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  • Review Article
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Regulation of tumour necrosis factor signalling: live or let die

Key Points

  • The tumour necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise 19 ligands and 29 receptors, respectively. The signalling pathways induced by TNF engagement of TNFR1 — and, to a lesser extent, TNFR2 — are the primary focus of this review.

  • TNF signalling through TNFR1 and TNFR2 leading to nuclear factor-κB (NF-κB) activation promotes cell survival. A hallmark of TNF-dependent NF-κB signalling is the complex regulation of receptor-interacting serine/threonine protein kinase 1 (RIPK1) activation through linear and branched ubiquitylation.

  • RIPK1 ubiquitylation can be modulated by enzymes such as cellular inhibitor of apoptosis protein 1 (cIAP1), cIAP2, A20, Cezanne and cylindromatosis (CYLD).

  • TNF-mediated signalling through non-ubiquitylated RIPK1 induces either apoptosis or necroptosis.

  • Caspase activity is needed to induce TNF-dependent apoptosis and inactivate RIPK1 and RIPK3 by cleavage. Whereas the long isoform of FLICE-like inhibitory protein (FLIPL) blocks apoptosis, the short isoform (FLIPS) triggers necroptosis that depends on non-ubiquitylated RIPK1 and impaired caspase activity.

  • RIPK3-dependent phosphorylation of mixed lineage kinase domain-like (MLKL) is essential for necroptosis but not apoptosis.

  • TNF is involved in some autoimmune and inflammatory diseases, and therapeutic targeting of TNF has been successful for 20 years. However, TNF-specific therapies show little or no efficacy in other inflammatory disorders even when TNF apparently has a role in the pathology. New strategies for targeting TNF are currently being explored.

Abstract

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that has important roles in mammalian immunity and cellular homeostasis. Deregulation of TNF receptor (TNFR) signalling is associated with many inflammatory disorders, including various types of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases. This Review focuses on the recent advances that have been made in understanding TNFR signalling and the consequences of its deregulation for cellular survival, apoptosis and regulated necrosis. We discuss how TNF-induced survival signals are distinguished from those that lead to cell death. Finally, we provide a brief overview of the role of TNF in inflammatory and autoimmune diseases, and we discuss up-to-date and future treatment strategies for these disorders.

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Figure 1: TNFR1 complex I contains ubiquitylated RIPK1 and activates nuclear factor-κB, JNK and p38 signalling.
Figure 2: TNF-induced apoptosis requires non-ubiquitylated RIPK1 and active caspases.
Figure 3: TNF-induced necroptosis requires non-ubiquitylated RIPK1 and inactive caspases.

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Acknowledgements

The authors thank M. Saunders for excellent scientific editing and M. Brenner for general support. D.B. is supported by the ATTRACT Programme of the National Research Fund Luxembourg (FNR).

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Brenner, D., Blaser, H. & Mak, T. Regulation of tumour necrosis factor signalling: live or let die. Nat Rev Immunol 15, 362–374 (2015). https://doi.org/10.1038/nri3834

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