An incoherent feedforward loop interprets NFκB/RelA dynamics to determine TNF-induced necroptosis decisions

Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor {kappa}B (NF{kappa}B), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro-inflammatory form of cell death. Whether TNF-induced NF{kappa}B cross-regulates TNF-induced necroptosis fate decisions is unclear. Live-cell microscopy and model-aided analysis of death kinetics identified a molecular circuit that interprets TNF-induced NF{kappa}B/RelA dynamics to control necroptosis decisions. Inducible expression of TNFAIP3/A20 forms an incoherent feedforward loop to interfere with the RIPK3-containing necrosome complex and protect a fraction of cells from transient, but not long-term TNF exposure. Furthermore, dysregulated NF{kappa}B dynamics often associated with disease diminish TNF-induced necroptosis. Our results suggest that TNFs dual roles in either coordinating cellular responses to inflammation, or further amplifying inflammation are determined by a dynamic NF{kappa}B-A20-RIPK3 circuit, that could be targeted to treat inflammation and cancer.