Programmed necrosis. From molecules to health and disease

During the past decade, cell death researchers have witnessed a gradual but deep conceptual revolution: it has been unequivocally shown that necrosis, which for long had been considered as a purely accidental cell death mode, can also be induced by finely regulated signal transduction pathways. In particular, when caspases are inhibited by pharmacological or genetic means, the ligation of death receptors such as the tumor necrosis factor receptor 1 (TNFR1) can lead to the assembly of a supramolecular complex containing the receptor-interacting protein kinases 1 and 3 (RIP1 and RIP3) that delivers a pronecrotic signal. Such complex has recently been dubbed necrosome and mediates the execution of a specific instance of regulated necrosis, necroptosis. Soon, it turned out that programmed necrosis occurs in nonmammalian model organisms and that it is implicated in human diseases including ischemia and viral infection. In this review, we first describe the historical evolution of the concept of programmed necrosis and the molecular mechanisms that underlie necroptosis initiation and execution. We then provide evidence suggesting that necroptosis represents an ancient and evolutionarily conserved cell death modality that may be targeted for drug development.