Regulated necrosis: the expanding network of non-apoptotic cell death pathways

  title={Regulated necrosis: the expanding network of non-apoptotic cell death pathways},
  author={Tom Vanden Berghe and Andreas Linkermann and Sandrine Jouan-Lanhouet and Henning Walczak and Peter Vandenabeele},
  journal={Nature Reviews Molecular Cell Biology},
Cell death research was revitalized by the understanding that necrosis can occur in a highly regulated and genetically controlled manner. Although RIPK1 (receptor-interacting protein kinase 1)- and RIPK3–MLKL (mixed lineage kinase domain-like)-mediated necroptosis is the most understood form of regulated necrosis, other examples of this process are emerging, including cell death mechanisms known as parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis. Elucidating how these… 

Programmed necrosis and necroptosis signalling

This minireview aims to introduce the emerging and dynamic field of necroptosis to the reader, with a specific focus on intracellular signalling pathways involved in this process.

Regulated necrosis: disease relevance and therapeutic opportunities

This Review describes forms of regulated necrotic cell death, including necroptosis, the emerging cell death modality of ferroptosis (and the related oxytosis) and the less well comprehended parthanatos and cyclophilin D-mediated necrosis.

The molecular machinery of regulated cell death

The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

Necroptosis: a regulated inflammatory mode of cell death

The molecular mechanisms of necroptosis and its relevance to diseases are discussed, with a focus on cancer, neurodegenerative diseases, and inflammatory diseases.

Regulation of necroptosis signaling and cell death by reactive oxygen species

The evidence for and against a role of ROS in necroptosis are discussed, as they are highly reactive and can cause (ir)reversible posttranslational modifications.

Regulated Cell Death

  • W. Land
  • Biology
    Damage-Associated Molecular Patterns in Human Diseases
  • 2018
The chapter ends up with a discussion on the characteristic feature of regulated necrosis: the passive release of large amounts of constitutive DAMPs as a consequence of final plasma membrane rupture as well as the active secretion of inducible DAMPs earlier during the dying process.

Necroptosis and its role in inflammation

The mechanisms regulating necroptosis and its potential role in inflammation and disease are discussed and RIPK1 has important kinase-dependent and scaffolding functions that inhibit or trigger necroPTosis and apoptosis.

Role of necroptosis in the pathogenesis of solid organ injury

Novel insights into the involvement of necroptosis in specific injury of different organs, and the therapeutic platform that it provides for treatment are summarized.

Differences of Key Proteins between Apoptosis and Necroptosis

The key proteins between apoptosis and necroptosis are summarized and it is shown that caspase-8, receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3 are crucial proteins in charge of the switching between these two pathways, resulting in the activation or inhibition of necroPTosis.



Molecular mechanisms of necroptosis: an ordered cellular explosion

Evidence now reveals that necrosis can also occur in a regulated manner, and necroptosis participates in the pathogenesis of diseases, including ischaemic injury, neurodegeneration and viral infection, thereby representing an attractive target for the avoidance of unwarranted cell death.

RIP3: a molecular switch for necrosis and inflammation.

The current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases is reviewed.

New components of the necroptotic pathway

The new members of this necroptosis pathway, MLKL, PGAM5, Drp1 and DAI are reviewed, and some of their possible applications according to recent findings are discussed.

Apoptosis: controlled demolition at the cellular level

This work has shown that during the demolition phase of apoptosis, members of the caspase family of cysteine proteases target several hundred proteins for restricted proteolysis in a controlled manner that minimizes damage and disruption to neighbouring cells and avoids the release of immunostimulatory molecules.

RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to Necrosis

The protein kinase receptor-interacting protein 3 (RIP3) was identified as a molecular switch between TNF-induced apoptosis and necrosis in NIH 3T3 cells and found that RIP3 was required for necrosisin other cells.

Programmed necrosis from molecules to health and disease.

Antigen-mediated T cell expansion regulated by parallel pathways of death

The selective genetic ablation of caspase-8, NFκB, and Ripk1, reveals two forms of cell death that can regulate virus-specific T cell expansion.

Identification of RIP1 kinase as a specific cellular target of necrostatins.

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented and necrostatins are established as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis.

Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

It is demonstrated that necroptosis contributes to delayed mouse ischemic brain injury in vivo through a mechanism distinct from that of apoptosis and offers a new therapeutic target for stroke with an extended window for neuroprotection.

Molecular mechanisms and pathophysiology of necrotic cell death.

This review will focus on the intracellular and intercellular signaling events in necrosis induced by different stimuli, such as oxidative stress, cytokines and pathogen-associated molecular patterns (PAMPs), which can be linked to several pathologies such as stroke, cardiac failure, neurodegenerative diseases, and infections.