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Published: 9 March 2023

Last updated: 10 March 2023

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1

Zeberg, Lennart, and Tor Olofsson. "Differential Expression of Granzymes A and K in Subsets of Human T-Cells and NK-Cells." Blood 106, no. 11 (November 16, 2005): 3917. http://dx.doi.org/10.1182/blood.v106.11.3917.3917.

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Abstract Granzymes are highly specific proteases stored in secretory granule in T-cells and NK-cells. Five different granzymes are known in human (A, B, H, K and M). A and B are the best studied and both can induce apotosis when delivered to target cells. The role for granzyme H, K and M are principally unknown. We have studied the expression of granzymes in subsets of T-cells and NK-cells both in fresh circulating cells and cultured cells stimulated with IL-2, IL-15 and OKT3/antiCD28. Protein expression (biosynthesis/immunoprecipitation) and mRNA level (RT-PCR) was studied in parallel. This report focus on Granzyme A and K which are close relatives, both tryptases located 70 kb apart on chromosome 5. Granzyme A have the highest expression in NK-cells were granzyme K are barely detected. Granzyme K on the other hand have a particular high expression in CD8+ T cells. Stimulation with IL-2 or IL-15 give a strong upregulation of both enzymes in NK-cells. Stimulation of CD8+ T cells gives mainly upregulation of granzyme A. Fresh CD4+ T cells show very weak synthesis of granzymes but treatment with IL-2 or IL-15 give a clear upregulation of both granzyme A and K. T-cells (both CD4+ and CD8+) are highly responsive to stimulation with OKT3/anti CD28 producing granzyme B but not A and K. This rather discordant pattern of expression for granzyme A and K talks in favour of different modes of regulation and most likely different functions. A striking difference between granzyme A and K concern the propensity for granzyme A to be secreted into the culture medium after stimulation while this is not the case for granzyme K. The secreted form of granzyme A has a molecular weight slightly higher than the intracellular form indicating the presence of a proform. Secretion of granzymes to the extracellular medium is probably not only an in vitro phenomena since both granzyme A and B can be detected in serum from healthy individuals in picomolar concentrations. Moreover, significant elevation of granzyme levels in serum can bee seen in different diseases with activation of cellular immunity and in T- and NK-cells malignancies. We have previously reported that proforms of certain serine proteases including the five human granzymes have a downregulating activity on myeloid proliferation, a mechanism probably implicated in certain forms of neutropenia. We propose that secreted granzymes (especially A, B and H) constitute a part of T regulatory function working both locally at the site of inflammation and distantly via the circulation.

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2

Shresta, Sujan, Pam Goda, Robin Wesselschmidt, and Timothy J. Ley. "Residual Cytotoxicity and Granzyme K Expression in Granzyme A-deficient Cytotoxic Lymphocytes." Journal of Biological Chemistry 272, no. 32 (August 8, 1997): 20236–44. http://dx.doi.org/10.1074/jbc.272.32.20236.

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3

Joeckel, L. T., R. Wallich, P. Martin, D. Sanchez-Martinez, F. C. Weber, S. F. Martin, C. Borner, J. Pardo, C. Froelich, and M. M. Simon. "Mouse granzyme K has pro-inflammatory potential." Cell Death & Differentiation 18, no. 7 (February 11, 2011): 1112–19. http://dx.doi.org/10.1038/cdd.2011.5.

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4

Cooper, Dawn M., Dmitri V. Pechkovsky, Tillie L. Hackett, Darryl A. Knight, and David J. Granville. "Granzyme K Activates Protease-Activated Receptor-1." PLoS ONE 6, no. 6 (June 30, 2011): e21484. http://dx.doi.org/10.1371/journal.pone.0021484.

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5

&NA;. "DIFFERENTIAL EXPRESSION OF CYTOTOXIC MOLECULES GRANZYME A, GRANZYME B AND GRANZYME K IN HUMAN CD8+ T CELLS." Transplantation 82, Suppl 2 (July 2006): 1029. http://dx.doi.org/10.1097/00007890-200607152-02928.

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6

Wilharm, Elke, Marina A. A. Parry, Rainer Friebel, Harald Tschesche, Gabriele Matschiner, Christian P. Sommerhoff, and Dieter E. Jenne. "Generation of Catalytically Active Granzyme K fromEscherichia coliInclusion Bodies and Identification of Efficient Granzyme K Inhibitors in Human Plasma." Journal of Biological Chemistry 274, no. 38 (September 17, 1999): 27331–37. http://dx.doi.org/10.1074/jbc.274.38.27331.

