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Gene Review

GZMA  -  granzyme A (granzyme 1, cytotoxic T...

Homo sapiens

Synonyms: CTL tryptase, CTLA3, Cytotoxic T-lymphocyte proteinase 1, Fragmentin-1, Granzyme A, ...
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Disease relevance of GZMA


Psychiatry related information on GZMA

  • METHODS: Family environment of 24 families with at least one parent with bipolar disorder (BPD) and 27 families with healthy parents (healthy families, HF) were assessed using the Family Environment Scale (FES) [6].
  • RESULTS: Seventeen (71%) of the 24 BPD families had at least one child with a mood disorder and one (3.7%) of the 27 HF had a child with a mood disorder [6].

High impact information on GZMA

  • Messenger RNA (mRNA) encoding the cytotoxic proteins perforin and granzyme B and a constitutively expressed cyclophilin B gene were measured with the use of a competitive, quantitative polymerase chain reaction, and the level of expression was correlated with allograft status [7].
  • The cytolytic pathway involves calcium-dependent exocytosis of perforin and granzyme proteases, as well as Fas-mediated programmed cell death, whereas the noncytolytic pathway involves the release of chemokines that prevent viral entry [8].
  • Using granzyme A as a marker of cytolytic granule proteins, and macrophage inflammatory protein (MIP)-1alpha and RANTES as markers of HIV-1 inhibitory chemokines, we show that these two very different mediators of viral inhibition are both localized in the cytolytic granules of HIV-1-specific CD8+ cytotoxic T lymphocytes (CTL) [8].
  • (2005) in this issue of Immunity examines the mechanisms used by granzyme A to kill target cells after its cytoplasmic injection by cytotoxic lymphocytes [9].
  • Cytotoxic T lymphocytes and natural killer cells use the perforin/granzyme pathway to kill virally infected cells and tumor cells [10].

Chemical compound and disease context of GZMA


Biological context of GZMA


Anatomical context of GZMA

  • Inter-alpha-trypsin inhibitor and free bikunin have the potential to neutralize extracellular granzyme K activity after T cell degranulation and may thus control unspecific damage of bystander cells at sites of inflammatory reactions [1].
  • The natural proform of granzyme K with the amino-terminal propeptide Met-Glu was expressed as inclusion bodies and converted to its active enzyme by cathepsin C after refolding of precursor molecules [1].
  • Granzyme K activity was shown to be inhibited by the synthetic compounds Phe-Pro-Arg-chloromethyl ketone, phenylmethylsulfonyl fluoride, PefablocSC, and benzamidine, by the Kunitz-type inhibitor aprotinin and by human blood plasma [1].
  • NK cells stimulated with CD40L-DC resulted in the induction of the cell surface expression of TRAIL, the production of IFN-gamma and intracellular accumulation of granzyme B [20].
  • GZMA is one of the apoptotic effectors localized in cytotoxic T lymphocytes and is considered to mediate glucocorticoid-induced apoptosis of human leukemia 697 cells [21].

Associations of GZMA with chemical compounds

  • Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-Like Immunoreceptor [22].
  • It hydrolyzed N alpha-carbobenzyloxy-L-lysyl-thiobenzyl ester (BLT), and this BLT esterase activity was most efficient at slightly alkaline pH and was relatively more active near neutral pH than mouse CTL tryptase [23].
  • The human granzyme A (HFSP, CTLA3) gene maps to 5q11-q12 and defines a new locus of the serine protease superfamily [24].
  • In the present study, we identified a novel 5' variant transcript of GZMA in dexamethasone (DEX)-treated 697 cells [21].
  • Granzyme B is an aspartic acid protease similar to members of the interleukin 1beta converting enzyme (ICE) family [25].

Physical interactions of GZMA


Enzymatic interactions of GZMA


Co-localisations of GZMA

  • Cathepsin B colocalizes with granzyme A in both normal and I-cells indicating that lysosomal proteins can also use the Man-6-P receptor-independent pathway in these cells [34].

