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Tumor necrosis factor-mediated cell death: to break or to burst, that’s the question

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Abstract

In this review, we discuss the signal-transduction pathways of three major cellular responses induced by tumor necrosis factor (TNF): cell survival through NF-κB activation, apoptosis, and necrosis. Recruitment and activation of caspases plays a crucial role in the initiation and execution of TNF-induced apoptosis. However, experimental inhibition of caspases reveals an alternative cell death pathway, namely necrosis, also called necroptosis, suggesting that caspases actively suppress the latter outcome. TNF-induced necrotic cell death crucially depends on the kinase activity of receptor interacting protein serine-threonine kinase 1 (RIP1) and RIP3. It was recently demonstrated that ubiquitination of RIP1 determines whether it will function as a pro-survival or pro-cell death molecule. Deeper insight into the mechanisms that control the molecular switches between cell survival and cell death will help us to understand why TNF can exert so many different biological functions in the etiology and pathogenesis of human diseases.

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Acknowledgments

We thank Amin Bredan for editing the manuscript. FVH is funded by a Postdoc grant from APO-SYS, FP7. NF is a postdoctoral fellow of FWO (Fonds Wetenschappelijk Onderzoek–Vlaanderen), PV and WD are research professors at the Ghent University. This work has been supported by Flanders Institute for Biotechnology (VIB) and several grants from the European Union (EC Marie Curie Training and Mobility Program, FP6, ApopTrain, MRTN-CT-035624; EC RTD Integrated Project, FP6, Epistem, LSHB-CT-2005-019067, APO-SYS, FP7, HEALTH-F4-2007-200767), the Interuniversity Poles of Attraction-Belgian Science Policy (IAP6/18), the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (G.0133.05 and 3G.0218.06), and the Special Research Fund of Ghent University (Geconcerteerde Onderzoekstacties 12.0505.02). PV is holder of a Methusalem grant from the Flemish government.

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  1. Unit For Molecular Signalling and Cell Death, Department for Molecular Biomedical Research, VIB, Technologiepark 927, 9052, Ghent (Zwijnaarde), Belgium

    Franky Van Herreweghe, Wim Declercq & Peter Vandenabeele

  2. Unit for Molecular Signalling and Cell Death, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 927, 9052, Ghent, Belgium

    Franky Van Herreweghe, Wim Declercq & Peter Vandenabeele

  3. Unit for Molecular Glycobiology, Department for Molecular Biomedical Research, VIB, Ghent University, Technologiepark 927, 9052, Ghent, Belgium

    Nele Festjens

  4. Laboratory for Protein Biochemistry and Biomolecular Engineering, Department of Biochemistry and Microbiology, Ghent University, Ledeganckstraat 35, 9052, Ghent, Belgium

    Nele Festjens

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  1. Franky Van Herreweghe
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  2. Nele Festjens
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  4. Peter Vandenabeele
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Correspondence to Peter Vandenabeele.

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Van Herreweghe, F., Festjens, N., Declercq, W. et al. Tumor necrosis factor-mediated cell death: to break or to burst, that’s the question. Cell. Mol. Life Sci. 67, 1567–1579 (2010). https://doi.org/10.1007/s00018-010-0283-0

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