A protein-protein interaction map of the TNF-induced NF-\u03baB signal transduction pathway

Emmy Van Quickelberghe,Delphine De Sutter,Geert Van Loo,Kris Gevaert,Sven Eyckerman

doi:10.1038/sdata.2018.289

Abstract

Tumor Necrosis Factor (TNF) has a crucial role in inflammation, cell proliferation and cell death. Dysregulation of TNF receptor 1 (TNFR1)-induced Nuclear Factor-kappa B (NF-κB) signaling leads to chronic inflammation and is associated with several human inflammatory pathologies. Hence, TNF neutralization suppresses inflammation and attenuates inflammatory pathology. However, despite its beneficial effects, anti-TNF therapy suffers from efficacy issues and severe immune side effects. There is thus an urging need to identify novel targets for pharmaceutical intervention in the NF-κB signaling pathway. Here, we present a protein-protein interaction dataset of the TNFR1-induced signaling pathway. For this, we used Virotrap, a novel method for studying protein complexes without disrupting the cellular integrity, on 12 central proteins controlling NF-κB and cell death signaling, both under resting conditions as well as upon TNF stimulation. Our dataset reveals dynamic interactions in TNFR1-induced NF-κB signaling and identifies both known as well as novel interactors that may help to further unravel the molecular mechanisms steering TNF-induced inflammatory signaling and pathology.

Highlights

Background & SummaryTumor Necrosis Factor (TNF) is a major inflammatory cytokine activating the transcription factor Nuclear Factor-kappa B (NF-κB), but TNF is able to induce apoptosis and necroptosis[1,2]
Most inflammatory effects of TNF are mediated through TNF Receptor 1 (TNFR1), and neutralization of TNFR1-NF-κB signaling, as seen with TNF antagonists, possesses beneficial effects in autoimmune and inflammatory syndromes[3,4,5,6]
Besides its importance in the activation of NF-κB, another complex, cytosolic complex II, can assemble upon TNFR1 ligation, involving the dissociation of TRADD from complex I and the recruitment of FADD (Fas-associated death domain protein) and procaspase-8, leading to caspase-8 activation and apoptosis induction[3,5,8] (Fig. 1). This whole process of TNFR1-induced NF-κB signaling and cell death depends on protein-protein interactions (PPIs) and post-translational modifications

Summary

Background & Summary

Tumor Necrosis Factor (TNF) is a major inflammatory cytokine activating the transcription factor Nuclear Factor-kappa B (NF-κB), but TNF is able to induce apoptosis and necroptosis[1,2]. Besides its importance in the activation of NF-κB, another complex, cytosolic complex II, can assemble upon TNFR1 ligation, involving the dissociation of TRADD from complex I and the recruitment of FADD (Fas-associated death domain protein) and procaspase-8, leading to caspase-8 activation and apoptosis induction[3,5,8] (Fig. 1) This whole process of TNFR1-induced NF-κB signaling and cell death depends on protein-protein interactions (PPIs) and post-translational modifications. Our interaction map identifies both known protein partners as well as novel ones, and provides a valuable resource for further studying the molecular mechanisms steering inflammatory signaling processes and cell death

Methods

Data Records

Technical Validation

Usage Notes

Findings

Additional Information