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Cited by 339Cell death mechanisms and regulationNF-κB Signaling PathwaysUbiquitin and proteasome pathways

cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent reactive oxygen species production

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Vanlangenakker, N, Vanden Berghe, T, Bogaert, P, Laukens, B, Zobel, K, Deshayes, K, Vucic, D, Fulda, S +2 more·2011·Cell Death & Differentiation
DOI 10.1038/cdd.2010.138PMC PMC3131911
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Abstract

Three members of the IAP family (X-linked inhibitor of apoptosis (XIAP), cellular inhibitor of apoptosis proteins-1/-2 (cIAP1 and cIAP2)) are potent suppressors of apoptosis. Recent studies have shown that cIAP1 and cIAP2, unlike XIAP, are not direct caspase inhibitors, but block apoptosis by functioning as E3 ligases for effector caspases and receptor-interacting protein 1 (RIP1). cIAP-mediated polyubiquitination of RIP1 allows it to bind to the pro-survival kinase transforming growth factor-β-activated kinase 1 (TAK1) which prevents it from activating caspase-8-dependent death, a process reverted by the de-ubiquitinase CYLD. RIP1 is also a regulator of necrosis, a caspase-independent type of cell death. Here, we show that cells depleted of the IAPs by treatment with the IAP antagonist BV6 are greatly sensitized to tumor necrosis factor (TNF)-induced necrosis, but not to necrotic death induced by anti-Fas, poly(I:C) oxidative stress. Specific targeting of the IAPs by RNAi revealed that repression of cIAP1 is responsible for the sensitization. Similarly, lowering TAK1 levels or inhibiting its kinase activity sensitized cells to TNF-induced necrosis, whereas repressing CYLD had the opposite effect. We show that this sensitization to death is accompanied by enhanced RIP1 kinase activity, increased recruitment of RIP1 to Fas-associated via death domain and RIP3 (which allows necrosome formation), and elevated RIP1 kinase-dependent accumulation of reactive oxygen species (ROS). In conclusion, our data indicate that cIAP1 and TAK1 protect cells from TNF-induced necrosis by preventing RIP1/RIP3-dependent ROS production.

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Authors
Vanlangenakker, N., Vanden Berghe, T., Bogaert, P., Laukens, B., Zobel, K., Deshayes, K., Vucic, D., Fulda, S., Vandenabeele, P., & Bertrand, M. J. M.
Affiliations
  • Vlaams Instituut voor Biotechnologie (BE)
  • Goethe University Frankfurt (DE)
  • Genentech (US)
Corresponding author
Vandenabeele, P
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2010-11-05
Volume
18
Issue
4
Pages
656-665
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2010.138
PMC
PMC3131911
OpenAlex
W2008596036
Cited by
339
References
41
Citations by year
2026: 6 · 2025: 15 · 2024: 14 · 2023: 19 · 2022: 22 · 2021: 17 · 2020: 19 · 2019: 15 · 2018: 26 · 2017: 17 · 2016: 27 · 2015: 20 · 2014: 42 · 2013: 36 · 2012: 26
FWCI
10.42
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cell Death and Differentiation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
  • Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders
  • European Commission (200767)
  • Deutsche Forschungsgemeinschaft
  • Fonds Wetenschappelijk Onderzoek
  • Universiteit Gent (01M00709)
  • Vlaamse regering
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
cIAP1, TAK1, necrosis, TNF-induced cell death, RIPK1, RIPK3, reactive oxygen species, IAP family, E3 ubiquitin ligase, necrosome, FADD, CYLD, caspase-independent cell death, BV6, apoptosis
MeSH terms
Deubiquitinating Enzyme CYLD, MAP Kinase Kinase Kinase 7, Animals, Cell Line, Cysteine Endopeptidases, Humans, Necrosis, Reactive Oxygen Species, Oxidative Stress, GTPase-Activating Proteins, MAP Kinase Kinase Kinases, RNA Interference, Tumor Necrosis Factors, Inhibitor of Apoptosis Proteins, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Ubiquitination

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