Regulatory relationships of GZMA

  • CCR6(+) CD8(+) T cells express granzyme A and a low level of perforin but not granzyme B [35].
  • Silencing NM23-H1 or TREX1 inhibits DNA damage and death of cells treated with perforin (PFN) and granzyme A, but not of cells treated with perforin and granzyme B (GzmB) [36].
  • Single-stranded DNA damage is initiated when the endonuclease NM23-H1 becomes activated to nick DNA after granzyme A cleaves its inhibitor, SET [36].
  • Granzyme A is a specific tryptase that concentrates in the nucleus of targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B [37].
  • The memory-type CD28(+) CTLs induced by anti-4-1BB costimulation acquired a greatly enhanced content of granzyme B, a cytolytic mediator, and enhanced cytotoxic activity as compared with CD28(-) CTLs [38].

Other interactions of GZMA


Analytical, diagnostic and therapeutic context of GZMA


  1. Generation of catalytically active granzyme K from Escherichia coli inclusion bodies and identification of efficient granzyme K inhibitors in human plasma. Wilharm, E., Parry, M.A., Friebel, R., Tschesche, H., Matschiner, G., Sommerhoff, C.P., Jenne, D.E. J. Biol. Chem. (1999) [Pubmed]
  2. Expression of nm23-H1 is associated with poor prognosis in peripheral T-cell lymphoma. Niitsu, N., Nakamine, H., Okamoto, M., Akamatsu, H., Honma, Y., Higashihara, M., Okabe-Kado, J., Hirano, M. Br. J. Haematol. (2003) [Pubmed]
  3. The receptor for hyaluronic acid-mediated motility induces specific CD8+ T cell response in healthy donors and patients with chronic myeloid leukemia after allogeneic stem cell transplantation. Chen, J., Schmitt, A., Bunjes, D., Chen, B., Schmitt, M. Int. J. Oncol. (2007) [Pubmed]
  4. Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation. Meth, M.J., Sperber, K.E. Mt. Sinai J. Med. (2006) [Pubmed]
  5. Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease. Vernooy, J.H., Möller, G.M., van Suylen, R.J., van Spijk, M.P., Cloots, R.H., Hoet, P.H., Pennings, H.J., Wouters, E.F. Am. J. Respir. Crit. Care Med. (2007) [Pubmed]
  6. Family environment in families with versus families without parental bipolar disorder: a preliminary comparison study. Romero, S., Delbello, M.P., Soutullo, C.A., Stanford, K., Strakowski, S.M. Bipolar disorders. (2005) [Pubmed]
  7. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. Li, B., Hartono, C., Ding, R., Sharma, V.K., Ramaswamy, R., Qian, B., Serur, D., Mouradian, J., Schwartz, J.E., Suthanthiran, M. N. Engl. J. Med. (2001) [Pubmed]
  8. Beta-chemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Wagner, L., Yang, O.O., Garcia-Zepeda, E.A., Ge, Y., Kalams, S.A., Walker, B.D., Pasternack, M.S., Luster, A.D. Nature (1998) [Pubmed]
  9. Do cytotoxic lymphocytes kill via reactive oxygen species? Williams, M.S., Henkart, P.A. Immunity (2005) [Pubmed]
  10. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Grossman, W.J., Verbsky, J.W., Barchet, W., Colonna, M., Atkinson, J.P., Ley, T.J. Immunity (2004) [Pubmed]
  11. The serine protease granzyme M is preferentially expressed in NK-cell, gamma delta T-cell, and intestinal T-cell lymphomas: evidence of origin from lymphocytes involved in innate immunity. Krenacs, L., Smyth, M.J., Bagdi, E., Krenacs, T., Kopper, L., Rudiger, T., Zettl, A., Muller-Hermelink, H.K., Jaffe, E.S., Raffeld, M. Blood (2003) [Pubmed]
  12. Treatment of melanoma with 5-fluorouracil or dacarbazine in vitro sensitizes cells to antigen-specific CTL lysis through perforin/granzyme- and Fas-mediated pathways. Yang, S., Haluska, F.G. J. Immunol. (2004) [Pubmed]
