Granzyme A

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Granzyme A
Identifiers
EC no. 3.4.21.78
CAS no. 143180-73-8
Databases
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NCBI proteins
GZMA
Protein GZMA PDB 1op8.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GZMA , CTLA3, HFSP, granzyme A
External IDs OMIM: 140050 MGI: 109266 HomoloGene: 21237 GeneCards: GZMA
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_006144

NM_010370

RefSeq (protein)

NP_006135

NP_034500

Location (UCSC) Chr 5: 55.1 – 55.11 Mb Chr 13: 113.23 – 113.24 Mb
PubMed search [3] [4]
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Granzyme A (GzmA, EC 3.4.21.78, CTLA3, HuTPS, T-cell associated protease 1, cytotoxic T lymphocyte serine protease, TSP-1, T-cell derived serine proteinase) is a tryptase [5] [6] [7] and is one of the five granzymes encoded in the human genome. [8] [9] [10] 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.

Contents

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 [11] and lamin B [12] are shared with Granzyme B. Substrates of GzmA include Pro-IL-1β, [13] NDUFS3, [14] SET, APE1, and Ku70 among others. In vitro studies suggest that GzmA may have less cytotoxic capabilities than GzmB. [15] [16]

In colorectal cancer, GzmA was associated with promotion of cancer development, which may be due to activation of inflammation-inducing cytokines from macrophages. [17]

See also

Related Research Articles

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Perforin-1</span> Mammalian protein found in Homo sapiens

Perforin-1 is a protein that in humans is encoded by the PRF1 gene and the Prf1 gene in mice.

Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.

Granzyme B (GrB) is one of the serine protease granzymes most commonly found in the granules of natural killer cells and cytotoxic T cells. It is secreted by these cells along with the pore forming protein perforin to mediate apoptosis in target cells.

<span class="mw-page-title-main">Neutrophil elastase</span> Protein-coding gene in the species Homo sapiens

Neutrophil elastase is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Neutrophil elastase is secreted by neutrophils during inflammation, and destroys bacteria and host tissue. It also localizes to neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.

<span class="mw-page-title-main">Cathepsin G</span> Protein-coding gene in the species Homo sapiens

Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes and mast cells. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

<span class="mw-page-title-main">GZMB</span> Protein-coding gene in the species Homo sapiens

Granzyme B is a serine protease that in humans is encoded by the GZMB gene. Granzyme B is expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells.

<span class="mw-page-title-main">TPSAB1</span> Protein-coding gene in the species Homo sapiens

Tryptase alpha-1 and tryptase beta-1 are enzymes that in humans are encoded by the same TPSAB1 gene. Beta tryptases appear to be the main isoenzymes expressed in mast cells; whereas in basophils, alpha tryptases predominate.

<span class="mw-page-title-main">Acidic leucine-rich nuclear phosphoprotein 32 family member A</span> Protein-coding gene in the species Homo sapiens

Acidic leucine-rich nuclear phosphoprotein 32 family member A is a protein that in humans is encoded by the ANP32A gene. It is one of the targets of an oncomiR, MIRN21.

<span class="mw-page-title-main">Protein SET</span> Protein-coding gene in the species Homo sapiens

Protein SET, also known as Protein SET 1, is a protein that in humans is encoded by the SET gene.

<span class="mw-page-title-main">HMGB2</span> Protein-coding gene in the species Homo sapiens

High-mobility group protein B2 also known as high-mobility group protein 2 (HMG-2) is a protein that in humans is encoded by the HMGB2 gene.

<span class="mw-page-title-main">HTRA1</span> Protein-coding gene in the species Homo sapiens

Serine protease HTRA1 is an enzyme that in humans is encoded by the HTRA1 gene. The HTRA1 protein is composed of four distinct protein domains. They are from amino-terminus to carboxyl-terminus an Insulin-like growth factor binding domain, a kazal domain, a trypsin-like peptidase domain and a PDZ domain.

<span class="mw-page-title-main">GNLY</span> Protein-coding gene in the species Homo sapiens

Granulysin (GNLY) is a protein expressed in most mammals which functions as an antimicrobial peptide released by killer lymphocytes in cytotoxic granules. It is a pore-forming peptide, as it can puncture a microbial cell wall, allowing for other death-inducing enzymes to enter the microbe and cause microptosis. GNLY is inhibited by cholesterol, and is most effective in helping to kill cholesterol-deficient microbes.

<span class="mw-page-title-main">SERPINB9</span> Protein-coding gene in the species Homo sapiens

Serpin B9 is a protein that in humans is encoded by the SERPINB9 gene. PI9 belongs to the large superfamily of serine proteinase inhibitors (serpins), which bind to and inactivate serine proteinases. These interactions are involved in many cellular processes, including coagulation, fibrinolysis, complement fixation, matrix remodeling, and apoptosis .[supplied by OMIM]

<span class="mw-page-title-main">DPP7</span> Protein-coding gene in the species Homo sapiens

Dipeptidyl-peptidase 2 is an enzyme that in humans is encoded by the DPP7 gene.