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7

Dutta, Dibyendu, In Park, Hiwot Guililat, Samuel Sang, Arpita Talapatra, Barkha Singhal, and Nathaniel C. Mills. "Testosterone regulates granzyme K expression in rat testes." Endocrine Regulations 51, no. 4 (October 26, 2017): 193–204. http://dx.doi.org/10.1515/enr-2017-0020.

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Abstract Objective. Testosterone depletion induces increased germ cell apoptosis in testes. However, limited studies exist on genes that regulate the germ cell apoptosis. Granzymes (GZM) are serine proteases that induce apoptosis in various tissues. Multiple granzymes, including GZMA, GZMB and GZMN, are present in testes. Th us, we investigated which granzyme may be testosterone responsive and possibly may have a role in germ cell apoptosis aft er testosterone depletion. Methods. Ethylene dimethane sulfonate (EDS), a toxicant that selectively ablates the Leydig cells, was injected into rats to withdraw the testosterone. The testosterone depletion effects after 7 days post-EDS were verified by replacing the testosterone exogenously into EDS-treated rats. Serum or testicular testosterone was measured by radioimmunoassay. Using qPCR, mRNAs of granzyme variants in testes were quantified. The germ cell apoptosis was identified by TUNEL assay and the localization of GZMK was by immunohistochemistry. Results. EDS treatment eliminated the Leydig cells and depleted serum and testicular testosterone. At 7 days post-EDS, testis weights were reduced 18% with increased germ cell apoptosis plus elevation GZMK expression. GZMK was not associated with TUNEL-positive cells, but was localized to stripped cytoplasm of spermatids. In addition, apoptotic round spermatids were observed in the caput epididymis. Conclusions. GZMK expression in testes is testosterone dependent. GZMK is located adjacent to germ cells in seminiferous tubules and the presence of apoptotic round spermatids in the epididymis suggest its role in the degradation of microtubules in ectoplasmic specializations. Thus, overexpression of GZMK may indirectly regulate germ cell apoptosis by premature release of round spermatids from seminiferous tubule lumen.

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8

Richardson, K., C. Turner, S. Hiroyasu, R. Crawford, A. Burleigh, and D. Granville. "081 Granzyme K: A potential mediator of psoriasis." Journal of Investigative Dermatology 140, no. 7 (July 2020): S9. http://dx.doi.org/10.1016/j.jid.2020.03.083.

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9

Jenkins, Misty R., Joseph A. Trapani, Peter C. Doherty, and Stephen J. Turner. "Granzyme K Expressing Cytotoxic T Lymphocytes Protects Against Influenza Virus in Granzyme AB−/−Mice." Viral Immunology 21, no. 3 (September 2008): 341–46. http://dx.doi.org/10.1089/vim.2008.0036.

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10

Bovenschen, Niels, Razi Quadir, A. Lotte van den Berg, Arjan B. Brenkman, Isabel Vandenberghe, Bart Devreese, Jos Joore, and J. Alain Kummer. "Granzyme K Displays Highly Restricted Substrate Specificity That Only Partially Overlaps with Granzyme A." Journal of Biological Chemistry 284, no. 6 (December 5, 2008): 3504–12. http://dx.doi.org/10.1074/jbc.m806716200.

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11

Plasman, Kim, Hans Demol, Philip I. Bird, Kris Gevaert, and Petra Van Damme. "Substrate Specificities of the Granzyme Tryptases A and K." Journal of Proteome Research 13, no. 12 (November 19, 2014): 6067–77. http://dx.doi.org/10.1021/pr500968d.

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12

Wensink, Annette C., Maryse A. Wiewel, Lieneke H. Jongeneel, Marianne Boes, Tom van der Poll, C. Erik Hack, and Niels Bovenschen. "Granzyme M and K release in human experimental endotoxemia." Immunobiology 221, no. 7 (July 2016): 773–77. http://dx.doi.org/10.1016/j.imbio.2016.02.006.

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13

Tauh, K., K. Martyn, W. Enns, J. Choy, and D. Granville. "GRANZYME K - A NOVEL PLAYER IN CARDIAC ALLOGRAFT VASCULOPATHY." Canadian Journal of Cardiology 34, no. 10 (October 2018): S182. http://dx.doi.org/10.1016/j.cjca.2018.07.131.

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14

Bratke, K., A. Klug, P. Julius, M. Kuepper, M. Lommatzsch, G. Sparmann, W. Luttmann, and J. C. Virchow. "Granzyme K: a novel mediator in acute airway inflammation." Thorax 63, no. 11 (November 1, 2008): 1006–11. http://dx.doi.org/10.1136/thx.2007.091215.

