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 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. The granzymes bind directly to the nucleic acids DNA and RNA; this enhances their cleavage of nucleic acid binding proteins. 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. Extracellular granzyme B has been implicated in the pathogenesis of atherosclerosis, aneurysm, vascular leakage, chronic wound healing, and skin aging.
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.
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.
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". 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.
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". tags and the template
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