A term of recent vintage for regulated necrosis* carried out by so-called death receptors–e.g., tumour necrosis factor receptor 1, which requires receptor-interacting protein kinase 1–encoded by RIPK1 and receptor-interacting protein kinase 3–encoded by RIPK3.
Necroptosis requires the active disintegration of mitochondrial, lysosomal and plasma membranes and is pathogenetically linked to ischaemic injury, neurodegeneration and viral infection, making the process an attractive therapeutic target in the future.
*Which contrasts to apoptosis–formerly regarded as the only form of programmed cell death, to be carried out during development, homeostasis and disease, and to necrosis–regarded as an unregulated and uncontrollable process.
On tumour necrosis factor (TNF) binding, TNF receptor 1 (TNFR1) undergoes a conformational change, allowing for the intracellular assembly of the so-called TNFR complex I, which includes TNF receptor-associated death domain (TRADD), receptor-interacting protein 1 (RIP1; also known as RIPK1), cellular inhibitor of apoptosis proteins (cIAPs), TNF receptor-associated factor 2 (TRAF2) and TRAF5. On cIAP-mediated Lys63-ubiquitylation, RIP1 can serve as a scaffold for the recruitment of transforming growth factor-β activated kinase 1 (TAK1), TAK1-binding protein 2 (TAB2) and TAB3, which initiate the canonical nuclear factor-κB (NF-κB) activation pathway (Box 2). Riboflavin kinase (RFK) physically bridges the TNFR1 death domain to p22phox (also known as CYBA), the common subunit of multiple NADPH oxidases, including NADPH oxidase 1 (NOX1), which also contributes to TNFα-induced necroptosis by generating reactive oxygen species (ROS). Conversely, on deubiquitylation by cylindromatosis (CYLD; and perhaps also by A20 (also known as TNFAIP3), cezanne (also known as OTUD7B) or ubiquitin-specific peptidase 21 (USP21)), RIP1 exerts lethal functions, which can be executed by two distinct types of cell death. b | The internalization of TNFR1 is accompanied by a change in its binding partners that leads to the cytosolic assembly of TNFR complex II, which often (but not invariably) contains TRADD, FAS-associated protein with a death domain (FADD), caspase 8, RIP1 and RIP3 (also known as RIPK3). Normally, caspase 8 triggers apoptosis by activating the classical caspase cascade. It also cleaves, and hence inactivates, RIP1 and RIP3. c | If caspase 8 is blocked by pharmacological or genetic interventions, RIP1 and RIP3 become phosphorylated (perhaps by an unidentified kinase) and engage the effector mechanisms of necroptosis. FAD, flavin adenine nucleotide; FMN; flavin mononucleotide (copied from below reference).
Reference Nature Reviews Molecular Cell Biology 11, 700–714; 1 October 2010