GZMA (granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3))
Written | 2011-09 | Elena Catalan, Diego Sanchez-Martinez, Julián Pardo |
Dpto Bioquimica y Biologia Molecular y Celular, Fac Ciencias, Univ Zaragoza, Spain (EC, DSM, JP); Fundacion Aragon I+D (ARAID), Zaragoza, Spain (JP) |
(Note : for Links provided by Atlas : click)
1. Identity
Alias_names | General Information |
CTLA3 | |
granzyme A (granzyme 1 | |
Other alias | |
HGNC (Hugo) | GZMA |
LocusID (NCBI) | 3001 |
Atlas_Id | 51130 |
Location | 5q11.2 [Link to chromosome band 5q11] |
Location_base_pair | Starts at 55102646 and ends at 55110252 bp from pter ( according to hg19-Feb_2009) [Mapping GZMA.png] |
Local_order | Size: 7607 bases. Coordinates: 54398473. |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
2. DNA/RNA
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Figure 1. Genomic organization of human GZMA. A, human GZMA cluster. Arrow indicate the direction of transcription. B, representation of the GZMA genetic locus. White: untranslated regions; Blue: leader sequence; Green: mature enzyme. Solid lanes: splicing between the first and second exons. gre: glucocorticoid response element (adapted from Ruike et al., 2007). | |
Description | The GZMA gene, with 7607 bases in length, consists of 5 exons and 4 introns. GZMA gene is located in a gene cluster together with granzyme K (figure 1) (Grossman et al., 2003). |
Transcription | There are at least two transcripts of human GZMA whose expression is differentially regulated by glucocorticoid (Ruike et al., 2007). These transcripts generate two isoforms, GZMAα and GZMAβ, which have respective first exons: exon 1a and exon 1b (figure 1): GZMAα (exon 1a): canonical sequence, GZMAβ (exon 1b): lack aa 1-17; aa 18-23 LLLIPE --> MTKGLR. |
3. Protein
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Figure 2. Diagram of the crystal structure of human granzyme A dimer (Bell et al., 2003; Hink-Schauer et al., 2003). The cystein groups involved in disulphide bond-mediated dimer (green) and the three aminoacids forming the catalytic triad (red, blue and yellow) are shown. Representation from PDB (accession code 1OP8) deposited by Hink-Schauer C, Estébanez-Perpiñá E, Kurschus FC, Bode W, Jenne DE. Nat Struct Biol. 2003 Jul;10(7):535-40. | |
Description | Granzyme A is a tryptase (cleave proteins after Lys or Arg residues) expressed mainly in cytotoxic cells (cytotoxic T and Natural Killer cells) (Masson et al., 1986; Simon et al., 1986; Young et al., 1986). Protein is expressed as a preproenzyme (Jenne et al., 1988) containing a signal sequence that mediates targeting of the nascent enzyme to the ER. Cleavage of the signal peptide produces an inactive proenzyme that contains an N-terminal dipeptide that needs to be cleaved to produce an active protease. In the Golgi, a mannose-6-phosphate tag is added for transporting the proenzyme to cytotoxic granules. Within the cytotoxic granule, the N-terminal dipeptide is removed by cathepsin C (dipeptidyl peptidase I) (Pham et al., 1999), producing the active enzyme that is kept inactive at low pH. Native granzyme A is expressed as a dimer (Bell et al., 2003; Hink-Schauer et al., 2003). |
Expression | Cytotoxic CD8+ T cells, Natural Killer cells, CD4+ T cells, gamma-delta T cells, type II pneumocytes, alveolar macrophages, bronchiolar epithelial cells. |
Localisation | Cytotoxic granules. |
Function | Granzyme A is delivered from CTL or NK cytotoxic granules to the cytoplasm of target cell by a mechanism dependent on perforin (Baran et al., 2009; Praper et al., 2011; Thiery et al., 2011). There are some controversial findings about the physiological function of gzmA. It has been reported that human GzmA induces perforin-mediated caspase-independent cell death in some tumors cell lines (Hayes et al., 1989; Shi et al., 1992; Beresford et al., 1999; Shresta et al., 1999; Pardo et al., 2004). GzmA translocates to the nucleus and mitochondria where key substrates such as mitochondrial complex I protein, NADH dehydrogenase Fe-S protein 3 (NDUFS3) is cleaved, inducing the production of Radical