View source for Granzyme

{{short description|Class of proteins}}
'''Granzymes''' are [[serine protease]]s released by cytoplasmic [[Granule (cell biology)|granules]] within [[cytotoxic T cell]]s and [[natural killer cell|natural killer]] (NK) cells. They induce [[apoptosis|programmed cell death]] (apoptosis) in the target cell, thus eliminating cells that have become [[cancer]]ous or are infected with [[virus]]es or [[bacteria]].<ref name=Bots_2006>{{cite journal |vauthors=Bots M, Medema JP |title=Granzymes at a glance |journal=Journal of Cell Science |volume=119 |issue=Pt 24 |pages=5011–4 | date=December 2006 |pmid=17158907 |doi=10.1242/jcs.03239|doi-access=free }}</ref> Granzymes also kill bacteria<ref name="Walch">{{cite journal  |vauthors=Walch M, Dotiwala F, Mulik S, etal |title=Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes |journal=Cell |volume=157 |issue=6 |pages=1309–23 | date=June 2014 |pmid=24906149 |doi=10.1016/j.cell.2014.03.062 |pmc=4090916}}</ref> 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.<ref>{{cite journal  |vauthors=Peters PJ, Borst J, Oorschot V, etal |title=Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes |journal=The Journal of Experimental Medicine |volume=173 |issue=5 |pages=1099–109 | date=May 1991 |pmid=2022921 |pmc=2118839 |doi=10.1084/jem.173.5.1099}}</ref> They are closely related to other immune serine proteases expressed by innate immune cells, such as [[neutrophil elastase]] and [[cathepsin G]].<ref name="Thomas">{{cite journal  |vauthors=Thomas MP, Whangbo J, McCrossan G, etal |title=Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins |journal=Journal of Immunology |volume=192 |issue=11 |pages=5390–7 | date=June 2014 |pmid=24771851 |doi=10.4049/jimmunol.1303296 |pmc=4041364}}</ref>

[[Granzyme B]] activates apoptosis by activating [[caspase]]s (especially [[caspase-3]]), which cleaves many substrates, including [[caspase-activated DNase]] to execute cell death. Granzyme B also cleaves the protein [[BH3 interacting-domain death agonist|Bid]], which recruits the proteins [[Bcl-2-associated X protein|Bax]] and [[Bcl-2 homologous antagonist killer|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.<ref name=Bots_2006 />

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,<ref name="Walch" /> while granzyme B cleaves viral proteins to inhibit viral activation and replication.<ref>{{cite journal  |vauthors=Marcet-Palacios M, Duggan BL, Shostak I, etal |title=Granzyme B inhibits vaccinia virus production through proteolytic cleavage of eukaryotic initiation factor 4 gamma 3 |journal=PLOS Pathogens |volume=7 |issue=12 |pages=e1002447 | date=December 2011 |pmid=22194691 |pmc=3240606 |doi=10.1371/journal.ppat.1002447 |doi-access=free }}</ref> The granzymes bind directly to the nucleic acids DNA and RNA; this enhances their cleavage of nucleic acid binding proteins.<ref name="Thomas" />

