Granzyme A Explained

Granzyme A
Ec Number:	3.4.21.78
Cas Number:	143180-73-8

Granzyme A (GzmA,, CTLA3, HuTPS, T-cell associated protease 1, cytotoxic T lymphocyte serine protease, TSP-1, T-cell derived serine proteinase) is a tryptase^{[1] [2] [3]} and is one of the five granzymes encoded in the human genome.^{[4] [5] [6]} In humans, GzmA is encoded by the GZMA gene in proximity to the GZMK gene on chromosome 5. This enzyme is present in cytotoxic T lymphocyte (CTL) granules.

GzmA cleaves proteins after arginine or lysine basic residues. In CTL-targeted cells, it activates caspase-independent programmed cell death pathways that are unique and parallel to that of Granzyme B, although some substrates such as PARP-1^[7] and lamin B^[8] are shared with Granzyme B. Substrates of GzmA include Pro-IL-1β,^[9] NDUFS3,^[10] SET, APE1, and Ku70 among others. In vitro studies suggest that GzmA may have less cytotoxic capabilities than GzmB.^{[11] [12]}

In colorectal cancer, GzmA was associated with promotion of cancer development, which may be due to activation of inflammation-inducing cytokines from macrophages.^[13]

See also

• GZMA
• GZMK
• GZMB
• GZMH

Further reading

• Pasternack MS, Bleier KJ, McInerney TN . Granzyme A binding to target cell proteins. Granzyme A binds to and cleaves nucleolin in vitro . J. Biol. Chem. . 266 . 22 . 14703–8 . 1991 . 10.1016/S0021-9258(18)98743-0 . 1860869 . free .
• Poe M, Bennett CD, Biddison WE, etal . Human cytotoxic lymphocyte tryptase. Its purification from granules and the characterization of inhibitor and substrate specificity . J. Biol. Chem. . 263 . 26 . 13215–22 . 1988 . 10.1016/S0021-9258(18)37694-4 . 3047119 . free .
• Murphy ME, Moult J, Bleackley RC, etal . Comparative molecular model building of two serine proteinases from cytotoxic T lymphocytes . Proteins . 4 . 3 . 190–204 . 1989 . 3237717 . 10.1002/prot.340040306 . 35164948 .
• Gershenfeld HK, Hershberger RJ, Shows TB, Weissman IL . Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease . Proc. Natl. Acad. Sci. U.S.A. . 85 . 4 . 1184–8 . 1988 . 3257574 . 10.1073/pnas.85.4.1184 . 279731 . 1988PNAS...85.1184G . free .
• Krähenbühl O, Rey C, Jenne D, etal . Characterization of granzymes A and B isolated from granules of cloned human cytotoxic T lymphocytes . J. Immunol. . 141 . 10 . 3471–7 . 1988 . 10.4049/jimmunol.141.10.3471 . 3263427 . free .
• Baetz K, Isaaz S, Griffiths GM . Loss of cytotoxic T lymphocyte function in Chediak-Higashi syndrome arises from a secretory defect that prevents lytic granule exocytosis . J. Immunol. . 154 . 11 . 6122–31 . 1995 . 10.4049/jimmunol.154.11.6122 . 7751653 . free .
• Inoue M, Hoshino T, Fukuma T, etal . Close co-localization of CD4 and a serine esterase tryptase TL2 on the cell-surface of human monocytoid and CD4+ lymphoid cells . Biochem. Biophys. Res. Commun. . 201 . 3 . 1390–5 . 1994 . 7912927 . 10.1006/bbrc.1994.1857 .
• Fink TM, Lichter P, Wekerle H, etal . The human granzyme A (HFSP, CTLA3) gene maps to 5q11-q12 and defines a new locus of the serine protease superfamily . Genomics . 18 . 2 . 401–3 . 1994 . 8288245 . 10.1006/geno.1993.1483 .
• Beresford PJ, Kam CM, Powers JC, Lieberman J . Recombinant human granzyme A binds to two putative HLA-associated proteins and cleaves one of them . Proc. Natl. Acad. Sci. U.S.A. . 94 . 17 . 9285–90 . 1997 . 9256474 . 10.1073/pnas.94.17.9285 . 23158 . 1997PNAS...94.9285B . free .
• Spaeny-Dekking EH, Hanna WL, Wolbink AM, etal . Extracellular granzymes A and B in humans: detection of native species during CTL responses in vitro and in vivo . J. Immunol. . 160 . 7 . 3610–6 . 1998 . 10.4049/jimmunol.160.7.3610 . 9531325 . free .
• Zhang D, Beresford PJ, Greenberg AH, Lieberman J . Granzymes A and B directly cleave lamins and disrupt the nuclear lamina during granule-mediated cytolysis . Proc. Natl. Acad. Sci. U.S.A. . 98 . 10 . 5746–51 . 2001 . 11331782 . 10.1073/pnas.101329598 . 33284 . 2001PNAS...98.5746Z . free .
• Beresford PJ, Zhang D, Oh DY, etal . Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks . J. Biol. Chem. . 276 . 46 . 43285–93 . 2001 . 11555662 . 10.1074/jbc.M108137200 . free .
• 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 . Mol. Cell. Biol. . 22 . 8 . 2810–20 . 2002 . 11909973 . 10.1128/MCB.22.8.2810-2820.2002 . 133744 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Fan Z, Beresford PJ, Zhang D, etal . Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A . Nat. Immunol. . 4 . 2 . 145–53 . 2003 . 12524539 . 10.1038/ni885 . 29433133 .
• Pinkoski MJ, Green DR . Granzyme A: the road less traveled . Nat. Immunol. . 4 . 2 . 106–8 . 2003 . 12555094 . 10.1038/ni0203-106 . 38687759 .
• Saito S, Iida A, Sekine A, etal . Catalog of 680 variations among eight cytochrome p450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population . J. Hum. Genet. . 48 . 5 . 249–70 . 2003 . 12721789 . 10.1007/s10038-003-0021-7 . free .
• Bell JK, Goetz DH, Mahrus S, etal . The oligomeric structure of human granzyme A is a determinant of its extended substrate specificity . Nat. Struct. Biol. . 10 . 7 . 527–34 . 2003 . 12819769 . 10.1038/nsb944 . 9608837 .