Oxygen Species (ROS). ROS production induces the activation of the SET complex that translocates into the nucleus in order to repair DNA damage induced by ROS. Once there, granzyme A cleaves components of the endoplasmic reticulum-associated SET complex, releasing the endonuclease NM23H1 that induces single strand nicks in the DNA and ultimately cell death (Lieberman, 2011). Other authors have reported that the cytotoxic potential of granzyme A is low, but induce expression of pro-inflammatory cytokines in monocytes-like cells by a caspase-1 dependent mechanism (Metkar et al., 2008). Granzyme A is able to cleave several extracellular substrates like thrombin receptor, fibronectin, collagen IV, proteinase-activated receptor-2, Pro-urokinase plasminogen activator and myelin basic protein (Kramer et al., 1987; Buzza et al., 2006; Hendel et al., 2011). Granzyme and granzyme B double deficient mice are more susceptible than granzyme B deficient mice to transplanted tumors suggesting a contribution of granzyme A to tumor control in vivo (Pardo et al., 2002; Cao et al., 2007). |
Homology | Mouse granzyme A; Rat granzyme A; Chicken granzyme A; Fish granzyme A (Common Carp, Atlantic cod, Channel catfish) (Praveen et al., 2006; Praveen et al., 2006; Wernersson et al., 2006). |
4. Mutations
Note | Not known. |
5. Implicated in
Note | |
Entity | Sepsis (Froelich et al., 2009; Hendel et al., 2011) |
Disease | Several findings suggest that gzmA contributes to septic shock. Native and recombinant human granzyme A as well as a human NK cell line expressing gzmA induces human adherent peripheral blood mononuclear cells to express proinflammatory cytokines including interleukin-beta interleukin-6, inteleukin-8 and TNF-alpha (Sower et al., 1996; Metkar et al., 2008). Granzyme A deficient mice are more resistant than wild type mice to septic shock induced by LPS (Metkar et al., 2008). |
Entity | Rheumatoid arthritis |
Prognosis | Granzyme A levels are higher in serum and synovial fluid of patients with rheumatoid arthritis (Griffiths et al., 1992; Nordstrom et al., 1992; Kummer et al., 1994; Tak et al., 1994; Muller-Ladner et al., 1995; Spaeny-Dekking et al., 1998; Tak et al., 1999). |
Entity | Chronic obstructive pulmonary disease |
Prognosis | Granzyme A is expressed in type II pneumocytes of patients with severe chronic obstructive pulmonary disease (Vernooy et al., 2007). |
Entity | Hypersensitivity pneumonitis |
Prognosis | Granzyme A is elevated in bronchoalveolar lavage fluid from patients with hypersensitivity pneumonitis (Tremblay et al., 2000). |
Entity | Sjögren's syndrome |
Prognosis | Granzyme A is expressed in salivary glands from patients with Sjögren's syndrome (Alpert et al., 1994). |
Entity | Poxvirus infection |
Disease | Granzyme A deficient mice are more susceptible than wild type mice to mousepox virus (ectromelia) (Mullbacher et al., 1996). |
Entity | Herpes virus infection |
Disease | Granzyme A deficient mice are more susceptible than wild type mice to herpes simplex virus type 1 (HSV-1) (Pereira et al., 2000) and mouse cytomegalovirus (CMV) infection (Riera et al., 2000). |
6. Bibliography
Expression of granzyme A in salivary gland biopsies from patients with primary Sjogren's syndrome. |
Alpert S, Kang HI, Weissman I, Fox RI. |
Arthritis Rheum. 1994 Jul;37(7):1046-54. |
PMID 8024614 |
The molecular basis for perforin oligomerization and transmembrane pore assembly. |
Baran K, Dunstone M, Chia J, Ciccone A, Browne KA, Clarke CJ, Lukoyanova N, Saibil H, Whisstock JC, Voskoboinik I, Trapani JA. |
Immunity. 2009 May;30(5):684-95. Epub 2009 May 14. |
PMID 19446473 |
The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity. |
Bell JK, Goetz DH, Mahrus S, Harris JL, Fletterick RJ, Craik CS. |
Nat Struct Biol. 2003 Jul;10(7):527-34. |
PMID 12819769 |
Granzyme A loading induces rapid cytolysis and a novel form of DNA damage independently of caspase activation. |
Beresford PJ, Xia Z, Greenberg AH, Lieberman J. |
Immunity. 1999 May;10(5):585-94. |
PMID 10367904 |
Extracellular granzymes: current perspectives. |
Buzza MS, Bird PI. |
