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Molecular mechanisms of necroptosis: an ordered cellular explosion

Nature Reviews Molecular Cell Biology volume 11, pages 700–714 (2010)Cite this article

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Key Points

  • Although for a long time necrosis was considered to be a purely accidental cell death subroutine, multiple lines of evidence now show that necrotic cell death can be regulated, both in its occurrence and in its course. The term 'necroptosis' was introduced by Yuan's research group in 2005 to indicate 'programmed' (as opposed to 'accidental') necrosis.

  • The best characterized signal transduction cascade leading to necroptosis is initiated by ligand-bound tumour necrosis factor (TNF) receptor 1 (TNFR1), which allows for the assembly of a cytoplasmic supramolecular complex — TNFR complex I — that includes (among other proteins) TNFR-associated death domain (TRADD), cellular inhibitor of apoptosis 1 (cIAP1), cIAP2 and receptor-interacting protein kinase 1 (RIP1; also known as RIPK1).

  • In complex I, RIP1 can be ubiquitylated by cIAPs and deubiquitylated by cylindromatosis (CYLD) and A20 (also known as TNFAIP3). Whereas ubiquitylated RIP1 promotes the activation of the nuclear factor κB (NF-κB) system, deubiquitylated RIP1 functions as a cell death-inducing kinase.

  • On TNFR1 internalization, the so-called TNFR complex II is formed, which contains TRADD, FAS-associated protein with a death domain (FADD) and caspase 8. Normally, caspase 8 becomes activated in complex II, thereby igniting a pro-apoptotic caspase cascade. When caspase activation is prevented, however, RIP1 physically and functionally interacts with RIP3 (also known as RIPK3), thereby generating a necroptosis-inducing complex known as the necrosome.

  • Necroptosis can also be ignited by pathogen recognition receptors, including Toll-like receptors, NOD-like receptors and retinoic acid-inducible gene I-like receptors, as well as in response to DNA damage, presumably by a poly(ADP-ribose) polymerase-1 (PARP1)-dependent signalling pathway.

  • Although the underlying molecular mechanisms remain obscure, reactive oxygen species (ROS), bioenergetic metabolic cascades and the release of cytotoxic factors from lysosomes and mitochondria all contribute to the execution of necroptosis.

  • Regulated necrosis has been seen in multiple, evolutionarily distant model organisms, including yeast, nematodes, fruit flies, rodents, primates and human cells, corroborating the notion that necroptosis may represent a phylogenetically conserved mechanism for programmed cell death.

  • Numerous in vivo studies indicate that the inhibition of necroptosis (by genetic means or by RIP1-targeting agents called necrostatins) can confer consistent cytoprotection, suggesting that necroptosis may constitute a promising target for drug development.

Abstract

For a long time, apoptosis was considered the sole form of programmed cell death during development, homeostasis and disease, whereas necrosis was regarded as an unregulated and uncontrollable process. Evidence now reveals that necrosis can also occur in a regulated manner. The initiation of programmed necrosis, 'necroptosis', by death receptors (such as tumour necrosis factor receptor 1) requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3), and its execution involves the active disintegration of mitochondrial, lysosomal and plasma membranes. 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.

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Figure 1: TNFR1-elicited signalling pathways.
Figure 2: Execution of necroptosis.

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Acknowledgements

We apologize to our colleagues for not citing all primary research papers owing to space restrictions, and we thank W. Declercq for fruitful discussions. Electron microscopy pictures in Box 1 were kindly provided by D. Krysko, Ghent University, VIB, Belgium. P.V. holds a Methusalem grant from the Flemish Government (BOF09/01M00709) and is supported by the Flanders Institute for Biotechnology (VIB), the Interuniversity Poles of Attraction-Belgian Science Policy (IAP6/18), Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO, G.0133.05 and 3G.0218.06), The Special Research Fund of Ghent University (Geconcerteerde Onderzoekstacties 12.0505.02) and the European Commission (EU Marie Curie Training and Mobility Program, ApopTrain, MRTN-CT-035,624; EU FP7 Integrated Project, APO-SYS, HEALTH-F4-2007-200,767; EU FP6 Integrated Project, Epistem, LSHB-CT-2005-019,067; Marie Curie Training and Mobility Program). L.G. and T.V.B. are financed by APO-SYS and FWO, respectively. G.K. is supported by Ligue Nationale contre le Cancer (Equipe labellisée), Agence Nationale pour la Recherche (ANR), the European Commission (APO-SYS, ChemoRes, ApopTrain, Active p53), Fondation pour la Recherche Médicale (FRM), Institut National du Cancer (INCa) and Cancéropôle Ile-de-France.

