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

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Oliver Metzig, Marie, Tang, Ying, Mitchell, Simon, Taylor, Brooks, Foreman, Robert, Wollman, Roy and Hoffmann, Alexander (2020) An incoherent feedforward loop interprets NFκB/RelA dynamics to determine TNF-induced necroptosis decisions. Molecular Systems Biology, 16 (12). e9677 1-17. ISSN 1744-4292

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Official URL: https://doi.org/10.15252/msb.20209677

Abstract

Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor κB (NFκB), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro-inflammatory form of cell death. Whether TNF-induced NFκB affects the fate decision to undergo TNF-induced necroptosis is unclear. Live-cell microscopy and model-aided analysis of death kinetics identified a molecular circuit that interprets TNF-induced NFκB/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 NFκB dynamics often associated with disease diminish TNF-induced necroptosis. Our results suggest that TNF's dual roles in either coordinating cellular responses to inflammation, or further amplifying inflammation are determined by a dynamic NFκB-A20-RIPK3 circuit, that could be targeted to treat inflammation and cancer.

Item Type:	Article
Keywords:	A20, NFκB dynamics, TNF, computational modeling, necroptosis fate decisions
Schools and Departments:	Brighton and Sussex Medical School > Clinical and Experimental Medicine
SWORD Depositor:	Mx Elements Account
Depositing User:	Mx Elements Account
Date Deposited:	20 Jan 2021 07:54
Last Modified:	20 Jan 2021 08:01
URI:	http://sro.sussex.ac.uk/id/eprint/96584

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