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A new kind of cell suicide: mechanisms and functions of programmed necrosis
Abstract:
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.
Insights
Programmed necrosis, or necroptosis, is a caspase-inhibited cell death pathway involving RIP3 and MLKL. This regulated cell death is crucial for immune responses and implicated in diseases involving tissue damage.
Area of Science:
- Cell Biology
- Immunology
- Pathology
Background:
- Classical cell death pathways include unregulated necrosis and programmed apoptosis.
- A third regulated cell death pathway, necroptosis, is inhibited by caspases.
- Recent research has elucidated the molecular mechanisms and physiological roles of necroptosis.
Purpose of the Study:
- To review recent advances in understanding programmed necrosis (necroptosis).
- To discuss the mechanistic details of RIP3/MLKL-mediated cell death.
- To explore the physiological functions of necroptosis in immunity and disease.
Main Methods:
- Literature review of recent studies on necroptosis.
- Analysis of the roles of RIP3 and MLKL in programmed necrosis.
- Examination of data from animal models investigating necroptosis functions.
Main Results:
- The core components of necroptosis, RIP3 and MLKL, have been identified.
- RIP3/MLKL-mediated cell death plays a significant role in host defense against microbial infections.
- Dysregulation of necroptosis is implicated in the development of diseases characterized by tissue damage.
Conclusions:
- Necroptosis represents a critical, caspase-inhibited regulated cell death pathway.
- The RIP3-MLKL axis is central to the execution of necroptosis.
- Programmed necrosis has substantial implications for both physiological immune responses and pathological conditions.