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15

Li, Qing, Maiko Kobayashi, and Tomoyuki Kawada. "DDVP markedly decreases the expression of granzyme B and granzyme 3/K in human NK cells." Toxicology 243, no. 3 (January 2008): 294–302. http://dx.doi.org/10.1016/j.tox.2007.10.018.

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16

Camell, Christina D. "Taa Cells and Granzyme K: Old Players with New Tricks." Immunity 54, no. 1 (January 2021): 6–8. http://dx.doi.org/10.1016/j.immuni.2020.12.008.

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17

Rönnberg, Elin, Gabriela Calounova, Bengt Guss, Anders Lundequist, and Gunnar Pejler. "Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation." Infection and Immunity 81, no. 6 (March 25, 2013): 2085–94. http://dx.doi.org/10.1128/iai.00290-13.

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ABSTRACTGranzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.

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18

Joeckel, Lars T., Cody C. Allison, Marc Pellegrini, Catherina H. Bird, and Phillip I. Bird. "Granzyme K‐deficient mice show no evidence of impaired antiviral immunity." Immunology & Cell Biology 95, no. 8 (May 23, 2017): 676–83. http://dx.doi.org/10.1038/icb.2017.35.

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19

Wensink, A. C., V. Kemp, J. Fermie, M. I. Garcia Laorden, T. van der Poll, C. E. Hack, and N. Bovenschen. "Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes." Proceedings of the National Academy of Sciences 111, no. 16 (April 7, 2014): 5974–79. http://dx.doi.org/10.1073/pnas.1317347111.

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20

Tyrrell, Daniel, and Daniel Goldstein. "AGE-ASSOCIATED GRANZYME K-EXPRESSING CD8+ T-CELLS ENHANCE ATHEROSCLEROSIS IN MICE." Innovation in Aging 6, Supplement_1 (November 1, 2022): 196. http://dx.doi.org/10.1093/geroni/igac059.784.

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Abstract A novel population of age-associated Granzyme K (GZMK)-expressing CD8 T cells was found in mice and humans. These cells enhance local tissue senescence and inflammation and are distinct from central memory and conventional Granzyme B- or Interferon γ-producing effector memory CD8 T cells. It is unknown whether these cells drive chronic disease; thus, we induced atherosclerosis in young (3-mo) and aged (18-mo) wild-type mice via the PCSK9-AAV model and used scRNAseq to demonstrate that this GZMK-CD8 T cell population homes to atherosclerotic lesions exclusively in aged mice. Neutralizing CD8 T cells demonstrates that GZMK-CD8 cells drive age-enhance atherosclerosis. Finally, we transferred GZMK-CD8 cells from different aged donors into young CD8-/- hosts and demonstrate that GZMK-CD8 cells from aged but not young donors drive atherosclerosis. In conclusion, we identified a novel role for this recently described population of aging-specific GZMK-expressing CD8+ T cells as a critical driver of chronic disease.

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21

Hua, Guoqiang, Shuo Wang, Chao Zhong, Peng Xue, and Zusen Fan. "Ignition of p53 Bomb Sensitizes Tumor Cells to Granzyme K-Mediated Cytolysis." Journal of Immunology 182, no. 4 (February 6, 2009): 2152–59. http://dx.doi.org/10.4049/jimmunol.0802307.

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22

Vrazo, Alexandra C., Adrianne E. Hontz, Sarah K. Figueira, Braeden L. Butler, Julie M. Ferrell, Brock F. Binkowski, Jinzhu Li, and Kimberly A. Risma. "Live cell evaluation of granzyme delivery and death receptor signaling in tumor cells targeted by human natural killer cells." Blood 126, no. 8 (August 20, 2015): e1-e10. http://dx.doi.org/10.1182/blood-2015-03-632273.

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Key Points Natural killer cell granzyme B, A, and K delivery and subsequent caspase activation is rapid after conjugation with tumor target cells. Natural killer cells also induce caspase activation through death receptor ligation that can be monitored in real time.

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23

Rucevic, Marijana, Loren D. Fast, Gregory D. Jay, Flor M. Trespalcios, Andrew Sucov, Edward Siryaporn, and Yow-Pin Lim. "ALTERED LEVELS AND MOLECULAR FORMS OF GRANZYME K IN PLASMA FROM SEPTIC PATIENTS." Shock 27, no. 5 (May 2007): 488–93. http://dx.doi.org/10.1097/01.shk.0000246905.24895.e5.