Notes and References

1. Simon MM, Hoschützky H, Fruth U, Simon HG, Kramer MD . Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes . The EMBO Journal . 5 . 12 . 3267–74 . December 1986 . 10.1002/j.1460-2075.1986.tb04638.x . 3545816 . 1167321 .
2. Gershenfeld HK, Hershberger RJ, Shows TB, Weissman IL . Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease . Proceedings of the National Academy of Sciences of the United States of America . 85 . 4 . 1184–8 . February 1988 . 3257574 . 279731 . 10.1073/pnas.85.4.1184 . 1988PNAS...85.1184G . free .
3. Odake S, Kam CM, Narasimhan L, Poe M, Blake JT, Krahenbuhl O, Tschopp J, Powers JC . Human and murine cytotoxic T lymphocyte serine proteases: subsite mapping with peptide thioester substrates and inhibition of enzyme activity and cytolysis by isocoumarins . Biochemistry . 30 . 8 . 2217–27 . February 1991 . 1998680 . 10.1021/bi00222a027 .
4. Hameed A, Lowrey DM, Lichtenheld M, Podack ER . Characterization of three serine esterases isolated from human IL-2 activated killer cells . J Immunol . 141 . 9 . 3142–7 . Nov 1988 . 10.4049/jimmunol.141.9.3142 . 3262682 . free .
5. Masson D, Zamai M, Tschopp J . Identification of granzyme A isolated from cytotoxic T-lymphocyte-granules as one of the proteases encoded by CTL-specific genes . FEBS Lett . 208 . 1 . 84–8 . Dec 1986 . 3533635 . 10.1016/0014-5793(86)81537-X . 10670230 . free .
6. Web site: Entrez Gene: GZMA granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3).
7. Zhu . Pengcheng . Martinvalet . Denis . Chowdhury . Dipanjan . Zhang . Dong . Schlesinger . Ann . Lieberman . Judy . 2009-08-06 . The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1 . Blood . 114 . 6 . 1205–1216 . 10.1182/blood-2008-12-195768 . 1528-0020 . 2723016 . 19506301.
8. Zhang . D. . Beresford . P. J. . Greenberg . A. H. . Lieberman . J. . 2001-05-08 . 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 . 98 . 10 . 5746–5751 . 10.1073/pnas.101329598 . 0027-8424 . 11331782. 33284 . 2001PNAS...98.5746Z . free .
9. Irmler . M. . Hertig . S. . MacDonald . H. R. . Sadoul . R. . Becherer . J. D. . Proudfoot . A. . Solari . R. . Tschopp . J. . 1995-05-01 . Granzyme A is an interleukin 1 beta-converting enzyme . The Journal of Experimental Medicine . 181 . 5 . 1917–1922 . 10.1084/jem.181.5.1917 . 0022-1007 . 2191995 . 7722467.
10. Martinvalet . Denis . Dykxhoorn . Derek M. . Ferrini . Roger . Lieberman . Judy . 2008-05-16 . Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death . Cell . 133 . 4 . 681–692 . 10.1016/j.cell.2008.03.032 . 1097-4172 . 2840390 . 18485875.
11. Martinvalet . Denis . Walch . Michael . Jensen . Danielle . Thiery . Jerome . Lieberman . Judy . Oct 29, 2009 . Response: Granzyme A: cell death–inducing protease, proinflammatory agent, or both? . Blood . 114 . 8 . 3969–3970. 10.1182/blood-2009-08-233577 . 2773496 .
12. Metkar . Sunil S. . Menaa . Cheikh . Pardo . Julian . Wang . Baikun . Wallich . Reinhard . Freudenberg . Marina . Kim . Stephen . Raja . Srikumar M. . Shi . Lianfa . Simon . Markus M. . Froelich . Christopher J. . 2008-11-14 . Human and mouse granzyme A induce a proinflammatory cytokine response . Immunity . 29 . 5 . 720–733 . 10.1016/j.immuni.2008.08.014 . 1097-4180 . 18951048. free .
13. Santiago . Llipsy . Castro . Marta . Sanz-Pamplona . Rebeca . Garzón . Marcela . Ramirez-Labrada . Ariel . Tapia . Elena . Moreno . Víctor . Layunta . Elena . Gil-Gómez . Gabriel . Garrido . Marta . Peña . Raúl . Lanuza . Pilar M. . Comas . Laura . Jaime-Sanchez . Paula . Uranga-Murillo . Iratxe . 2020-07-07 . Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation . Cell Reports . 32 . 1 . 107847 . 10.1016/j.celrep.2020.107847 . 2211-1247 . 32640217. 10230/45276 . free .