<span class="mw-page-title-main">Cathepsin W</span> Protein-coding gene in the species Homo sapiens

Cathepsin W is a protein that in humans is encoded by the CTSW gene.

<span class="mw-page-title-main">GZMH</span> Protein-coding gene in the species Homo sapiens

Granzyme H is a protein that in humans is encoded by the GZMH gene.

<span class="mw-page-title-main">GZMK</span> Protein-coding gene in the species Homo sapiens

Granzyme K (GrK) is a protein that is encoded by the GZMK gene on chromosome 5 in humans. Granzymes are a family of serine proteases which have various intracellular and extracellular roles. GrK is found in granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and is traditionally described as being cytotoxic towards targeted foreign, infected, or cancerous cells. NK cells and CTLs can induce apoptosis through the granule secretory pathway, which involves the secretion of granzymes along with perforin at immunological synapses.

<span class="mw-page-title-main">GZMM</span> Protein-coding gene in the species Homo sapiens

Granzyme M is a protein that in humans is encoded by the GZMM gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145649 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000023132 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Simon MM, Hoschützky H, Fruth U, Simon HG, Kramer MD (December 1986). "Purification and characterization of a T cell specific serine proteinase (TSP-1) from cloned cytolytic T lymphocytes". The EMBO Journal. 5 (12): 3267–74. doi:10.1002/j.1460-2075.1986.tb04638.x. PMC   1167321 . PMID   3545816.
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  7. Odake S, Kam CM, Narasimhan L, Poe M, Blake JT, Krahenbuhl O, Tschopp J, Powers JC (February 1991). "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. doi:10.1021/bi00222a027. PMID   1998680.
  8. Hameed A, Lowrey DM, Lichtenheld M, Podack ER (Nov 1988). "Characterization of three serine esterases isolated from human IL-2 activated killer cells". J Immunol. 141 (9): 3142–7. doi:10.4049/jimmunol.141.9.3142. PMID   3262682.
  9. Masson D, Zamai M, Tschopp J (Dec 1986). "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. doi: 10.1016/0014-5793(86)81537-X . PMID   3533635. S2CID   10670230.
  10. "Entrez Gene: GZMA granzyme A (granzyme 1, cytotoxic T-lymphocyte-associated serine esterase 3)".
  11. Zhu P, Martinvalet D, Chowdhury D, Zhang D, Schlesinger A, Lieberman J (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. doi:10.1182/blood-2008-12-195768. ISSN   1528-0020. PMC   2723016 . PMID   19506301.
  12. Zhang D, Beresford PJ, Greenberg AH, 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. Bibcode:2001PNAS...98.5746Z. doi: 10.1073/pnas.101329598 . ISSN   0027-8424. PMC   33284 . PMID   11331782.
  13. Irmler M, Hertig S, MacDonald HR, Sadoul R, Becherer JD, 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. doi:10.1084/jem.181.5.1917. ISSN   0022-1007. PMC   2191995 . PMID   7722467.
  14. Martinvalet D, Dykxhoorn DM, Ferrini R, Lieberman J (2008-05-16). "Granzyme A cleaves a mitochondrial complex I protein to initiate caspase-independent cell death". Cell. 133 (4): 681–692. doi:10.1016/j.cell.2008.03.032. ISSN   1097-4172. PMC   2840390 . PMID   18485875.
  15. Martinvalet D, Walch M, Jensen D, Thiery J, Lieberman J (Oct 29, 2009). "Response: Granzyme A: cell death–inducing protease, proinflammatory agent, or both?". Blood. 114 (8): 3969–3970. doi:10.1182/blood-2009-08-233577. PMC   2773496 .
  16. Metkar SS, Menaa C, Pardo J, Wang B, Wallich R, Freudenberg M, Kim S, Raja SM, Shi L, Simon MM, Froelich CJ (2008-11-14). "Human and mouse granzyme A induce a proinflammatory cytokine response". Immunity. 29 (5): 720–733. doi: 10.1016/j.immuni.2008.08.014 . ISSN   1097-4180. PMID   18951048.
  17. Santiago L, Castro M, Sanz-Pamplona R, Garzón M, Ramirez-Labrada A, Tapia E, Moreno V, Layunta E, Gil-Gómez G, Garrido M, Peña R, Lanuza PM, Comas L, Jaime-Sanchez P, Uranga-Murillo I (2020-07-07). "Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation". Cell Reports. 32 (1): 107847. doi:10.1016/j.celrep.2020.107847. hdl: 10230/45276 . ISSN   2211-1247. PMID   32640217.

Further reading