Granzyme

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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. [1] Granzymes also kill bacteria [2] 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. [3] They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G. [4]

Contents

Granzyme B activates apoptosis by activating caspases (especially caspase-3), which cleaves many substrates, including caspase-activated DNase to execute cell death. Granzyme B also cleaves the protein Bid, which recruits the proteins Bax and Bak to change the membrane permeability of the mitochondria, causing the release of cytochrome c (which is one of the parts needed to activate caspase-9 via the apoptosome), Smac/Diablo and Omi/HtrA2 (which suppress the inhibitor of apoptosis proteins (IAPs)), among other proteins. Granzyme B also cleaves many of the proteins responsible for apoptosis in the absence of caspase activity. The other granzymes activate cell death by caspase-dependent and caspase-independent mechanisms. [1]

In addition to killing their target cells, granzymes can target and kill intracellular pathogens. Granzymes A and B induce lethal oxidative damage in bacteria by cleaving components of the electron transport chain, [2] while granzyme B cleaves viral proteins to inhibit viral activation and replication. [5] The granzymes bind directly to the nucleic acids DNA and RNA; this enhances their cleavage of nucleic acid binding proteins. [4]

More recently, in addition to T lymphocytes, granzymes have been shown to be expressed in other types of immune cells such as dendritic cells, B cells and mast cells. In addition, granzymes may also be expressed in non-immune cells such as keratinocytes, pneumocytes and chondrocytes. [6] As many of these cell types either do not express perforin or do not form immunological synapses, granzyme B is released extracellularly. Extracellular granzyme B can accumulate in the extracellular space in diseases associated with dysregulated or chronic inflammation leading to the degradation of extracellular matrix proteins and impaired tissue healing and remodelling. [7] Extracellular granzyme B has been implicated in the pathogenesis of atherosclerosis, [8] aneurysm, [9] [10] vascular leakage, [11] chronic wound healing, [10] [12] and skin aging. [13]

History

In 1986 Jürg Tschopp and his group published a paper on their discovery of granzymes. In the paper they discussed how they purified, characterized and discovered a variety of granzymes found within cytolytic granules that were carried by cytotoxic T lymphocytes and natural killer cells. Jürg was able to identify 8 different granzymes and discovered partial amino acid sequences for each. The molecules were unofficially named Grs for five years before Jürg and his team came up with the name granzymes which was widely accepted by the scientific community. [14]

Granzyme secretion can be detected and measured using Western Blot or ELISA techniques. Granzyme secreting cells can be identified and quantified by flow cytometry or ELISPOT. Alternatively, granzyme activity can be assayed by virtue of their protease activity.[ citation needed ]

Other functions

In Cullen's paper “Granzymes in Cancer and Immunity” he discusses how granzyme A has been known to be found in elevated levels within patients who currently have an infectious disease and/or in a pro-inflammatory state. Granzymes have also been found to help initiate the inflammatory response. “For example, rheumatoid arthritis patients have increased levels of granzyme A in the synovial fluid of swollen joints”. [15] When granzymes are in an extracellular state they have the ability to activate macrophages and mast cells to initiate the inflammatory response. The interaction between the granzymes and somatic cells are still unexplainable but advances in understanding the process are being made constantly. Other granzymes like granzyme K have been found in high levels of patients who have gone septic. Granzyme H has been found to have a direct correlation with patients who have a viral infection. Scientists are able to conclude that granzyme H specializes in detecting ‘proteolytic degradation’ which is found in viral proteins. [15]

Cullen further states in his paper that granzymes may have a role in immunomodulation, or the job of maintaining homeostasis in the immune system during an infection. “In humans, loss of perforin function leads to a syndrome called familial hemophagocytic lymphohistiocytosis […]”. [15] This syndrome can lead to death because both T cells and macrophages multiply to fight the pathogen, resulting in harmful levels of proinflammatory cytokines. The overactivation can lead to inflammation of vital organs, anemia via overactivated macrophages phagocytosing blood cells, and can potentially be fatal.

