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Necroptosis is a form of regulated necrosis that is dependent on receptor interacting serine/threonine kinase 1 (RIPK1), RIPK3, and its substrate, mixed lineage kinase domain like pseudokinase (MLKL). Necroptosis occurs as a result of disturbances of the intracellular or extracellular microenvironment which are detected by death receptors such as TNFR1.
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Necroptosis is initiated by activation of TNFR1, which induces the formation of a complex (complex I), comprising the TNFR-associated death protein (TRADD) and RIPK1. Deubiquination of RIPK1 enables the release of RIPK1 from complex I which then forms a complex with RIPK3, known as the necrosome. The assembly of the necrosome is dependent on caspase 8 inactivation and the release of RIPK1 from complex I. Active RIPK3 then catalyzes the phosphorylation of MLKL leading to oligomerization of MLKL; these oligomers then translocate to the plasma membrane triggering membrane permeabilization. The mechanism by which MLKL triggers necroptosis is not fully understood. Necroptosis may also be initiated by other death receptors, such as fas (first apoptosis signal), interferons, toll-like receptors and Z-DNA-binding protein 1 (ZBP1).
Evidence suggests a proinflammatory role for necroptosis. One mechanism by which this is thought to occur is that dying cells may trigger the release of damage-associated molecular patterns (DAMPs), although further evidence is required to support this theory. Necroptosis may also induce disruption of epithelial barriers allowing pathogens to enter and trigger an immune response. Necroptotic cells are detected and removed by phagocytes. Necroptosis is thought to have a role in a range of inflammatory conditions, such as inflammatory bowel disease, steatohepatitis and psoriasis.
Tocris offers the following scientific literature for Necroptosis to showcase our products. We invite you to request* or download your copy today!
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