10.5068/D1W09J
Oliver Metzig, Marie
0000-0003-1182-8121
University of California Los Angeles
An incoherent feedforward loop interprets NFkappaB/RelA dynamics to
determine TNF-induced necroptosis decisions
Dryad
dataset
2020
2020-12-08T00:00:00Z
2020-12-08T00:00:00Z
en
https://doi.org/10.5068/D1C38J
693132873 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Balancing cell death is essential to maintain healthy tissue homeostasis
and prevent disease. Tumor necrosis factor (TNF) not only activates
nuclear factor kB (NFkappaB), which coordinates the cellular response to
inflammation, but may also trigger necroptosis, a pro-inflammatory form of
cell death. Whether TNF-induced NFkappaB 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 NFkappaB/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 NFkappaB 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 NFkappaB-A20-RIPK3 circuit, that could be targeted to treat
inflammation and cancer.