In Trapani's paper he talks about how granzymes may have other functions, in addition to their ability to fight off infection. Granzyme A contains certain chemicals that allow it to cause proliferation in B cells to reduce the chance of cancer growth and formation. Test on mice have shown that granzyme A and B might not have a direct link to controlling viral infections, but helping accelerate the immune systems response. [16]

In cancer research

In Cullen's paper “Granzymes in Cancer and Immunity” he describes the process of “immune surveillance [as] the process whereby precancerous and malignant cells are recognized by the immune system as damaged and are consequently targeted for elimination”. [15] For a tumor to progress it requires conditions within the body and surrounding area to be growth-promoting. Almost all people have suitable immune cells to fight off tumors in the body. Studies have shown that the immune system even has the ability to prevent precancerous cells from growing and arbitrate the regression of established tumors. The dangerous thing about cancer cells is they have the ability to inhibit the function of the immune system. Although a tumor may be in its beginning stage and very weak, it may be giving off chemicals that inhibit the function of the immune system allowing it to grow and become harmful. Tests have shown that mice without granzymes and perforins are at high risk to have tumors spread throughout their body. [15]

Tumors have the ability to escape from immune surveillance by secreting immunosuppressive TGF-β. This inhibits proliferation and activation of T cells. TGF-β production is the most potent mechanism of immune avoidance used by tumors. TGF-β inhibits expression of five different cytotoxic genes including perforin, granzyme A, and granzyme B, which then inhibits T cell-mediated tumor clearance.

Perforin's role in protecting the body against lymphoma was emphasized when scientists discovered that p53 did not have as big of a role in lymphoma surveillance as its counterpart perforin. Perforin and granzymes have been found to have a directly related ability to protect the body against the formation of different kinds of lymphomas. [15]

Genes

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">Caspase</span> Family of cysteine proteases

Caspases are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cysteine protease activity – a cysteine in its active site nucleophilically attacks and cleaves a target protein only after an aspartic acid residue. As of 2009, there are 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions.

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

Perforin-1 Perforin (PRF), encoded by the PRF1 gene, is a pore-forming toxic protein housed in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Together, these cells are known as cytotoxic lymphocytes (CLs).

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">Granzyme A</span> Class of enzymes

Granzyme A is a tryptase and is one of the five granzymes encoded in the human genome. 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.

<i>Myxoma virus</i> Species of virus

Myxoma virus is a poxvirus in the genus Leporipoxvirus. The two broad geographic types of myxoma virus are Californian and South American. Californian myxoma virus is found on the West Coast of the United States, the Baja Peninsula of Mexico, and the southwest coast of Canada. South American or Brazilian myxoma virus is found in South and Central America. South American myxoma virus circulates in the jungle rabbit or tapeti, whereas Californian myxoma virus circulates in the brush rabbit. In their native hosts, the viruses cause the formation of benign cutaneous fibromas rather than systemic disease.

<span class="mw-page-title-main">Death-inducing signaling complex</span>

The death-inducing signaling complex or DISC is a multi-protein complex formed by members of the death receptor family of apoptosis-inducing cellular receptors. A typical example is FasR, which forms the DISC upon trimerization as a result of its ligand (FasL) binding. The DISC is composed of the death receptor, FADD, and caspase 8. It transduces a downstream signal cascade resulting in apoptosis.

<span class="mw-page-title-main">Caspase-9</span> Enzyme found in humans

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

<span class="mw-page-title-main">Caspase 8</span> Protein found in humans

Caspase-8 is a caspase protein, encoded by the CASP8 gene. It most likely acts upon caspase-3. CASP8 orthologs have been identified in numerous mammals for which complete genome data are available. These unique orthologs are also present in birds.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

<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. 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">Caspase 2</span> Enzyme found in humans

Caspase 2 also known as CASP2 is an enzyme that, in humans, is encoded by the CASP2 gene. CASP2 orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

<span class="mw-page-title-main">Caspase 3</span> Protein found in humans

Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the CASP3 gene. CASP3 orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also present in birds, lizards, lissamphibians, and teleosts.

The Membrane Attack Complex/Perforin (MACPF) superfamily, sometimes referred to as the MACPF/CDC superfamily, is named after a domain that is common to the membrane attack complex (MAC) proteins of the complement system and perforin (PF). Members of this protein family are pore-forming toxins (PFTs). In eukaryotes, MACPF proteins play a role in immunity and development.

<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">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">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.

Jürg Tschopp was a Swiss biochemist, known for his research on apoptosis and the immunology of inflammation. His greatest achievement was perhaps his team's discovery and scientific description of the inflammasome.

