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Initiation and execution mechanisms of necroptosis: an overview
Open accessAbstract
Necroptosis is a form of regulated cell death, which is induced by ligand binding to TNF family death domain receptors, pattern recognizing receptors and virus sensors. The common feature of these receptor systems is the implication of proteins, which contain a receptor interaction protein kinase (RIPK) homology interaction motif (RHIM) mediating recruitment and activation of receptor-interacting protein kinase 3 (RIPK3), which ultimately activates the necroptosis executioner mixed lineage kinase domain-like (MLKL). In case of the TNF family members, the initiator is the survival- and cell death-regulating RIPK1 kinase, in the case of Toll-like receptor 3/4 (TLR3/4), a RHIM-containing adaptor, called TRIF, while in the case of Z-DNA-binding protein ZBP1/DAI, the cytosolic viral sensor itself contains a RHIM domain. In this review, we discuss the different protein complexes that serve as nucleation platforms for necroptosis and the mechanism of execution of necroptosis. Transgenic models (knockout, kinase-dead knock-in) and pharmacologic inhibition indicate that RIPK1, RIPK3 or MLKL are implicated in many inflammatory, degenerative and infectious diseases. However, the conclusion of necroptosis being solely involved in the etiology of diseases is blurred by the pleiotropic roles of RIPK1 and RIPK3 in other cellular processes such as apoptosis and inflammasome activation.
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“In particular, the activation of RIPK3 downstream of TNFR1 ligation relies on the formation of a RIPK1-containing and RIPK3-containing amyloid-like signaling complex commonly known as necrosome [436, 470], wherein first RIPK1 and then RIPK3 undergo a series of trans-phosphorylation or auto-phosphorylation events that are required for MLKL recruitment and necroptosis activation [437, 438, 442, 471]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [470]
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BackgroundRegulation of programmed cell death by Brd4
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BackgroundMitochondrial ROS prime the hyperglycemic shift from apoptosis to necroptosis
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“Dox-inducible hMLKL((1-140))-2Fv-Venus in mlkl¡/¡ MEF, stably expressed with hCHMP4B-mCherry, were treated with 2 mg/mL Dox overnight, followed by 25 nM B/B for 15 min.”
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“Moreover, TNF signaling pathway was also found to be involved in balancing cell survival and necroptosis.(28) Univariate Cox analysis suggested that EZH2, PGAM5, TLR4, and TRAF2 were associated with the prognosis of STAD patients.”
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“The physical interaction between RIPK1, RIPK3, and MLKL within the necrosome complex leads to MLKL phosphorylation, resulting in its oligomerization and execution of necroptosis [33].”
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“, 2017) Necroptosis (Pasparakis and Vandenabeele, 2015; Grootjans et al., 2017) NETosis (Li et al.”
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“, oncosis)” which is unregulated, instantaneous accidental cell death as the direct result of massive cellular and/or membrane damage caused by extreme physicochemical conditions, and “necroptosis” a form of regulated, protein-based cell death occurring in response to signaling cues and milder physicochemical conditio…”
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Metadata
- Authors
- Grootjans, S., Vanden Berghe, T., & Vandenabeele, P.
- Affiliations
- Ghent University (BE)
- Corresponding author
- Vandenabeele, Peter
- Venue
- Cell Death & Differentiation
- Published
- 2017-05-12
- Volume
- 24
- Issue
- 7
- Pages
- 1184-1195
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC5520172
- OpenAlex
- W2612992363
- Cited by
- 566
- References
- 152
- Citations by year
- 2026: 45 · 2025: 66 · 2024: 68 · 2023: 78 · 2022: 89 · 2021: 64 · 2020: 54 · 2019: 47 · 2018: 41 · 2017: 14
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Belgian Federal Science Policy Office (IAP7/32)
- Fonds Wetenschappelijk Onderzoek (G.0875.11, FWO G.0A45.12N, FWO G0E04.16N, G078713N, FWO G0787.13N, FWO G.0C37.14N, G0C3714N, G.0A45.12N, FWO G.0875.11, BOF16/MET_V/007, G0E0416N)
- Universiteit Gent (BOF16/MET_V/007, 01M00709)
- Vlaams Instituut voor Biotechnologie (BOF09/01M00709)
- Vlaamse regering (BOF09/01M00709, BOF16/MET_V/007)
- Fondation contre le Cancer (2012-188)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- necroptosis, regulated cell death, RIPK3, RIPK1, MLKL, RHIM domain, Toll-like receptors, TRIF, ZBP1, DAI, pattern recognition receptors, inflammatory diseases, degenerative diseases, infectious diseases, apoptosis, inflammasome activation
- MeSH terms
- Amyloid, Animals, Humans, Models, Biological, Necrosis, Signal Transduction, Apoptosis, Receptor-Interacting Protein Serine-Threonine Kinases
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