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24

Turner, Christopher T., Matthew R. Zeglinski, Katlyn C. Richardson, Hongyan Zhao, Yue Shen, Anthony Papp, Phillip I. Bird, and David J. Granville. "Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling." Journal of Investigative Dermatology 139, no. 4 (April 2019): 930–39. http://dx.doi.org/10.1016/j.jid.2018.09.031.

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25

Fuller, Claudette L., Kodimangalam S. Ravichandran, and Vivian L. Braciale. "Phosphatidylinositol 3-Kinase-Dependent and -Independent Cytolytic Effector Functions." Journal of Immunology 162, no. 11 (June 1, 1999): 6337–40. http://dx.doi.org/10.4049/jimmunol.162.11.6337.

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Abstract Two distinct forms of short-term cytolysis have been described for CD8+ CTLs, the perforin/granzyme- and Fas ligand/Fas (CD95 ligand (CD95L)/CD95)-mediated pathways. However, the difference in signal transduction events leading to these cytolytic mechanisms remains unclear. We used wortmannin, an irreversible antagonist of phosphatidylinositol 3-kinase (PI3-K) activity, to investigate the role of PI3-K in influenza-specific CD8+ CTL cytolytic effector function. We found that the addition of wortmannin at concentrations as low as 1 nM significantly inhibited both the Ag/MHC-induced cytolysis of CD95− target cells and serine esterase release. In strong contrast, W did not inhibit the Ag/MHC-induced CD95L expression or the CD95L/CD95-mediated cytolysis of CD95+ targets. A combination of wortmannin and blocking mAb against CD95L inhibited the cytolysis of CD95+ targets, indicating that the wortmannin-independent cytolysis was due to CD95L/CD95 mediated cytolysis. These findings suggest a differential role for PI3-K in mediating cytolysis and, thus far, the earliest difference between perforin/granzyme- and CD95L/CD95-dependent cytolysis. Our data reinforce the idea of a TCR with modular signal transduction pathways that can be triggered or inhibited selectively, resulting in differential effector function.

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26

Kaiserman, Dion, Peishen Zhao, Caitlin Lorraine Rowe, Andrea Leong, Nicholas Barlow, Lars Thomas Joeckel, Corinne Hitchen, et al. "Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2." PLOS ONE 17, no. 7 (July 26, 2022): e0270584. http://dx.doi.org/10.1371/journal.pone.0270584.

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Granzyme K (GzmK) is a tryptic member of the granzyme family of chymotrypsin-like serine proteases produced by cells of the immune system. Previous studies have indicated that GzmK activates protease-activated receptor 1 (PAR1) enhancing activation of monocytes and wound healing in endothelial cells. Here, we show using peptides and full length proteins that GzmK and, to a lesser extent the related protease GzmA, are capable of activating PAR1 and PAR2. These cleavage events occur at the canonical arginine P1 residue and involve exosite interactions between protease and receptor. Despite cleaving PAR2 at the same point as trypsin, GzmK does not induce a classical Ca2+ flux but instead activates a distinct signalling cascade, involving recruitment of β-arrestin and phosphorylation of ERK. In epithelial A549 cells, PAR2 activation by GzmK results in the release of inflammatory cytokines IL-6 and IL-8. These data suggest that during an immune response GzmK acts as a pro-inflammatory regulator, rather than as a cytotoxin.

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27

Wilharm, Elke, Jürg Tschopp, and Dieter E. Jenne. "Biological activities of granzyme K are conserved in the mouse and account for residual Z-Lys-SBzl activity in granzyme A-deficient mice." FEBS Letters 459, no. 1 (September 27, 1999): 139–42. http://dx.doi.org/10.1016/s0014-5793(99)01200-4.

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28

Shiver, John W., Lishan Su, and Pierre A. Henkart. "Cytotoxicity with target DNA breakdown by rat basophilic leukemia cells expressing both cytolysin and granzyme A." Cell 71, no. 2 (October 1992): 315–22. http://dx.doi.org/10.1016/0092-8674(92)90359-k.

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29

Jiang, Wenzheng, Noo Ri Chai, Dragan Maric, and Bibiana Bielekova. "Unexpected Role for Granzyme K in CD56bright NK Cell-Mediated Immunoregulation of Multiple Sclerosis." Journal of Immunology 187, no. 2 (June 10, 2011): 781–90. http://dx.doi.org/10.4049/jimmunol.1100789.

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30

van Domselaar, R., S. A. H. de Poot, E. B. M. Remmerswaal, K. W. Lai, I. J. M. ten Berge, and N. Bovenschen. "Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication." Cell Death & Differentiation 20, no. 3 (October 26, 2012): 419–29. http://dx.doi.org/10.1038/cdd.2012.132.