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Authors and Affiliations

  1. Department for Molecular Biomedical Research, Molecular Signalling and Cell Death Unit, VIB,

    Peter Vandenabeele & Tom Vanden Berghe

  2. Department of Biomedical Molecular Biology, Ghent University, Ghent, B-9052, Belgium

    Peter Vandenabeele & Tom Vanden Berghe

  3. INSERM, U848, Villejuif, F-94805, France

    Lorenzo Galluzzi & Guido Kroemer

  4. Institut Gustave Roussy, and Université Paris-Sud XI, Villejuif, F-94805, France

    Lorenzo Galluzzi

  5. Metabolomics Platform, Institut Gustave Roussy, Villejuif, F-94805, France

    Guido Kroemer

  6. Centre de Recherche des Cordoliers, Paris, F-75,005, France

    Guido Kroemer

  7. Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, AP-HP, F-75908, France

    Guido Kroemer

  8. Université Paris Descartes V, Paris, F-75270, France

    Guido Kroemer

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  1. Peter Vandenabeele
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Supplementary information

Supplementary information S1 (Table)

Components of the molecular machinery for programmed necrosis. (PDF 137 kb)

Supplementary information S2 (Table)

Examples of RIP-targeting strategies underscoring the pathophysiological relevance of necroptosis in vitro (PDF 249 kb)

Supplementary Information S3 (Table)

Examples of pharmacological interventions underscoring the pathophysiological relevance of necroptosis-related factors in vivo (PDF 177 kb)

Supplementary Information S4 (Table)

Examples of genetic interventions underscoring the pathophysiological relevance of necroptosis-related factors in vivo (PDF 226 kb)

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Glossary

Heterophagy

A term of Greek origin indicating the cellular digestion of an exogenous substance, cell or subcellular particle that has been taken up from the extracellular microenvironment.

Autophagy

A pathway for the recycling of cellular contents, in which materials inside the cell are packaged into vesicles and are then targeted to the vacuole or lysosome for bulk turnover. Autophagy is thought to be prominently cytoprotective.

Caspase

A Cys protease that cleaves its substrate after an Asp residue. Caspases play a crucial part in both the initiation (caspase 2, caspase 8, caspase 9 and caspase 10) and execution (caspase 3, caspase 6 and caspase 7) of apoptosis, and they are also required for many processes that are unrelated to cell death, such as the differentiation of several cell types161.

Glutaminolysis

The bioenergetic pathway by which Glu or Gln is converted to α-ketoglutarate, an intermediate of the Krebs cycle. Thus, glutaminolysis can provide substrates for ATP generation by oxidative phosphorylation or stimulate the generation of pyruvate through malate decarboxylation.

Mitochondrial permeability transition

Long-lasting openings of the PTPC lead to an abrupt increase in the inner mitochondrial membrane's permeability to ions and low-molecular-mass solutes, thus provoking osmotic swelling of the mitochondrial matrix and rupture of the mitochondrial outer membrane.

Apoptotic body

A membrane-surrounded vesicle that is shed from dying cells during the late stages of apoptosis and that may include portions of the nucleus and/or apparently normal organelles.

Inflammasome

A supramolecular complex comprising a pattern recognition receptor (such as NLRP3) and an adaptor protein (such as ASC) that is required for the autocatalytic activation of pro-caspase 1. Active caspase 1 catalyses the proteolytic maturation of interleukin-1β, a potent pro-inflammatory cytokine.

Activation-induced cell death

After an adaptive immune response, superfluous lymphocytes are eliminated on T cell receptor re-stimulation by a mechanism that may involve the CD95–CD95L system.

Polyubiquitylation

The attachment of chains of the small protein ubiquitin to Lys residues of proteins, often as a tag for rapid cellular degradation.

Necrostatin 1

A Trp-based molecule (5-(1H-indol-3-ylmethyl)-3-methyl-2-thioxo-4- imidazolidinone) that was first identified as a specific and potent inhibitor of necroptosis7.

Oncogene addiction

An expression coined by Weinberg in 2002 (Ref. 170) to describe the observation that tumour maintenance often depends on the continued activity of some oncogenes.

Mitochondrial transmembrane potential (Δψm)

The electrochemical gradient built across the inner mitochondrial membrane by the proton pumps associated with the respiratory chain. The Δψm creates a proton-moving force that is required for mitochondrial ATP generation by the F1–FO ATP synthase, and its permanent dissipation is considered an early sign of apoptosis.

Advanced glycation end product (AGE)

The product of a chain of chemical reactions that most often is initiated by non-enzymatic protein glycosylation. Increased extracellular glucose favours the accumulation of AGEs, which interact with specific receptors on the plasma membrane to stimulate the generation of intracellular ROS.

Haber–Weiss reaction

The generation of hydroxyl radicals from hydrogen peroxide and superoxide (H2O2 + O.2− ← OH.+HO−+O2). The reaction is very slow, but is catalysed by ferric ions (Fe3+).

Fenton reaction

The ferrous ion (Fe2+)-dependent decomposition of dihydrogen peroxide, generating the highly reactive hydroxyl radical (Fe2+ + H2O2 ← Fe3+ + OH. + OH−).

Lipid peroxidation

The biochemical reaction whereby free radicals 'steal' electrons from lipids in cell membranes, resulting in ultrastructural damage to organelles.

Labile iron pool

A cytosolic fraction of iron ions loosely bound to macromolecules (for example, ferritin) — also known as a chelatable iron pool — that harbours the metabolically active (and hence potentially toxic) forms of ferrous (Fe2+) and ferric (Fe3+) ions.

Oxidative phosphorylation

The process whereby respiratory chain complexes embedded in the inner mitochondrial membrane catalyse a series of redox reactions that provide the free energy to generate the Δψm.

Macropinosome

A large intracellular vesicle filled with extracellular fluids and macromolecules that is formed by macropinocytosis.

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Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. et al. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11, 700–714 (2010). https://doi.org/10.1038/nrm2970

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