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Review
. 2016 Aug;37(8):535-545.
doi: 10.1016/j.it.2016.06.002. Epub 2016 Jul 13.

More to Life than NF-κB in TNFR1 Signaling

Adrian T Ting  1 , Mathieu J M Bertrand  2
Affiliations
Review

More to Life than NF-κB in TNFR1 Signaling

Adrian T Ting et al. Trends Immunol. 2016 Aug.

Abstract

TNF is a master proinflammatory cytokine whose pathogenic role in inflammatory disorders has long been attributed to induction of proinflammatory mediators. TNF also activates cell survival and death pathways, and recent studies demonstrated that TNF also causes inflammation by inducing cell death. The default response of most cells to TNF is survival and NF-κB-mediated upregulation of prosurvival molecules is a well-documented protective mechanism downstream of TNFR1. Recent studies revealed the existence of an NF-κB-independent cell death checkpoint that restricts cell demise by inactivating RIPK1. Disruption of this checkpoint leads to RIPK1 kinase-dependent death and causes inflammation in vivo. These revelations bring complexity to the control of TNF-induced cell death, and suggest clinical benefit of RIPK1 inhibitors in TNF-driven human inflammatory disorders.

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Figures

Figure 1
Figure 1. Two sequential cell death checkpoints in the TNFR1 pathway
Most cells are protected from TNF-mediated cell death due to the presence two sequential cell death checkpoints that are turned on upon initiation of signaling from TNFR1. The early checkpoint is initiated by the ubiquitylation of RIPK1 by the TRAF2-cIAP1/2 and LUBAC E3 ligases. This process does not require gene transcription and occurs within seconds after ligand binding. Ubiquitylation of RIPK1 functions as a scaffold to recruit the TAB2/3-TAK1 and NEMO-IKKα/β kinase complexes to activate the latter. Within a few minutes after stimulation, NEMO-IKKα/β then phosphorylates RIPK1, which prevents RIPK1 from associating with and activating downstream death-signaling molecules. Under these conditions, RIPK1 functions in a survival-signaling mode. Active NEMO-IKKα/β also leads to the late checkpoint by phosphorylating IκBα, resulting in its degradation and induction of NF-κB-dependent gene transcription. The late checkpoint is dependent on the NF-κB-mediated induction of pro-survival genes, which occurs within an hour after stimulation and serves to reinforce the early checkpoint and to inhibit the formation of death-signaling complexes. Since NF-κB also induces a number of pro-inflammatory genes, this leads to an inflammatory response.
Figure 2
Figure 2. Disruption of the checkpoints leads to cell death via different mechanisms
(Left panel) If the late NF-κB-dependent checkpoint is disrupted, this leads to FADD/Caspase-8-dependent apoptosis. This is caused by the failure to replenish cFLIP, an NF-κB-inducible gene that antagonizes Caspase-8, allowing Caspase-8 to undergo auto-catalytic processing and activation. In this case, the activation of Caspase-8 and apoptosis does not require RIPK1. This death-signaling complex has been termed complex IIa. TNF-mediated apoptosis resulting from disruption of the late checkpoint, via the combined deletion of REL-A, REL-B and c-REL in the gut, resulted in only minimal inflammation in vivo. (Right panel) If the early NF-κB-independent checkpoint is disrupted, RIPK1 converts to a death-signaling mode where it associates with Caspase-8 to initiate apoptosis. This death-signaling complex has been termed complex IIb. If Caspase-8 is not available, RIPK1 can associate with RIPK3 to initiate necroptosis. In both forms of cell death, the enzymatic activity of RIPK1 is required. In vivo studies have shown that disruption of the early checkpoint and subsequent RIPK1 kinase-dependent cell death to be highly inflammatory. RIPK1 kinase-dependent necroptosis may cause inflammation via the release of DAMPs. RIPK1 kinase-dependent apoptosis may cause inflammation via the loss of barrier function thereby facilitating microbial intrusion or via incomplete removal of excessive apoptotic debris, which then undergoes secondary necrosis to generate DAMPs. In both panels, the loss of the checkpoint is indicated by the faded molecules, signifying their absence or lack of activity.
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References

    1. Kolb WP, Granger GA. Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin. Proc Natl Acad Sci U S A. 1968;61:1250–1255. - PMC - PubMed
    1. Ruddle NH, Waksman BH. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. 3. Analysis of mechanism. J Exp Med. 1968;128:1267–1279. - PMC - PubMed
    1. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nature reviews. Rheumatology. 2016;12:49–62. - PMC - PubMed
    1. Pasparakis M, Vandenabeele P. Necroptosis and its role in inflammation. Nature. 2015;517:311–320. - PubMed
    1. Hsu H, et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell. 1996;84:299–308. - PubMed

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