A new kind of cell suicide: mechanisms and functions of programmed necrosis

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 39; no. 12; pp. 587 - 593
• Main Authors: Sun, Liming, Wang, Xiaodong
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2014
• Subjects: Animals; Apoptosis; Cell Death; Humans; mixed lineage kinase domain-like protein (MLKL); Models, Biological; necroptosis; Necrosis; necrosis biomarker; necrosis inhibitors; programmed necrosis; pseudokinase; Signal Transduction; Terminology as Topic; programmed necrosis; necrosis biomarker; necrosis inhibitors; mixed lineage kinase domain-like protein (MLKL); pseudokinase; necroptosis
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2014.10.003

•Caspases negatively regulate necrosis.•Initiation of necrosis signaling depends on receptor interacting kinase 1/3 (RIP1/RIP3) activation.•Mixed lineage kinase domain-like protein (MLKL) is the core machinery of necrosis execution.•Recent successes include the development of necrosis inhibitors and biomarkers.
Classically, there are two major forms of cell death: necrosis, an unregulated digestion of cellular components; and apoptosis, a programmed mechanism that is promoted by caspases. However, another form of cell death has recently been identified that is inhibited by caspases, and yet occurs through a regulated mechanism, termed programmed necrosis or necroptosis. The biochemical basis of this program has begun to emerge, with the discovery of the receptor-interacting kinase RIP3 and its substrate, the pseudokinase mixed lineage kinase domain-like protein (MLKL), as core components. Furthermore, animal models have revealed significant functions for RIP3/MLKL-mediated necrotic cell death in immune responses against microbial infection and in the etiology of diseases involving tissue damage. This review discusses recent advances in our understanding of the mechanistic details and physiological functions of programmed necrosis.