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.<ref>{{cite journal |vauthors=Hendel A, Hiebert PR, Boivin WA, Williams SJ, Granville DJ |title=Granzymes in age-related cardiovascular and pulmonary diseases |journal=Cell Death and Differentiation |volume=17 |issue=4 |pages=596–606 | date=April 2010 |pmid=20139894 |doi=10.1038/cdd.2010.5|doi-access=free }}</ref> 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.<ref>{{cite journal |vauthors=Hiebert PR, Granville DJ |title=Granzyme B in injury, inflammation, and repair |journal=Trends in Molecular Medicine |volume=18 |issue=12 |pages=732–41 | date=December 2012 |pmid=23099058 |doi=10.1016/j.molmed.2012.09.009}}</ref> Extracellular granzyme B has been implicated in the pathogenesis of atherosclerosis,<ref>{{cite journal |vauthors=Hiebert PR, Boivin WA, Zhao H, McManus BM, Granville DJ |title=Perforin and granzyme B have separate and distinct roles during atherosclerotic plaque development in apolipoprotein E knockout mice |journal=PLOS ONE |volume=8 |issue=10 |pages=e78939 |year=2013 |pmid=24205352 |pmc=3811993 |doi=10.1371/journal.pone.0078939|bibcode=2013PLoSO...878939H |doi-access=free }}</ref> aneurysm,<ref>{{cite journal  |vauthors=Chamberlain CM, Ang LS, Boivin WA, etal |title=Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm |journal=The American Journal of Pathology |volume=176 |issue=2 |pages=1038–49 | date=February 2010 |pmid=20035050 |pmc=2808106 |doi=10.2353/ajpath.2010.090700}}</ref><ref name=pmid25299783>{{cite journal  |vauthors=Hsu I, Parkinson LG, Shen Y, etal |title=Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing |journal=Cell Death & Disease |volume=5 |issue= 10|pages=e1458 |year=2014 |pmid=25299783 |pmc=4237249 |doi=10.1038/cddis.2014.423}}</ref> vascular leakage,<ref>{{cite journal |vauthors=Hendel A, Hsu I, Granville DJ |title=Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability |journal=Laboratory Investigation |volume=94 |issue=7 |pages=716–25 | date=July 2014 |pmid=24791744 |doi=10.1038/labinvest.2014.62 |pmc=4074428}}</ref> chronic wound healing,<ref name=pmid25299783/><ref>{{cite journal |vauthors=Hiebert PR, Wu D, Granville DJ |title=Granzyme B degrades extracellular matrix and contributes to delayed wound closure in apolipoprotein E knockout mice |journal=Cell Death and Differentiation |volume=20 |issue=10 |pages=1404–14 | date=October 2013 |pmid=23912712 |pmc=3770318 |doi=10.1038/cdd.2013.96}}</ref> and skin aging.<ref>{{cite journal |vauthors=Hiebert PR, Boivin WA, Abraham T, Pazooki S, Zhao H, Granville DJ |title=Granzyme B contributes to extracellular matrix remodeling and skin aging in apolipoprotein E knockout mice |journal=Experimental Gerontology |volume=46 |issue=6 |pages=489–99 | date=June 2011 |pmid=21316440 |doi=10.1016/j.exger.2011.02.004|s2cid=33176028 }}</ref>

==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.<ref>{{cite journal |vauthors=Ewen CL, Kane KP, Bleackley RC |title=A quarter century of granzymes |journal=Cell Death and Differentiation |volume=19 |issue=1 |pages=28–35 | date=January 2012 |pmid=22052191 |pmc=3252830 |doi=10.1038/cdd.2011.153}}</ref>

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|date=December 2014}}

==Other functions==

In Cullen's paper “Granzymes in Cancer and Immunity” he discusses how [[GZMA|granzyme A]] has been known to be found in elevated levels within patients who currently have an infectious disease and/or in a [[inflammation|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”.<ref name=pmid20075940>{{cite journal |vauthors=Cullen SP, Brunet M, Martin SJ |title=Granzymes in cancer and immunity |journal=Cell Death and Differentiation |volume=17 |issue=4 |pages=616–23 | date=April 2010 |pmid=20075940 |doi=10.1038/cdd.2009.206|doi-access=free }}</ref> 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 [[GZMK|granzyme K]] have been found in high levels of patients who have gone septic. [[GZMH|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.<ref name=pmid20075940/>

Cullen further states in his paper that granzymes may have a role in [[Homeostasis|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 […]”.<ref name=pmid20075940/> 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 [[Joseph Trapani (immunologist)|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.<ref>{{cite journal |author=[[Joseph Trapani (immunologist)|Trapani JA]] |title=Granzymes: a family of lymphocyte granule serine proteases |journal=Genome Biology |volume=2 |issue=12 |pages=REVIEWS3014 |year=2001 |pmid=11790262 |pmc=138995 |doi=10.1186/gb-2001-2-12-reviews3014 |doi-access=free }}</ref>

==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”.<ref name=pmid20075940/> 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.<ref name=pmid20075940/>

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.<ref name=pmid20075940/>

==Genes==
* {{Gene|GZMA}}
* {{Gene|GZMB}}
* {{Gene|GZMH}}
* {{Gene|GZMK}}
* {{Gene|GZMM}}

==References==
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{{Serine endopeptidases}}
{{Enzymes}}
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[[Category:EC 3.4.21]]
[[Category:Immune system]]
[[Category:Programmed cell death]]