Biol Chem. 2006 Jul;387(7):827-37. (REVIEW) |
PMID 16913832 |
Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. |
Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ. |
Immunity. 2007 Oct;27(4):635-46. Epub 2007 Oct 4. |
PMID 17919943 |
Granule-associated serine proteases: granzymes might not just be killer proteases. |
Froelich CJ, Pardo J, Simon MM. |
Trends Immunol. 2009 Mar;30(3):117-23. Epub 2009 Feb 13. (REVIEW) |
Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis. |
Griffiths GM, Alpert S, Lambert E, McGuire J, Weissman IL. |
Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):549-53. |
PMID 1731326 |
The orphan granzymes of humans and mice. |
Grossman WJ, Revell PA, Lu ZH, Johnson H, Bredemeyer AJ, Ley TJ. |
Curr Opin Immunol. 2003 Oct;15(5):544-52. |
PMID 14499263 |
Induction of target cell DNA release by the cytotoxic T lymphocyte granule protease granzyme A. |
Hayes MP, Berrebi GA, Henkart PA. |
J Exp Med. 1989 Sep 1;170(3):933-46. |
PMID 2788710 |
Granzymes in age-related cardiovascular and pulmonary diseases. |
Hendel A, Hiebert PR, Boivin WA, Williams SJ, Granville DJ. |
Cell Death Differ. 2010 Apr;17(4):596-606. Epub 2010 Feb 5. (REVIEW) |
PMID 20139894 |
Crystal structure of the apoptosis-inducing human granzyme A dimer. |
Hink-Schauer C, Estebanez-Perpina E, Kurschus FC, Bode W, Jenne DE. |
Nat Struct Biol. 2003 Jul;10(7):535-40. |
PMID 12819770 |
Granzymes, a family of serine proteases released from granules of cytolytic T lymphocytes upon T cell receptor stimulation. |
Jenne DE, Tschopp J. |
Immunol Rev. 1988 Mar;103:53-71. (REVIEW) |
PMID 3292396 |
Are Proteinases Functional Molecules of T Lymphocytes? |
Kramer MD, Simon MM |
Immunol Today. 1987;8:140-2. (REVIEW) |
Expression of granzymes A and B in synovial tissue from patients with rheumatoid arthritis and osteoarthritis. |
Kummer JA, Tak PP, Brinkman BM, van Tilborg AA, Kamp AM, Verweij CL, Daha MR, Meinders AE, Hack CE, Breedveld FC. |
Clin Immunol Immunopathol. 1994 Oct;73(1):88-95. |
PMID 7923921 |
Granzyme A activates another way to die. |
Lieberman J. |
Immunol Rev. 2010 May;235(1):93-104. (REVIEW) |
PMID 20536557 |
Identification of granzyme A isolated from cytotoxic T-lymphocyte-granules as one of the proteases encoded by CTL-specific genes. |
Masson D, Zamai M, Tschopp J. |
FEBS Lett. 1986 Nov 10;208(1):84-8. |
PMID 3533635 |
Human and mouse granzyme A induce a proinflammatory cytokine response. |
Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, Kim S, Raja SM, Shi L, Simon MM, Froelich CJ. |
Immunity. 2008 Nov 14;29(5):720-33. Epub 2008 Oct 23. |
PMID 18951048 |
Granzyme A is critical for recovery of mice from infection with the natural cytopathic viral pathogen, ectromelia. |
Mullbacher A, Ebnet K, Blanden RV, Hla RT, Stehle T, Museteanu C, Simon MM. |
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5783-7. |
PMID 8650169 |
Demonstration of granzyme A and perforin messenger RNA in the synovium of patients with rheumatoid arthritis. |
Muller-Ladner U, Kriegsmann J, Tschopp J, Gay RE, Gay S. |
Arthritis Rheum. 1995 Apr;38(4):477-84. |
PMID 7536415 |
Granzyme A-immunoreactive cells in synovial fluid in reactive and rheumatoid arthritis. |
Nordstrom DC, Konttinen YT, Sorsa T, Nykanen P, Pettersson T, Santavirta S, Tschopp J. |
Clin Rheumatol. 1992 Dec;11(4):529-32. |
PMID 1283120 |
Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. |
Pardo J, Balkow S, Anel A, Simon MM. |
Eur J Immunol. 2002 Oct;32(10):2881-7. |
PMID 12355441 |
Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis. |
Pardo J, Bosque A, Brehm R, Wallich R, Naval J, Mullbacher A, Anel A, Simon MM. |
J Cell Biol. 2004 Nov 8;167(3):457-68. |
PMID 15534000 |
Granzyme A, a noncytolytic component of CD8(+) cell granules, restricts the spread of herpes simplex virus in the peripheral nervous systems of experimentally infected mice. |
Pereira RA, Simon MM, Simmons A. |
J Virol. 2000 Jan;74(2):1029-32. |
PMID 10623769 |
Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. |
Pham CT, Ley TJ. |
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8627-32. |
PMID 10411926 |
