Apoptosis and survival - Granzyme A signaling

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Granzyme A signaling

Granzyme A is abundant serine protease, which induces apoptosis by caspase-independent pathways. Granzyme A is released by Cytotoxic T lymphocytes (CD8+ T cells) and Natural Killer (NK) cells as response on cell infection, cancer transformation, and antigens presentation [1].

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 [2], [3], [4]. This results in NK or CD8+ T cells polarization and maturation of cytotoxic granule inclusive Granzyme A and Perforin. Synaptotagmin VII [5], [6], Rab-27A and Unc-13 homolog D (Munc13-4) are essential regulators of cytotoxic granule maturation and fusion with the plasma membrane [7], [8], [9]. These granules are localized in contact with the target cells and contain also lysosome-resident proteins Lysosomal-associated membrane protein 1 (LAMP1), Lysosomal-associated membrane protein 2 (LAMP2) and CD63 [10]. Perforin and Granzyme A release from cytotoxic granules into the immunological synapse formed between target and immune (CD8+ T or NK) cells [1].

Granzyme A delivery to the cytosol, mitochondria and nucleus is dependent on Perforin [3], [11], [12].

Granzyme A accesses the mitochondrial matrix and cleaves the complex I protein NADH dehydrogenase Fe-S protein 3 (NDUFS3), subunit of the NADH: ubiquinone oxidoreductase complex I, to interfere with inhibition of oxidative phosphorylation cycle. NDUFS3 cleavage requires mitochondrial transmembral potential. Granzyme A directly causes a rapid increase in superoxide anion O(,2)('-). O(,2)('-) is key to nuclear translocation of another Granzyme A substrate, SET complex [1], [12].

Endoplasmic reticulum-associated SET complex contains Non-metastatic cells 1 protein expressed in (NDPK A), Three prime repair exonuclease 1 (TREX1), Acidic nuclear phosphoprotein 32 family member A (PHAP1 (pp32)) and three Granzyme A substrates, nucleosome assembly protein SET nuclear oncogene (SET) [13], DNA-bending protein High-mobility group box 2 (HMG2) [14] and the Base excision repair endonuclease APEX nuclease 1 (APEX) [15].

Granzyme A is translocated into nucleus and cleaves Lamin A/C and Lamin B1 [16], Histone cluster 1 H1b (Histone H1b), SET [13], HMG2 [14] and the tails of core histones Histone H2 and Histone H3 [17]. This disruption opens up chromatin to DNases [18]. Cleavage of SET liberates the Granzyme A-activated DNase NDPK A and results in DNA damage by single-stranded nicks [13], [19]. It is shown that NDPK A also activates tumor protein p53 that can induce p53-dependent apoptosis [20]. Granzyme A cleaves X-ray repair complementing defective repair in Chinese hamster cells 6 (Ku70) [21], a key component of the PK-DNA ligase 4 complex that recruits DNA ligase IV and X-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) for double-strand break repair [22]. DNA and mitochondria damages, lamina disruption, and loss of mitochondrial transmembrane potential cause DNA degradation, nucleus fragmentation, and lead to apoptosis in target cells [4], [18], [23].

References:

  1. 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
  2. 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
  3. Cullen SP, Martin SJ
    Mechanisms of granule-dependent killing. Cell death and differentiation 2008 Feb;15(2):251-62
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Jans DA, Briggs LJ, Jans P, Froelich CJ, Parasivam G, Kumar S, Sutton VR, Trapani JA
    Nuclear targeting of the serine protease granzyme A (fragmentin-1). Journal of cell science 1998 Sep;111 ( Pt 17):2645-54
  12. Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J
    Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 2008 May 16;133(4):681-92
  13. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J
    Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 2003 Mar 7;112(5):659-72
  14. Fan Z, Beresford PJ, Zhang D, Lieberman J
    HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Molecular and cellular biology 2002 Apr;22(8):2810-20
  15. Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J
    Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nature immunology 2003 Feb;4(2):145-53
  16. 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
  17. Zhang D, Pasternack MS, Beresford PJ, Wagner L, Greenberg AH, Lieberman J
    Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A. The Journal of biological chemistry 2001 Feb 2;276(5):3683-90
  18. Lieberman J, Fan Z
    Nuclear war: the granzyme A-bomb. Current opinion in immunology 2003 Oct;15(5):553-9
  19. Beresford PJ, Zhang D, Oh DY, Fan Z, Greer EL, Russo ML, Jaju M, Lieberman J
    Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. The Journal of biological chemistry 2001 Nov 16;276(46):43285-93
  20. Jung H, Seong HA, Ha H
    NM23-H1 tumor suppressor and its interacting partner STRAP activate p53 function. The Journal of biological chemistry 2007 Nov 30;282(48):35293-307
  21. Zhu P, Zhang D, Chowdhury D, Martinvalet D, Keefe D, Shi L, Lieberman J
    Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70. EMBO reports 2006 Apr;7(4):431-7
  22. Chen L, Trujillo K, Sung P, Tomkinson AE
    Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. The Journal of biological chemistry 2000 Aug 25;275(34):26196-205
  23. Bots M, Medema JP
    Granzymes at a glance. Journal of cell science 2006 Dec 15;119(Pt 24):5011-4

  1. 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
  2. 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
  3. Cullen SP, Martin SJ
    Mechanisms of granule-dependent killing. Cell death and differentiation 2008 Feb;15(2):251-62
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. Jans DA, Briggs LJ, Jans P, Froelich CJ, Parasivam G, Kumar S, Sutton VR, Trapani JA
    Nuclear targeting of the serine protease granzyme A (fragmentin-1). Journal of cell science 1998 Sep;111 ( Pt 17):2645-54
  12. Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J
    Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death. Cell 2008 May 16;133(4):681-92
  13. Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J
    Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 2003 Mar 7;112(5):659-72
  14. Fan Z, Beresford PJ, Zhang D, Lieberman J
    HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Molecular and cellular biology 2002 Apr;22(8):2810-20
  15. Fan Z, Beresford PJ, Zhang D, Xu Z, Novina CD, Yoshida A, Pommier Y, Lieberman J
    Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Nature immunology 2003 Feb;4(2):145-53
  16. 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
  17. Zhang D, Pasternack MS, Beresford PJ, Wagner L, Greenberg AH, Lieberman J
    Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A. The Journal of biological chemistry 2001 Feb 2;276(5):3683-90
  18. Lieberman J, Fan Z
    Nuclear war: the granzyme A-bomb. Current opinion in immunology 2003 Oct;15(5):553-9
  19. Beresford PJ, Zhang D, Oh DY, Fan Z, Greer EL, Russo ML, Jaju M, Lieberman J
    Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks. The Journal of biological chemistry 2001 Nov 16;276(46):43285-93
  20. Jung H, Seong HA, Ha H
    NM23-H1 tumor suppressor and its interacting partner STRAP activate p53 function. The Journal of biological chemistry 2007 Nov 30;282(48):35293-307
  21. Zhu P, Zhang D, Chowdhury D, Martinvalet D, Keefe D, Shi L, Lieberman J
    Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70. EMBO reports 2006 Apr;7(4):431-7
  22. Chen L, Trujillo K, Sung P, Tomkinson AE
    Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA-dependent protein kinase. The Journal of biological chemistry 2000 Aug 25;275(34):26196-205
  23. Bots M, Medema JP
    Granzymes at a glance. Journal of cell science 2006 Dec 15;119(Pt 24):5011-4

Target Details

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