  13. CD8 T lymphocytes do not express cytotoxic proteins in coronary artery aneurysms in acute Kawasaki disease. Guzman-Cottrill, J.A., Garcia, F.L., Shulman, S.T., Rowley, A.H. Pediatr. Infect. Dis. J. (2005) [Pubmed]
  14. Characterisation of tryptase and a granzyme H-like chymase isolated from equine mastocytoma tissue. Pemberton, A.D., McEuen, A.R., Scudamore, C.L. Vet. Immunol. Immunopathol. (2001) [Pubmed]
  15. The upregulation by peplomycin of signal transduction in human cells. Yamamoto, T., Yoneda, K., Ueta, E., Osaki, T. Jpn. J. Pharmacol. (2001) [Pubmed]
  16. Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A. Fan, Z., Beresford, P.J., Zhang, D., Xu, Z., Novina, C.D., Yoshida, A., Pommier, Y., Lieberman, J. Nat. Immunol. (2003) [Pubmed]
  17. HMG2 interacts with the nucleosome assembly protein SET and is a target of the cytotoxic T-lymphocyte protease granzyme A. Fan, Z., Beresford, P.J., Zhang, D., Lieberman, J. Mol. Cell. Biol. (2002) [Pubmed]
  18. The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity. Bell, J.K., Goetz, D.H., Mahrus, S., Harris, J.L., Fletterick, R.J., Craik, C.S. Nat. Struct. Biol. (2003) [Pubmed]
  19. Cloning and expression of a second human natural killer cell granule tryptase, HNK-Tryp-2/granzyme 3. Sayers, T.J., Lloyd, A.R., McVicar, D.W., O'Connor, M.D., Kelly, J.M., Carter, C.R., Wiltrout, T.A., Wiltrout, R.H., Smyth, M.J. J. Leukoc. Biol. (1996) [Pubmed]
  20. Gene transfer of the CD40-ligand to human dendritic cells induces NK-mediated antitumor effects against human carcinoma cells. Tomihara, K., Kato, K., Masuta, Y., Nakamura, K., Tanaka, T., Hiratsuka, H., Hamada, H. Int. J. Cancer (2007) [Pubmed]
  21. Glucocorticoid-induced alternative promoter usage for a novel 5' variant of granzyme A. Ruike, Y., Katsuma, S., Hirasawa, A., Tsujimoto, G. J. Hum. Genet. (2007) [Pubmed]
  22. Human CD4+ T Cells Lyse Target Cells via Granzyme/Perforin upon Circumvention of MHC Class II Restriction by an Antibody-Like Immunoreceptor. Hombach, A., K??hler, H., Rappl, G., Abken, H. J. Immunol. (2006) [Pubmed]
  23. Human cytotoxic lymphocyte tryptase. Its purification from granules and the characterization of inhibitor and substrate specificity. Poe, M., Bennett, C.D., Biddison, W.E., Blake, J.T., Norton, G.P., Rodkey, J.A., Sigal, N.H., Turner, R.V., Wu, J.K., Zweerink, H.J. J. Biol. Chem. (1988) [Pubmed]
  24. The human granzyme A (HFSP, CTLA3) gene maps to 5q11-q12 and defines a new locus of the serine protease superfamily. Fink, T.M., Lichter, P., Wekerle, H., Zimmer, M., Jenne, D.E. Genomics (1993) [Pubmed]
  25. Activation of apoptosis pathways by granzyme B. Greenberg, A.H. Cell Death Differ. (1996) [Pubmed]
  26. Hypothesis: cytotoxic lymphocyte granule serine proteases activate target cell endonucleases to trigger apoptosis. Smyth, M.J., Browne, K.A., Thia, K.Y., Apostolidis, V.A., Kershaw, M.H., Trapani, J.A. Clin. Exp. Pharmacol. Physiol. (1994) [Pubmed]
  27. The granzyme B-serglycin complex from cytotoxic granules requires dynamin for endocytosis. Veugelers, K., Motyka, B., Frantz, C., Shostak, I., Sawchuk, T., Bleackley, R.C. Blood (2004) [Pubmed]
  28. Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. Gross, C., Koelch, W., DeMaio, A., Arispe, N., Multhoff, G. J. Biol. Chem. (2003) [Pubmed]