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31

Jay, G. D. "Granzyme K Levels in Plasma of Septic Patients: A Potential Early Marker in Sepsis." Academic Emergency Medicine 12, Supplement 1 (May 1, 2005): 38. http://dx.doi.org/10.1197/j.aem.2005.03.099.

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32

Sharma, Mehul, Yulia Merkulova, Sheetal Raithatha, Leigh G. Parkinson, Yue Shen, Dawn Cooper, and David J. Granville. "Extracellular granzyme K mediates endothelial activation through the cleavage of protease‐activated receptor‐1." FEBS Journal 283, no. 9 (March 22, 2016): 1734–47. http://dx.doi.org/10.1111/febs.13699.

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33

Hardanto, Gery Rifano, Selamat Budijitno, and Hardian Hardian. "Effect of Artemisia vulgaris Extract on Granzyme Expression and Tumor Mass Diameter (Study of Adriamycin Cyclophosphamide Chemotherapy in Adenocarcinoma Mammae C3H Mice Model)." Jurnal Kedokteran Brawijaya 31, no. 4 (August 31, 2021): 1. http://dx.doi.org/10.21776/ub.jkb.2021.031.04.1.

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<p>Breast cancer incident continues to increase globally. The surgical management can be combined with other therapeutic modalities, including chemotherapy, radiation, and immunotherapy, such as Artemisia vulgaris (AV). This study aimed to determine the effect of AV extract on Granzyme expression and tumor mass diameter growth of C3H mice with adenocarcinoma mammae. Twenty-four female C3H mice were randomly divided into groups of K (control), P1 (AC chemotherapy), P2 (AV extract), and P3 (combination). Adenocarcinoma mammae were inoculated from donor mice. Two cycles of chemotherapy by Adriamycin 0.18 mg and Cyclophosphamide 1.8 mg were given intravenously, while Artemisia vulgaris 13 mg (0.2 ml) was given orally once per day. Granzyme expression was assessed using immunohistochemical staining, while tumor mass diameter growth was measured using tumor calipers. There was a significant negative correlation between and tumor mass diameter growth (p=0,001 and r=-0,911). Artemisia vulgaris increases the apoptotic effects of Adriamycin-Cyclophosphamide chemotherapy by increasing Granzyme expression and decreasing tumor mass diameter growth in adenocarcinoma mammae C3H mice.</p>

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34

Li, Tan, Chao Yang, Jingjing Jing, Liping Sun, and Yuan Yuan. "Granzyme K - A novel marker to identify the presence and rupture of abdominal aortic aneurysm." International Journal of Cardiology 338 (September 2021): 242–47. http://dx.doi.org/10.1016/j.ijcard.2021.06.014.

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35

Cooper, D. M., A. Hendel, and D. J. Granville. "467 Extracellular granzyme K induces endothelial activation through a protease activated receptor-1-dependent mechanism." Canadian Journal of Cardiology 27, no. 5 (September 2011): S231. http://dx.doi.org/10.1016/j.cjca.2011.07.390.

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36

Koetzier, Steven C., Jamie van Langelaar, Marie-José Melief, Annet F. Wierenga-Wolf, Cato E. A. Corsten, Katelijn M. Blok, Cindy Hoeks, et al. "Distinct Effector Programs of Brain-Homing CD8+ T Cells in Multiple Sclerosis." Cells 11, no. 10 (May 13, 2022): 1634. http://dx.doi.org/10.3390/cells11101634.

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The effector programs of CD8+ memory T cells are influenced by the transcription factors RUNX3, EOMES and T-bet. How these factors define brain-homing CD8+ memory T cells in multiple sclerosis (MS) remains unknown. To address this, we analyzed blood, CSF and brain tissues from MS patients for the impact of differential RUNX3, EOMES and T-bet expression on CD8+ T cell effector phenotypes. The frequencies of RUNX3- and EOMES-, but not T-bet-expressing CD8+ memory T cells were reduced in the blood of treatment-naïve MS patients as compared to healthy controls. Such reductions were not seen in MS patients treated with natalizumab (anti-VLA-4 Ab). We found an additional loss of T-bet in RUNX3-expressing cells, which was associated with the presence of MS risk SNP rs6672420 (RUNX3). RUNX3+EOMES+T-bet− CD8+ memory T cells were enriched for the brain residency-associated markers CCR5, granzyme K, CD20 and CD69 and selectively dominated the MS CSF. In MS brain tissues, T-bet coexpression was recovered in CD20dim and CD69+ CD8+ T cells, and was accompanied by increased coproduction of granzyme K and B. These results indicate that coexpression of RUNX3 and EOMES, but not T-bet, defines CD8+ memory T cells with a pre-existing brain residency-associated phenotype such that they are prone to enter the CNS in MS.

