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An incoherent feedforward loop interprets NF?B/RelA dynamics to determine TNF-induced necroptosis decisions
Version 2 2023-06-12, 09:41
Version 1 2023-06-09, 22:49
journal contribution
posted on 2023-06-12, 09:41 authored by Marie Oliver Metzig, Ying Tang, Simon MitchellSimon Mitchell, Brooks Taylor, Robert Foreman, Roy Wollman, Alexander HoffmannBalancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor ?B (NF?B), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro-inflammatory form of cell death. Whether TNF-induced NF?B 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 NF?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?B 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 NF?B-A20-RIPK3 circuit, that could be targeted to treat inflammation and cancer.
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Publication status
- Published
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- Published version
Journal
Molecular Systems BiologyISSN
1744-4292Publisher
Wiley Open AccessExternal DOI
Issue
12Volume
16Page range
1-17Article number
e9677Event location
EnglandDepartment affiliated with
- Clinical and Experimental Medicine Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-01-20First Open Access (FOA) Date
2021-01-20First Compliant Deposit (FCD) Date
2021-01-19Usage metrics
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