Global InformationGranzyme information
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]
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]
- ^ a b 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.
- ^ a b 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.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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.
- ^ 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.