Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Granzyme B

  • Christopher T. Turner
  • Valerio Russo
  • Stephanie Santacruz
  • Cameron Oram
  • David J. Granville
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101961

Synonyms

Historical Background

Perforin, a Ca2+-dependent pore forming protein found in the granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), was once proposed to be “the sole mediator of target cell destruction” (Ewen et al. 2012). However, in the late 1970s perforin was revealed to lack the protease activity required for apoptotic induction (Ewen et al. 2012). To identify other proteases that may be responsible, multiple researchers independently investigated the composition of CTL and NK cell granules (Boivin et al. 2009). Percoll density gradients were used to separate granules from NK cells and gel filtration then removed perforin, leaving an enriched pool of serine proteases. These “granule-associated enzymes” were subsequently named granzymes (Masson and Tschopp 1987). Cation exchange chromatography separated the granzymes into distinct clusters...

This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The authors wish to apologize to the many authors involved in studies that were uncited in this article and acknowledge that numerous references were not included due to space/reference limitation. Many of the references therefore refer to review articles where the original studies are cited.

References

  1. Afonina IS, Tynan GA, Logue SE, et al. Granzyme B-dependent proteolysis acts as a switch to enhance the pro-inflammatory activity of IL-1α. Mol Cell. 2011;44:265–78.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ang LS, Boivin WA, Williams SJ, Zhao H, Abraham T, Carmine-Simmen K, McManus BM, Bleackley RC, Granville DJ. Serpina3n attenuates granzyme B-mediated decorin cleavage and rupture in a murine model of aortic aneurysm. Cell Death Dis. 2011;2:e209.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Boivin WA, Cooper DM, Hiebert PR, Granville DJ. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma. Lab Investig. 2009;89(11):1195–220.PubMedCrossRefGoogle Scholar
  4. Boivin W, Shackleford M, Vanden Hoek A, et al. Granzyme B cleaves decorin, biglycan and soluble betaglycan, releasing active transforming growth factor-β1. PLoS One. 2012;7:e33163.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chowdhury D, Lieberman J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol. 2008;26:389–420.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Darrah E, Rosen A. Granzyme B cleavage of autoantigens in autoimmunity. Cell Death Differ. 2010;17(4):624–32.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Estébanez-Perpiña E, Fuentes-Prior P, Belorgey D, Braun M, Kiefersauer R, Maskos K, Huber R, Rubin H, Bode W. Crystal structure of the caspase activator human granzyme B, a proteinase highly specific for an Asp-P1 residue. Biol Chem. 2000;381(12):1203–14.PubMedCrossRefGoogle Scholar
  8. Ewen CL, Kane KP, Bleackley RC. A quarter century of granzymes. Cell Death Differ. 2012;19(1):28–35.PubMedCrossRefGoogle Scholar
  9. Haile Y, Carmine-Simmen K, Olechowski C, Kerr B, Bleackley C, Giuliani F. Granzyme B-inhibitor serpina3n induces neuroprotection in vitro and in vivo. J Neuroinflammation. 2015;12:157.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Hendel A, Hiebert PR, Boivin WA, Williams SJ, Granville DJ. Granzymes in age-related cardiovascular and pulmonary diseases. Cell Death Differ. 2010;17:596–606.PubMedCrossRefGoogle Scholar
  11. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407(6805):770–6.PubMedCrossRefGoogle Scholar
  12. Hiebert PR, Granville DJ. Granzyme B in injury, inflammation, and repair. Trends Mol Med. 2012;18(12):732–41.PubMedCrossRefGoogle Scholar
  13. Hiebert PR, Boivin WA, Zhao H, McManus BM, Granville DJ. Perforin and granzyme B have separate and distinct roles during atherosclerotic plaque development in apolipoprotein E knockout mice. PLoS One. 2013;8(10):e78939.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Hsu I, Parkinson LG, Shen Y, Toro A, Brown T, Zhao H, Bleackley RC, Granville DJ. Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing. Cell Death Dis. 2014;5:e1458.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Isaaz S, Baetz K, Olsen K, et al. Serial killing by cytotoxic T lymphocytes: T cell receptor triggers degranulation, re-filling of the lytic granules and secretion of lytic proteins via a non-granule pathway. Eur J Immunol. 1995;25:1071–9.PubMedCrossRefGoogle Scholar
  16. Kagi D, Ledermann B, Burki K, et al. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature. 1994;369:31–7.PubMedCrossRefGoogle Scholar
  17. Klein JL, Shows TB, Dupont B, et al. Genomic organization and chromosomal assignment for a serine protease gene (CSPB) expressed by human cytotoxic lymphocytes. Genomics. 1989;5:110–7.PubMedCrossRefGoogle Scholar
  18. Masson D, Tschopp J. A family of serine esterases in lytic granules of cytolytic T lymphocytes. Cell. 1987;49:679–85.CrossRefPubMedGoogle Scholar
  19. Parkinson LG, Toro A, Zhao H, Brown K, Tebbutt SJ, Granville DJ. Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation. Aging Cell. 2015;14(1):67–77.PubMedCrossRefGoogle Scholar
  20. Shen Y, Cheng F, Sharma M, et al. Granzyme B deficiency protects against angiotensin II-induced cardiac fibrosis. Am J Pathol. 2016;186:87–100.PubMedCrossRefGoogle Scholar
  21. Wang T, Lee MH, Choi E, et al. Granzyme B-induced neurotoxicity is mediated via activation of PAR-1 receptor and Kv1.3 channel. PLoS One. 2012;7:e43950.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Waugh SM, Harris JL, Fletterick R, et al. The structure of the proapoptotic protease granzyme B reveals the molecular determinants of its specificity. Nat Struct Biol. 2000;7:762–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Christopher T. Turner
    • 1
  • Valerio Russo
    • 1
  • Stephanie Santacruz
    • 1
  • Cameron Oram
    • 1
  • David J. Granville
    • 1
  1. 1.Granville Laboratory, ICORD, Faculty of MedicineUniversity of British ColumbiaVancouverCanada