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37

Smith, Corey, Diah Elhassen, Stephanie Gras, Katherine K. Wynn, Vijayendra Dasari, Judy Tellam, Siok-Keen Tey, et al. "Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells." Blood 120, no. 16 (October 18, 2012): 3237–45. http://dx.doi.org/10.1182/blood-2012-03-420182.

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Abstract T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8+ cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bethiEomeshi/lo), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-betintEomeshi). Paradoxically, the T-bethiEomeshi/lo dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-betintEomeshi subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8+ T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.

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38

Zhao, Tongbiao, Honglian Zhang, Yuming Guo, and Zusen Fan. "Granzyme K Directly Processes Bid to Release Cytochromecand Endonuclease G Leading to Mitochondria-dependent Cell Death." Journal of Biological Chemistry 282, no. 16 (February 16, 2007): 12104–11. http://dx.doi.org/10.1074/jbc.m611006200.

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39

Martins, Cátia D. F., M. Manuela M. Raposo, and Susana P. G. Costa. "A New Fluorogenic Substrate for Granzyme B Based on Fluorescence Resonance Energy Transfer." Chemistry Proceedings 3, no. 1 (November 14, 2020): 6. http://dx.doi.org/10.3390/ecsoc-24-08311.

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The synthesis and characterization of a new fluorogenic substrate for granzyme B (GzmB) is reported. The substrate design was based on the fluorescence resonance energy transfer (FRET) principle using 5-(2′-aminoethyl)aminonaphthalene sulfonic acid (Edans) and 4-[[4′-(N,N-dimethylamino)phenyl]diazenyl]benzoic acid (Dabcyl) as a donor–acceptor pair, linked to a specific sequence for GzmB (AAD), with an additional amino acid as the anchoring point (K). The tetrapeptide was synthesized by microwave-assisted solid-phase peptide synthesis (MW-SPPS) and coupled to Dabcyl and Edans at its N- and C-termini, respectively. The obtained probe was purified by semi-preparative HPLC and characterized by NMR, UV/Vis absorption and fluorescence spectroscopy and mass spectrometry.

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40

Bab, Lilia M., Sienna Yoast, Mark Dreyer, and Brian F. Schmidt. "Heterologous expression of human granzyme K in Bacillus subtilis and characterization of its hydrolytic activity in vitro." Biotechnology and Applied Biochemistry 27, no. 2 (April 1998): 117–24. http://dx.doi.org/10.1111/j.1470-8744.1998.tb01383.x.

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41

Zhao, T., H. Zhang, Y. Guo, Q. Zhang, G. Hua, H. Lu, Q. Hou, H. Liu, and Z. Fan. "Granzyme K cleaves the nucleosome assembly protein SET to induce single-stranded DNA nicks of target cells." Cell Death & Differentiation 14, no. 3 (September 29, 2006): 489–99. http://dx.doi.org/10.1038/sj.cdd.4402040.

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Hink-Schauer, Clara, Eva Estébanez-Perpiñá, Elke Wilharm, Pablo Fuentes-Prior, Wolfgang Klinkert, Wolfram Bode, and Dieter E. Jenne. "The 2.2-Å Crystal Structure of Human Pro-granzyme K Reveals a Rigid Zymogen with Unusual Features." Journal of Biological Chemistry 277, no. 52 (October 15, 2002): 50923–33. http://dx.doi.org/10.1074/jbc.m207962200.

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MacDonald, Glen, Lianfa Shi, Christine Vande Velde, Judy Lieberman, and Arnold H. Greenberg. "Mitochondria-dependent and -independent Regulation of Granzyme B–induced Apoptosis." Journal of Experimental Medicine 189, no. 1 (January 4, 1999): 131–44. http://dx.doi.org/10.1084/jem.189.1.131.

