necroptosis

thumbnail|right|The Necroptosis Signaling Pathway Necroptosis is a programmed form of necrosis and one of the many modalities of programmed cell death that has been described insofar. Conventionally, necrosis is associated damage caused by traumatic external forces, such as mechanical damage, heat, osmotic pressure and disruption by certain parasites. In contrast to orderly, programmed cell death via apoptosis, necrosis in this sense doesn't involve biological processes happening within the cell. The content of the cell only matters after its death: released into the extracellular environment, some molecules which are otherwise only present in intracellular compartments can be detected by other cells. Labelled as damage-associated molecular patterns (DAMPs), these molecules serve as sentinels of tissue damage, incurring corresponding responses from the recipient cells. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Necrotic death might be favourable for its speedy induction of cell-level reaction, represented by the multi-faceted orchestrated response of immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

The signaling pathway responsible for carrying out necroptosis is generally understood. TNF leads to stimulation of its receptor TNFR1. TNFR1 binding protein TNFR-associated death protein TRADD and TNF receptor-associated factor 2 TRAF2 signals to RIPK1 which recruits RIPK3 forming the necrosome also named ripoptosome. Phosphorylation of MLKL by the ripoptosome drives oligomerization of MLKL, allowing MLKL to insert into and permeabilize plasma membranes and organelles. Integration of MLKL leads to the inflammatory phenotype and release of (DAMPs), which elicit immune responses.