Griffith J, Krijgsveld J, Wulffraat N, Koch H, Heck AJ, Brose N, Kleijmeer M, van der Sluijs P
    Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Molecular biology of the cell 2005 Feb;16(2):731-41
  10. Ménager MM, Ménasché G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G
    Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nature immunology 2007 Mar;8(3):257-67
  11. Peters PJ, Borst J, Oorschot V, Fukuda M, Krähenbühl O, Tschopp J, Slot JW, Geuze HJ
    Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. The Journal of experimental medicine 1991 May 1;173(5):1099-109
  12. Pardo J, Aguilo JI, Anel A, Martin P, Joeckel L, Borner C, Wallich R, Müllbacher A, Froelich CJ, Simon MM
    The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation. Microbes and infection / Institut Pasteur 2009 Apr;11(4):452-9
  13. Jans DA, Jans P, Briggs LJ, Sutton V, Trapani JA
    Nuclear transport of granzyme B (fragmentin-2). Dependence of perforin in vivo and cytosolic factors in vitro. The Journal of biological chemistry 1996 Nov 29;271(48):30781-9
  14. Pinkoski MJ, Hobman M, Heibein JA, Tomaselli K, Li F, Seth P, Froelich CJ, Bleackley RC
    Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis. Blood 1998 Aug 1;92(3):1044-54
  15. Pinkoski MJ, Heibein JA, Barry M, Bleackley RC
    Nuclear translocation of granzyme B in target cell apoptosis. Cell death and differentiation 2000 Jan;7(1):17-24
  16. Han J, Goldstein LA, Gastman BR, Froelich CJ, Yin XM, Rabinowich H
    Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events. The Journal of biological chemistry 2004 May 21;279(21):22020-9
  17. Han J, Goldstein LA, Gastman BR, Rabinovitz A, Rabinowich H
    Disruption of Mcl-1.Bim complex in granzyme B-mediated mitochondrial apoptosis. The Journal of biological chemistry 2005 Apr 22;280(16):16383-92
  18. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH
    Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell death and differentiation 2000 Dec;7(12):1166-73
  19. Pinkoski MJ, Waterhouse NJ, Heibein JA, Wolf BB, Kuwana T, Goldstein JC, Newmeyer DD, Bleackley RC, Green DR
    Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. The Journal of biological chemistry 2001 Apr 13;276(15):12060-7
  20. Zhang D, Beresford PJ, Greenberg AH, Lieberman J
    Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proceedings of the National Academy of Sciences of the United States of America 2001 May 8;98(10):5746-51
  21. Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L
    Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 1998 Apr;8(4):451-60
  22. Loeb CR, Harris JL, Craik CS
    Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis. The Journal of biological chemistry 2006 Sep 22;281(38):28326-35
  23. Ko YH, Park S, Jin H, Woo H, Lee H, Park C, Kim K
    Granzyme B leakage-induced apoptosis is a crucial mechanism of cell death in nasal-type NK/T-cell lymphoma. Laboratory investigation; a journal of technical methods and pathology 2007 Mar;87(3):241-50
  24. Sharif-Askari E, Alam A, Rhéaume E, Beresford PJ, Scotto C, Sharma K, Lee D, DeWolf WE, Nuttall ME, Lieberman J, Sékaly RP
    Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation. The EMBO journal 2001 Jun 15;20(12):3101-13
  25. Sebbagh M, Hamelin J, Bertoglio J, Solary E, Bréard J
    Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. The Journal of experimental medicine 2005 Feb 7;201(3):465-71
  26. Yang CH, Lambie EJ, Snyder M
    NuMA: an unusually long coiled-coil related protein in the mammalian nucleus. The Journal of cell biology 1992 Mar;116(6):1303-17
  27. Elmore S
    Apoptosis: a review of programmed cell death. Toxicologic pathology 2007 Jun;35(4):495-516
  28. D'Amours D, Sallmann FR, Dixit VM, Poirier GG
    Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. Journal of cell science 2001 Oct;114(Pt 20):3771-8
  29. Goping IS, Sawchuk T, Underhill DA, Bleackley RC
    Identification of {alpha}-tubulin as a granzyme B substrate during CTL-mediated apoptosis. Journal of cell science 2006 Mar 1;119(Pt 5):858-65

  1. Adrain C, Murphy BM, Martin SJ
    Molecular ordering of the caspase activation cascade initiated by the cytotoxic T lymphocyte/natural killer (CTL/NK) protease granzyme B. The Journal of biological chemistry 2005 Feb 11;280(6):4663-73
  2. Bots M, Medema JP
    Granzymes at a glance. Journal of cell science 2006 Dec 15;119(Pt 24):5011-4
  3. Fassett MS, Davis DM, Valter MM, Cohen GB, Strominger JL
    Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Proceedings of the National Academy of Sciences of the United States of America 2001 Dec 4;98(25):14547-52
  4. Cullen SP, Martin SJ
    Mechanisms of granule-dependent killing. Cell death and differentiation 2008 Feb;15(2):251-62
  5. Chávez-Galán L, Arenas-Del Angel MC, Zenteno E, Chávez R, Lascurain R
    Cell death mechanisms induced by cytotoxic lymphocytes. Cellular & molecular immunology 2009 Feb;6(1):15-25
  6. Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL
    The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proceedings of the National Academy of Sciences of the United States of America 2003 Nov 25;100(24):14151-6
  7. Fowler KT, Andrews NW, Huleatt JW
    Expression and function of synaptotagmin VII in CTLs. Journal of immunology (Baltimore, Md. : 1950) 2007 Feb 1;178(3):1498-504
  8. Shirakawa R, Higashi T, Tabuchi A, Yoshioka A, Nishioka H, Fukuda M, Kita T, Horiuchi H
    Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets. The Journal of biological chemistry 2004 Mar 12;279(11):10730-7
  9. Neeft M, Wieffer M, de Jong AS, Negroiu G, Metz CH, van Loon A, Griffith J, Krijgsveld J, Wulffraat N, Koch H, Heck AJ, Brose N, Kleijmeer M, van der Sluijs P
    Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells. Molecular biology of the cell 2005 Feb;16(2):731-41
  10. Ménager MM, Ménasché G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G
    Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nature immunology 2007 Mar;8(3):257-67
  11. Peters PJ, Borst J, Oorschot V, Fukuda M, Krähenbühl O, Tschopp J, Slot JW, Geuze HJ
    Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. The Journal of experimental medicine 1991 May 1;173(5):1099-109
  12. Pardo J, Aguilo JI, Anel A, Martin P, Joeckel L, Borner C, Wallich R, Müllbacher A, Froelich CJ, Simon MM
    The biology of cytotoxic cell granule exocytosis pathway: granzymes have evolved to induce cell death and inflammation. Microbes and infection / Institut Pasteur 2009 Apr;11(4):452-9
  13. Jans DA, Jans P, Briggs LJ, Sutton V, Trapani JA
    Nuclear transport of granzyme B (fragmentin-2). Dependence of perforin in vivo and cytosolic factors in vitro. The Journal of biological chemistry 1996 Nov 29;271(48):30781-9
  14. Pinkoski MJ, Hobman M, Heibein JA, Tomaselli K, Li F, Seth P, Froelich CJ, Bleackley RC
    Entry and trafficking of granzyme B in target cells during granzyme B-perforin-mediated apoptosis. Blood 1998 Aug 1;92(3):1044-54
  15. Pinkoski MJ, Heibein JA, Barry M, Bleackley RC
    Nuclear translocation of granzyme B in target cell apoptosis. Cell death and differentiation 2000 Jan;7(1):17-24
  16. Han J, Goldstein LA, Gastman BR, Froelich CJ, Yin XM, Rabinowich H
    Degradation of Mcl-1 by granzyme B: implications for Bim-mediated mitochondrial apoptotic events. The Journal of biological chemistry 2004 May 21;279(21):22020-9
  17. Han J, Goldstein LA, Gastman BR, Rabinovitz A, Rabinowich H
    Disruption of Mcl-1.Bim complex in granzyme B-mediated mitochondrial apoptosis. The Journal of biological chemistry 2005 Apr 22;280(16):16383-92
  18. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH
    Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell death and differentiation 2000 Dec;7(12):1166-73
  19. Pinkoski MJ, Waterhouse NJ, Heibein JA, Wolf BB, Kuwana T, Goldstein JC, Newmeyer DD, Bleackley RC, Green DR
    Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. The Journal of biological chemistry 2001 Apr 13;276(15):12060-7
  20. Zhang D, Beresford PJ, Greenberg AH, Lieberman J
    Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis. Proceedings of the National Academy of Sciences of the United States of America 2001 May 8;98(10):5746-51
  21. Andrade F, Roy S, Nicholson D, Thornberry N, Rosen A, Casciola-Rosen L
    Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Immunity 1998 Apr;8(4):451-60
  22. Loeb CR, Harris JL, Craik CS
    Granzyme B proteolyzes receptors important to proliferation and survival, tipping the balance toward apoptosis. The Journal of biological chemistry 2006 Sep 22;281(38):28326-35
  23. Ko YH, Park S, Jin H, Woo H, Lee H, Park C, Kim K
    Granzyme B leakage-induced apoptosis is a crucial mechanism of cell death in nasal-type NK/T-cell lymphoma. Laboratory investigation; a journal of technical methods and pathology 2007 Mar;87(3):241-50
  24. Sharif-Askari E, Alam A, Rhéaume E, Beresford PJ, Scotto C, Sharma K, Lee D, DeWolf WE, Nuttall ME, Lieberman J, Sékaly RP
    Direct cleavage of the human DNA fragmentation factor-45 by granzyme B induces caspase-activated DNase release and DNA fragmentation. The EMBO journal 2001 Jun 15;20(12):3101-13
  25. Sebbagh M, Hamelin J, Bertoglio J, Solary E, Bréard J
    Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. The Journal of experimental medicine 2005 Feb 7;201(3):465-71
  26. Yang CH, Lambie EJ, Snyder M
    NuMA: an unusually long coiled-coil related protein in the mammalian nucleus. The Journal of cell biology 1992 Mar;116(6):1303-17
  27. Elmore S
    Apoptosis: a review of programmed cell death. Toxicologic pathology 2007 Jun;35(4):495-516
  28. D'Amours D, Sallmann FR, Dixit VM, Poirier GG
    Gain-of-function of poly(ADP-ribose) polymerase-1 upon cleavage by apoptotic proteases: implications for apoptosis. Journal of cell science 2001 Oct;114(Pt 20):3771-8
  29. Goping IS, Sawchuk T, Underhill DA, Bleackley RC
    Identification of {alpha}-tubulin as a granzyme B substrate during CTL-mediated apoptosis. Journal of cell science 2006 Mar 1;119(Pt 5):858-65

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