References

  1. 1 2 Bots M, Medema JP (December 2006). "Granzymes at a glance". Journal of Cell Science. 119 (Pt 24): 5011–4. doi: 10.1242/jcs.03239 . PMID   17158907.
  2. 1 2 Walch M, Dotiwala F, Mulik S, et al. (June 2014). "Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes". Cell. 157 (6): 1309–23. doi:10.1016/j.cell.2014.03.062. PMC   4090916 . PMID   24906149.
  3. ↑ Peters PJ, Borst J, Oorschot V, et al. (May 1991). "Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes". The Journal of Experimental Medicine. 173 (5): 1099–109. doi:10.1084/jem.173.5.1099. PMC   2118839 . PMID   2022921.
  4. 1 2 Thomas MP, Whangbo J, McCrossan G, et al. (June 2014). "Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins". Journal of Immunology. 192 (11): 5390–7. doi:10.4049/jimmunol.1303296. PMC   4041364 . PMID   24771851.
  5. ↑ Marcet-Palacios M, Duggan BL, Shostak I, et al. (December 2011). "Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3". PLOS Pathogens. 7 (12): e1002447. doi: 10.1371/journal.ppat.1002447 . PMC   3240606 . PMID   22194691.
  6. ↑ Hendel A, Hiebert PR, Boivin WA, Williams SJ, Granville DJ (April 2010). "Granzymes in age-related cardiovascular and pulmonary diseases". Cell Death and Differentiation. 17 (4): 596–606. doi: 10.1038/cdd.2010.5 . PMID   20139894.
  7. ↑ Hiebert PR, Granville DJ (December 2012). "Granzyme B in injury, inflammation, and repair". Trends in Molecular Medicine. 18 (12): 732–41. doi:10.1016/j.molmed.2012.09.009. PMID   23099058.
  8. ↑ Hiebert PR, Boivin WA, Zhao H, McManus BM, Granville DJ (2013). "Perforin and granzyme B have separate and distinct roles during atherosclerotic plaque development in apolipoprotein E knockout mice". PLOS ONE. 8 (10): e78939. Bibcode:2013PLoSO...878939H. doi: 10.1371/journal.pone.0078939 . PMC   3811993 . PMID   24205352.
  9. ↑ Chamberlain CM, Ang LS, Boivin WA, et al. (February 2010). "Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm". The American Journal of Pathology. 176 (2): 1038–49. doi:10.2353/ajpath.2010.090700. PMC   2808106 . PMID   20035050.
  10. 1 2 Hsu I, Parkinson LG, Shen Y, et al. (2014). "Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing". Cell Death & Disease. 5 (10): e1458. doi:10.1038/cddis.2014.423. PMC   4237249 . PMID   25299783.
  11. ↑ Hendel A, Hsu I, Granville DJ (July 2014). "Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability". Laboratory Investigation. 94 (7): 716–25. doi:10.1038/labinvest.2014.62. PMC   4074428 . PMID   24791744.
  12. ↑ Hiebert PR, Wu D, Granville DJ (October 2013). "Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice". Cell Death and Differentiation. 20 (10): 1404–14. doi:10.1038/cdd.2013.96. PMC   3770318 . PMID   23912712.
  13. ↑ Hiebert PR, Boivin WA, Abraham T, Pazooki S, Zhao H, Granville DJ (June 2011). "Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice". Experimental Gerontology. 46 (6): 489–99. doi:10.1016/j.exger.2011.02.004. PMID   21316440. S2CID   33176028.
  14. ↑ Ewen CL, Kane KP, Bleackley RC (January 2012). "A quarter century of granzymes". Cell Death and Differentiation. 19 (1): 28–35. doi:10.1038/cdd.2011.153. PMC   3252830 . PMID   22052191.
  15. 1 2 3 4 5 6 Cullen SP, Brunet M, Martin SJ (April 2010). "Granzymes in cancer and immunity". Cell Death and Differentiation. 17 (4): 616–23. doi: 10.1038/cdd.2009.206 . PMID   20075940.
  16. ↑ Trapani JA (2001). "Granzymes: a family of lymphocyte granule serine proteases". Genome Biology. 2 (12): REVIEWS3014. doi: 10.1186/gb-2001-2-12-reviews3014 . PMC   138995 . PMID   11790262.
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