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Granzyme B (GraB) is required for the efficient activation of apoptosis by cytotoxic T lymphocytes and natural killer cells. We find that GraB and perforin induce severe mitochondrial perturbation as evidenced by the release of cytochrome c into the cytosol and suppression of transmembrane potential (Δψ). The earliest mitochondrial event was the release of cytochrome c, which occurred at the same time as caspase 3 processing and consistently before the activation of apoptosis. Granzyme K/perforin or perforin treatment, both of which kill target cells efficiently but are poor activators of apoptosis in short-term assays, did not induce rapid cytochrome c release. However, they suppressed Δψ and increased reactive oxygen species generation, indicating that mitochondrial dysfunction is also associated with this nonapoptotic cell death. Pretreatment with peptide caspase inhibitors zVAD-FMK or YVAD-CHO prevented GraB apoptosis and cytochrome c release, whereas DEVD-CHO blocked apoptosis but did not prevent cytochrome c release, indicating that caspases act both up- and downstream of mitochondria. Of additional interest, Δψ suppression mediated by GraK or GraB and perforin was not affected by zVAD-FMK and thus was caspase independent. Overexpression of Bcl-2 and Bcl-XL suppressed caspase activation, mitochondrial cytochrome c release, Δψ suppression, and apoptosis and cell death induced by GraB, GraK, or perforin. In an in vitro cell free system, GraB activates nuclear apoptosis in S-100 cytosol at high doses, however the addition of mitochondria amplified GraB activity over 15-fold. GraB- induced caspase 3 processing to p17 in S-100 cytosol was increased only threefold in the presence of mitochondria, suggesting that another caspase(s) participates in the mitochondrial amplification of GraB apoptosis. We conclude that GraB-induced apoptosis is highly amplified by mitochondria in a caspase-dependent manner but that GraB can also initiate caspase 3 processing and apoptosis in the absence of mitochondria.

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Prunk, Mateja, Milica Perišić Nanut, Tanja Jakoš, Jerica Sabotič, Urban Švajger, and Janko Kos. "Extracellular Cystatin F Is Internalised by Cytotoxic T Lymphocytes and Decreases Their Cytotoxicity." Cancers 12, no. 12 (December 6, 2020): 3660. http://dx.doi.org/10.3390/cancers12123660.

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Cystatin F is a protein inhibitor of cysteine cathepsins, peptidases involved in the activation of the effector molecules of the perforin/granzyme pathway. Cystatin F was previously shown to regulate natural killer cell cytotoxicity. Here, we show that extracellular cystatin F has a role in regulating the killing efficiency of cytotoxic T lymphocytes (CTLs). Extracellular cystatin F was internalised into TALL-104 cells, a cytotoxic T cell line, and decreased their cathepsin C and H activity. Correspondingly, granzyme A and B activity was also decreased and, most importantly, the killing efficiency of TALL-104 cells as well as primary human CTLs was reduced. The N-terminally truncated form of cystatin F, which can directly inhibit cathepsin C (unlike the full-length form), was more effective than the full-length inhibitor. Furthermore, cystatin F decreased cathepsin L activity, which, however, did not affect perforin processing. Cystatin F derived from K-562 target cells could also decrease the cytotoxicity of TALL-104 cells. These results clearly show that, by inhibiting cysteine cathepsin proteolytic activity, extracellular cystatin F can decrease the cytotoxicity of CTLs and thus compromise their function.

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Guo, Yuming, Jun Chen, Tongbiao Zhao, and Zusen Fan. "Granzyme K degrades the redox/DNA repair enzyme Ape1 to trigger oxidative stress of target cells leading to cytotoxicity." Molecular Immunology 45, no. 8 (April 2008): 2225–35. http://dx.doi.org/10.1016/j.molimm.2007.11.020.

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Huang, Rong, Shan Zhong, Hong Liu, Renqiu Kong, Yaping Wang, Wei Hu, and Qionglin Guo. "Identification and characterization of common carp (Cyprinus carpio L.) granzyme A/K, a cytotoxic cell granule-associated serine protease." Fish & Shellfish Immunology 29, no. 3 (September 2010): 388–98. http://dx.doi.org/10.1016/j.fsi.2010.04.002.

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Benmohamed, Lbachir, Arif Khan, and Ruchi Srivastava. "Herpes simplex virus tegument protein VP11/12-derived epitopes preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect “humanized” HLA-A*02:01 transgenic mice against ocular herpes (VIR6P.1172)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 149.12. http://dx.doi.org/10.4049/jimmunol.194.supp.149.12.

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Abstract In this study, we used multiple prediction computer-assisted algorithms to identify 10 potential HLA-A*02:01-restricted CD8+ T cell epitopes from the 716 amino acids sequence of Herpes Simplex Virus type 1 virion tegument phosphoprotein 11/12 (HSV-1 VP11/12). Three out of ten epitopes exhibited high to moderate binding affinity to HLA-A*02:01 molecules. In ten sequentially studied HLA-A*02:01 positive, HSV seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease), the most frequent, robust and polyfunctional effector CD8+ T-cell responses, as assessed by a combination of tetramer frequency, granzyme B, granzyme K, perforin, CD107a/b cytotoxic degranulation, IFN-g and multiplex cytokines assays, were predominantly directed against three epitopes: VP11/1266-74, VP11/12220-228 and VP11/12702-710. Interestingly, ASYMP individuals had significantly higher proportion of CD45RAlowCCR7lowCD44highCD62LlowCD27lowCD28lowCD8+ effector memory T cells (TEM) specific to the three epitopes, compared to symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpetic disease). Moreover, immunization of HLA-A*02:01 transgenic mice with the three ASYMP CD8+ TEM cell epitopes induced a strong protective immunity against ocular herpes infection and disease. Our findings outline the features of protective HSV-specific CD8+ T cells that should guide the development of an effective T-cell-based herpes vaccine.

