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Cited by 312Cell death mechanisms and regulationNF-κB Signaling PathwaysDeath, Funerary Practices, and Mourning

RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition

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Dondelinger, Y, Aguileta, M A, Goossens, V, Dubuisson, C, Grootjans, S, Dejardin, E, Vandenabeele, P, Bertrand, M J M·2013·Cell Death & Differentiation
DOI 10.1038/cdd.2013.94PMC PMC3770330
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Abstract

Receptor-interacting protein kinase (RIPK) 1 and RIPK3 have emerged as essential kinases mediating a regulated form of necrosis, known as necroptosis, that can be induced by tumor necrosis factor (TNF) signaling. As a consequence, inhibiting RIPK1 kinase activity and repressing RIPK3 expression levels have become commonly used approaches to estimate the contribution of necroptosis to specific phenotypes. Here, we report that RIPK1 kinase activity and RIPK3 also contribute to TNF-induced apoptosis in conditions of cellular inhibitor of apoptosis 1 and 2 (cIAP1/2) depletion or TGF-β-activated kinase 1 (TAK1) kinase inhibition, implying that inhibition of RIPK1 kinase activity or depletion of RIPK3 under cell death conditions is not always a prerequisite to conclude on the involvement of necroptosis. Moreover, we found that, contrary to cIAP1/2 depletion, TAK1 kinase inhibition induces assembly of the cytosolic RIPK1/Fas-associated protein with death domain/caspase-8 apoptotic TNF receptor 1 (TNFR1) complex IIb without affecting the RIPK1 ubiquitylation status at the level of TNFR1 complex I. These results indicate that the recruitment of TAK1 to the ubiquitin (Ub) chains, and not the Ub chains per se, regulates the contribution of RIPK1 to the apoptotic death trigger. In line with this, we found that cylindromatosis repression only provided protection to TNF-mediated RIPK1-dependent apoptosis in condition of reduced RIPK1 ubiquitylation obtained by cIAP1/2 depletion but not upon TAK1 kinase inhibition, again arguing for a role of TAK1 in preventing RIPK1-dependent apoptosis downstream of RIPK1 ubiquitylation. Importantly, we found that this function of TAK1 was independent of its known role in canonical nuclear factor-κB (NF-κB) activation. Our study therefore reports a new function of TAK1 in regulating an early NF-κB-independent cell death checkpoint in the TNFR1 apoptotic pathway. In both TNF-induced RIPK1 kinase-dependent apoptotic models, we found that RIPK3 contributes to full caspase-8 activation independently of its kinase activity or intact RHIM domain. In contrast, RIPK3 participates in caspase-8 activation by acting downstream of the cytosolic death complex assembly, possibly via reactive oxygen species generation.

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  • Assembly of necrosome upon TNFR1 stimulation impinges on two conditions: pharmacological or genetic CASP8 inactivation, and RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by SMAC mimetics.

    “In addition, the assembly of the necrosome upon TNFR1 stimulation impinges on two conditions: (1) pharmacological or genetic CASP8 inactivation [478, 479], and (2) RIPK1 deubiquitination-dependent phosphorylation (at least in some settings), which can be favored by exogenously provided SMAC mimetics, ensuring the release of RIPK1 from complex I (see above) [334, 335, 480, 481].”

    From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [481]

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References 49 · Cited by 312

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Authors
Dondelinger, Y., Aguileta, M. A., Goossens, V, Dubuisson, C., Grootjans, S., Dejardin, E., Vandenabeele, P., & Bertrand, M. J. M.
Affiliations
  • Ghent University (BE)
  • University of Liège (BE)
Corresponding author
  • Vandenabeele, P
  • Bertrand, M J M
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2013-07-26
Volume
20
Issue
10
Pages
1381-1392
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2013.94
PMC
PMC3770330
OpenAlex
W1963848568
Cited by
312
References
49
Citations by year
2026: 11 · 2025: 20 · 2024: 16 · 2023: 21 · 2022: 29 · 2021: 30 · 2020: 19 · 2019: 34 · 2018: 32 · 2017: 24 · 2016: 30 · 2015: 20 · 2014: 23 · 2013: 2 · 2012: 1
FWCI
11.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Differentiation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • ORBi (University of Liège) (submittedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek (G.0875.11, FWO G.0172.12N, FWO G.0A45.12N, FWO G.0973.11, G.0973.11, G.0A45.12N, FWO G.0875.11)
  • Universiteit Gent (01M00709)
  • Vlaamse regering (BOF09/01M00709)
  • Fondation contre le Cancer
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
  • Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
Keywords
RIPK3, RIPK1, necroptosis, TNFR1, TNF-induced apoptosis, cIAP1/2, TAK1, caspase-8 activation, ubiquitin chains, CYLD, reactive oxygen species, death receptor signaling, RHIM domain
MeSH terms
MAP Kinase Kinase Kinase 7, Animals, Humans, Transfection, Signal Transduction, NF-kappa B, Apoptosis, Reactive Oxygen Species, MAP Kinase Kinase Kinases, Receptors, Tumor Necrosis Factor, Type I, Inhibitor of Apoptosis Proteins, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, HEK293 Cells

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