Human perforin employs different avenues to damage membranes. |
Praper T, Sonnen A, Viero G, Kladnik A, Froelich CJ, Anderluh G, Dalla Serra M, Gilbert RJ. |
J Biol Chem. 2011 Jan 28;286(4):2946-55. Epub 2010 Oct 2. |
PMID 20889983 |
Nonspecific cytotoxic cells of teleosts are armed with multiple granzymes and other components of the granule exocytosis pathway. |
Praveen K, Leary JH 3rd, Evans DL, Jaso-Friedmann L. |
Mol Immunol. 2006 Mar;43(8):1152-62. Epub 2005 Aug 30. |
PMID 16137766 |
Murine cytomegalovirus replication in salivary glands is controlled by both perforin and granzymes during acute infection. |
Riera L, Gariglio M, Valente G, Mullbacher A, Museteanu C, Landolfo S, Simon MM. |
Eur J Immunol. 2000 May;30(5):1350-5. |
PMID 10820381 |
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;52(2):172-8. Epub 2006 Dec 19. |
PMID 17180578 |
A natural killer cell granule protein that induces DNA fragmentation and apoptosis. |
Shi L, Kraut RP, Aebersold R, Greenberg AH. |
J Exp Med. 1992 Feb 1;175(2):553-66. |
PMID 1732416 |
Granzyme A initiates an alternative pathway for granule-mediated apoptosis. |
Shresta S, Graubert TA, Thomas DA, Raptis SZ, Ley TJ. |
Immunity. 1999 May;10(5):595-605. |
PMID 10367905 |
Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes. |
Simon MM, Hoschutzky H, Fruth U, Simon HG, Kramer MD. |
EMBO J. 1986 Dec 1;5(12):3267-74. |
PMID 3545816 |
Extracellular activities of human granzymes. I. Granzyme A induces IL6 and IL8 production in fibroblast and epithelial cell lines. |
Sower LE, Klimpel GR, Hanna W, Froelich CJ. |
Cell Immunol. 1996 Jul 10;171(1):159-63. |
PMID 8754861 |
Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo. |
Spaeny-Dekking EH, Hanna WL, Wolbink AM, Wever PC, Kummer JA, Swaak AJ, Middeldorp JM, Huisman HG, Froelich CJ, Hack CE. |
J Immunol. 1998 Apr 1;160(7):3610-6. |
PMID 9531325 |
Granzyme-positive cytotoxic cells are specifically increased in early rheumatoid synovial tissue. |
Tak PP, Kummer JA, Hack CE, Daha MR, Smeets TJ, Erkelens GW, Meinders AE, Kluin PM, Breedveld FC. |
Arthritis Rheum. 1994 Dec;37(12):1735-43. |
PMID 7986219 |
The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA). |
Tak PP, Spaeny-Dekking L, Kraan MC, Breedveld FC, Froelich CJ, Hack CE. |
Clin Exp Immunol. 1999 May;116(2):366-70. |
PMID 10337032 |
Perforin pores in the endosomal membrane trigger the release of endocytosed granzyme B into the cytosol of target cells. |
Thiery J, Keefe D, Boulant S, Boucrot E, Walch M, Martinvalet D, Goping IS, Bleackley RC, Kirchhausen T, Lieberman J. |
Nat Immunol. 2011 Jun 19;12(8):770-7. doi: 10.1038/ni.2050. |
PMID 21685908 |
Granzyme activity in the inflamed lung is not controlled by endogenous serine proteinase inhibitors. |
Tremblay GM, Wolbink AM, Cormier Y, Hack CE. |
J Immunol. 2000 Oct 1;165(7):3966-9. |
PMID 11034405 |
Increased granzyme A expression in type II pneumocytes of patients with severe chronic obstructive pulmonary disease. |
Vernooy JH, Moller GM, van Suylen RJ, van Spijk MP, Cloots RH, Hoet PH, Pennings HJ, Wouters EF. |
Am J Respir Crit Care Med. 2007 Mar 1;175(5):464-72. Epub 2006 Nov 30. |
PMID 17138956 |
Granzyme-like sequences in bony fish shed light on the emergence of hematopoietic serine proteases during vertebrate evolution. |
Wernersson S, Reimer JM, Poorafshar M, Karlson U, Wermenstam N, Bengten E, Wilson M, Pilstrom L, Hellman L. |
Dev Comp Immunol. 2006;30(10):901-18. Epub 2005 Dec 27. |
PMID 16413608 |
Purification and characterization of a cytolytic pore-forming protein from granules of cloned lymphocytes with natural killer activity. |
Young JD, Hengartner H, Podack ER, Cohn ZA. |
Cell. 1986 Mar 28;44(6):849-59. |
PMID 2420467 |
7. Citation
This paper should be referenced as such : |
Catalan, E ; Sanchez-Martinez, D ; Pardo, J |
GZMA (granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3)) |
Atlas Genet Cytogenet Oncol Haematol. 2012;16(2):123-126. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/GZMAID51130ch5q11.html |
8. External links
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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