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Janiszewski, Tomasz, Sonia Kołt, Dion Kaiserman, Scott J. Snipas, Shuang Li, Julita Kulbacka, Jolanta Saczko, et al. "Noninvasive optical detection of granzyme B from natural killer cells with enzyme-activated fluorogenic probes." Journal of Biological Chemistry 295, no. 28 (May 21, 2020): 9567–82. http://dx.doi.org/10.1074/jbc.ra120.013204.

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Natural killer (NK) cells are key innate immunity effectors that combat viral infections and control several cancer types. For their immune function, human NK cells rely largely on five different cytotoxic proteases, called granzymes (A/B/H/K/M). Granzyme B (GrB) initiates at least three distinct cell death pathways, but key aspects of its function remain unexplored because selective probes that detect its activity are currently lacking. In this study, we used a set of unnatural amino acids to fully map the substrate preferences of GrB, demonstrating previously unknown GrB substrate preferences. We then used these preferences to design substrate-based inhibitors and a GrB-activatable activity-based fluorogenic probe. We show that our GrB probes do not significantly react with caspases, making them ideal for in-depth analyses of GrB localization and function in cells. Using our quenched fluorescence substrate, we observed GrB within the cytotoxic granules of human YT cells. When used as cytotoxic effectors, YT cells loaded with GrB attacked MDA-MB-231 target cells, and active GrB influenced its target cell-killing efficiency. In summary, we have developed a set of molecular tools for investigating GrB function in NK cells and demonstrate noninvasive visual detection of GrB with an enzyme-activated fluorescent substrate.

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Woodard, Susan L., Stephanie A. Fraser, Ulrike Winkler, Delwin S. Jackson, Chih-Min Kam, James C. Powers, and Dorothy Hudig. "Purification and Characterization of Lymphocyte Chymase I, a Granzyme Implicated in Perforin-Mediated Lysis." Journal of Immunology 160, no. 10 (May 15, 1998): 4988–93. http://dx.doi.org/10.4049/jimmunol.160.10.4988.

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Abstract One mechanism of killing by cytotoxic lymphocytes involves the exocytosis of specialized granules. The released granules contain perforin, which assembles into pores in the membranes of cells targeted for death. Serine proteases termed granzymes are present in the cytotoxic granules and include several chymases (with chymotrypsin-like specificity of cleavage). One chymase is selectively reactive with an inhibitor, Biotinyl-Aca-Aca-Phe-Leu-PheP(OPh)2, that blocks perforin lysis. We report the purification and characterization of this chymase, lymphocyte chymase I, from rat natural killer cell (RNK)-16 granules. Lymphocyte chymase I is 30 kDa with a pH 7.5 to 9 optimum and primary substrate preference for tryptophan, a preference distinct from rat mast cell chymases. This chymase also reacts with other selective serine protease inhibitors that block perforin pore formation. It elutes by Cu2+-immobilized metal affinity chromatography with other granzymes and has the N-terminal protein sequence conserved among granzymes. Chymase I reduces pore formation when preincubated with perforin at 37°C. In contrast, addition of the chymase without preincubation had little effect on lysis. It should be noted that the perforin preparation contained sufficient residual chymase activity to support lysis. Thus, the reduction of lysis may represent an effect of excess prolytic chymase I or a means to limit perforin lysis of bystander cells. In contrast, other chymases and granzyme K were without effect when added to perforin during similar preincubation. Identification of the natural substrate of chymase I will help resolve how it regulates perforin-mediated pore formation.

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Ramljak, Deni, Martina Vukoja, Marina Curlin, Katarina Vukojevic, Maja Barbaric, Una Glamoclija, Bejana Purisevic, Olivera Peric, and Violeta Soljic. "Early Response of CD8+ T Cells in COVID-19 Patients." Journal of Personalized Medicine 11, no. 12 (December 3, 2021): 1291. http://dx.doi.org/10.3390/jpm11121291.

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Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

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