  29. Down-regulation of human granzyme B expression by glucocorticoids. Dexamethasone inhibits binding to the Ikaros and AP-1 regulatory elements of the granzyme B promoter. Wargnier, A., Lafaurie, C., Legros-Maïda, S., Bourge, J.F., Sigaux, F., Sasportes, M., Paul, P. J. Biol. Chem. (1998) [Pubmed]
  30. Functional dissociation between proforms and mature forms of proteinase 3, azurocidin, and granzyme B in regulation of granulopoiesis. Sköld, S., Zeberg, L., Gullberg, U., Olofsson, T. Exp. Hematol. (2002) [Pubmed]
  31. Filamin (280-kDa actin-binding protein) is a caspase substrate and is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apoptosis. Browne, K.A., Johnstone, R.W., Jans, D.A., Trapani, J.A. J. Biol. Chem. (2000) [Pubmed]
  32. Granzyme B directly and efficiently cleaves several downstream caspase substrates: implications for CTL-induced apoptosis. Andrade, F., Roy, S., Nicholson, D., Thornberry, N., Rosen, A., Casciola-Rosen, L. Immunity (1998) [Pubmed]
  33. Apoptosis of the teratocarcinoma cell line Tera-1 leads to the cleavage of HERV-K10gag proteins by caspases and/or granzyme B. Beyer, T.D., Kolowos, W., Dumitriu, I.E., Voll, R.E., Heyder, P., Gaipl, U.S., Kalden, J.R., Herrmann, M. Scand. J. Immunol. (2002) [Pubmed]
  34. Granzymes A and B are targeted to the lytic granules of lymphocytes by the mannose-6-phosphate receptor. Griffiths, G.M., Isaaz, S. J. Cell Biol. (1993) [Pubmed]
  35. Functional expression of chemokine receptor CCR6 on human effector memory CD8(+) T cells. Kondo, T., Takata, H., Takiguchi, M. Eur. J. Immunol. (2007) [Pubmed]
  36. The exonuclease TREX1 is in the SET complex and acts in concert with NM23-H1 to degrade DNA during granzyme A-mediated cell death. Chowdhury, D., Beresford, P.J., Zhu, P., Zhang, D., Sung, J.S., Demple, B., Perrino, F.W., Lieberman, J. Mol. Cell (2006) [Pubmed]
  37. Induction of rapid histone degradation by the cytotoxic T lymphocyte protease Granzyme A. Zhang, D., Pasternack, M.S., Beresford, P.J., Wagner, L., Greenberg, A.H., Lieberman, J. J. Biol. Chem. (2001) [Pubmed]
  38. Role of 4-1BB (CD137) in the functional activation of cord blood CD28(-)CD8(+) T cells. Kim, Y.J., Brutkiewicz, R.R., Broxmeyer, H.E. Blood (2002) [Pubmed]
  39. Recombinant human granzyme A binds to two putative HLA-associated proteins and cleaves one of them. Beresford, P.J., Kam, C.M., Powers, J.C., Lieberman, J. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  40. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Grossman, W.J., Verbsky, J.W., Tollefsen, B.L., Kemper, C., Atkinson, J.P., Ley, T.J. Blood (2004) [Pubmed]
  41. Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes. Krähenbühl, O., Rey, C., Jenne, D., Lanzavecchia, A., Groscurth, P., Carrel, S., Tschopp, J. J. Immunol. (1988) [Pubmed]
  42. Characterization of three serine esterases isolated from human IL-2 activated killer cells. Hameed, A., Lowrey, D.M., Lichtenheld, M., Podack, E.R. J. Immunol. (1988) [Pubmed]
  43. Loss of cytotoxic T lymphocyte function in Chediak-Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis. Baetz, K., Isaaz, S., Griffiths, G.M. J. Immunol. (1995) [Pubmed]
  44. Granzyme A binding to target cell proteins. Granzyme A binds to and cleaves nucleolin in vitro. Pasternack, M.S., Bleier, K.J., McInerney, T.N. J. Biol. Chem. (1991) [Pubmed]
  45. A role for heat shock protein 27 in CTL-mediated cell death. Beresford, P.J., Jaju, M., Friedman, R.S., Yoon, M.J., Lieberman, J. J. Immunol. (1998) [Pubmed]
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