Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

Adamson, Antony; Boddington, Christopher; Downton, Polly; Rowe, William; Bagnall, James; Lam, Connie W.; Maya-Mendoza, Apolinar; Schmidt, Lorraine; Harper, Claire V.; Spiller, David G.; Rand, D.A.J.; Jackson, Dean A.; White, Michael R. H.; Paszek, Pawel

doi:10.1038/ncomms12057

Cited by 81 publications

(129 citation statements)

References 72 publications

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“…Through many studies in the past years, it became evident that protein level variations represent a combination of fluctuations caused by the stochastic nature of biochemical reactions (Bar-Even et al, 2006;Pedraza & Paulsson, 2008;Lestas et al, 2010), cellspecific activity of regulatory processes (Colman-Lerner et al, 2005) and influences from population microenvironment (Snijder et al, 2009;Snijder & Pelkmans, 2011). These processes affect mammalian signaling systems to varying degrees (Feinerman et al, 2008;Snijder et al, 2009;Spencer et al, 2009;Kallenberger et al, 2014;Frechin et al, 2015;Adamson et al, 2016). Depending on the lifetime of the associated biomolecules, fluctuations from stochastic processes are supposed to vary on shorter time scales compared to regulated sources of cellular heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Cell‐specific responses to the cytokine TGF β are determined by variability in protein levels

Strasen¹,

Sarma

Jentsch

et al. 2018

Molecular Systems Biology

115

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The cytokine TGFβ provides important information during embryonic development, adult tissue homeostasis, and regeneration. Alterations in the cellular response to TGFβ are involved in severe human diseases. To understand how cells encode the extracellular input and transmit its information to elicit appropriate responses, we acquired quantitative time‐resolved measurements of pathway activation at the single‐cell level. We established dynamic time warping to quantitatively compare signaling dynamics of thousands of individual cells and described heterogeneous single‐cell responses by mathematical modeling. Our combined experimental and theoretical study revealed that the response to a given dose of TGFβ is determined cell specifically by the levels of defined signaling proteins. This heterogeneity in signaling protein expression leads to decomposition of cells into classes with qualitatively distinct signaling dynamics and phenotypic outcome. Negative feedback regulators promote heterogeneous signaling, as a SMAD7 knock‐out specifically affected the signal duration in a subpopulation of cells. Taken together, we propose a quantitative framework that allows predicting and testing sources of cellular signaling heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Cell‐specific responses to the cytokine TGF β are determined by variability in protein levels

Strasen¹,

Sarma

Jentsch

et al. 2018

Molecular Systems Biology

115

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“…In the first attempt to investigate these mechanisms, we utilised IL1β cytokine, which is known to activate IKK via signal transduction pathway parallel to that of TNFα ( Fig. 2A) (Adamson et al, 2016;DeFelice et al, 2019;Shembade et al, 2010;Werner et al, 2008). Using a treatment protocol analogous to that for TNFα ( Fig.…”

Section: Recovery Of the Hs-mediated Nf-κb Signalling Response Is Cytmentioning

confidence: 99%

“…Temperature stimulation results in redistribution of HSPi (and HSPc) from the HSF1 complex, then HSF1 forms trimers and activates transcription of HSPi, creating a regulatory feedback loop that restores proteome homeostasis and eventually inhibits HSF1 activity (Richter et al, 2010). In addition, we utilised our existing model of the IKK-NF-κB signalosome (Adamson et al, 2016) involving TNFα and IL1β transduction pathways, each comprising a cognate receptor and upstream kinase (IKKK, Inhibitory κ B kinase kinase) that in parallel regulate IKK activity (Fig. 4B).…”

Section: Hs-mediated Nf-κb Responses Are Conferred Via Ikk Signalosomementioning

confidence: 99%

“…The NF-κB system integrates a variety of signals, including proinflammatory cytokines, such as Tumour Necrosis Factor α (TNFα) and Interleukin 1β (IL1β), bacterial products, viruses, foreign DNA/RNA and many others (Perkins, 2007). Selective signal integration relies on activation of the inhibitory κ B kinase (IKK), a multiprotein signalosome complex composed of IKKα and IKKβ subunits, required for IκB degradation and NF-κB translocation into the nucleus (Adamson et al, 2016;DeFelice et al, 2019;Shembade et al, 2010;Werner et al, 2005). In resting cells, NF-κB is sequestered in the cytoplasm by association with the Inhibitory κ B proteins (IκB), but upon stimulation undergoes nuclear-tocytoplasmic oscillations as a result of cyclic degradation and NF-κB-dependent resynthesis of IκB and A20 (Hoffmann et al, 2002;Nelson et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Heat shock response pathways regulate stimulus-specificity and sensitivity of NF-κB signalling to temperature stress

Paszek

Kardyńska

Bagnall

et al. 2019

Preprint

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Ability to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Here we report that Heat Shock (HS) induces a temporally-coordinated and stimulus-specific adaptation of the signalling and gene expression responses of the Nuclear Factor κ B (NF-κB) transcription factor. We show that exposure of MCF7 breast adenocarcinoma cells to 43°C 1h HS inhibits the immediate signalling response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines. Within 4h after HS treatment IL1β-induced responses return to normal levels, but the recovery of the TNFα-induced responses is delayed. Using siRNA knock-down of Heat Shock Factor 1 and mathematical modelling we show that the stimulus-specificity is conferred via the Inhibitory κ B kinase signalosome, with HSR differentially controlling individual cytokine transduction pathways. Finally, using a novel mathematical model we predict and experimentally validate that the HSR cross-talk confers differential cytokine sensitivity of the NF-κB system to a range of physiological and clinically-relevant temperatures. This quantitative understanding of NF-κB and HSR crosstalk mechanisms is fundamentally important for the potential improvement of current hyperthermia protocols.

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“…The interesting question is how frequently this bit of information can be transmitted. The ability to respond to frequent pulses is controlled by the refractory time, which may depend on the specific cytokine or other stimuli, and as found by Adamson et al [45] can be shorter when one type of the stimuli is replaced by another. Based on the proposed model, we theoretically demonstrate that the NF-κB pathway can transmit information about the short TNFα pulses as long as their frequency does not exceed 1 per hour.…”

Section: Introductionmentioning

confidence: 99%

Importins promote high-frequency NF-κB oscillations increasing information channel capacity

et al. 2016

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BackgroundImportins and exportins influence gene expression by enabling nucleocytoplasmic shuttling of transcription factors. A key transcription factor of innate immunity, NF-κB, is sequestered in the cytoplasm by its inhibitor, IκBα, which masks nuclear localization sequence of NF-κB. In response to TNFα or LPS, IκBα is degraded, which allows importins to bind NF-κB and shepherd it across nuclear pores. NF-κB nuclear activity is terminated when newly synthesized IκBα enters the nucleus, binds NF-κB and exportin which directs the complex to the cytoplasm. Although importins/exportins are known to regulate spatiotemporal kinetics of NF-κB and other transcription factors governing innate immunity, the mechanistic details of these interactions have not been elucidated and mathematically modelled.ResultsBased on our quantitative experimental data, we pursue NF-κB system modelling by explicitly including NF-κB–importin and IκBα–exportin binding to show that the competition between importins and IκBα enables NF-κB nuclear translocation despite high levels of IκBα. These interactions reduce the effective relaxation time and allow the NF-κB regulatory pathway to respond to recurrent TNFα pulses of 45-min period, which is about twice shorter than the characteristic period of NF-κB oscillations. By stochastic simulations of model dynamics we demonstrate that randomly appearing, short TNFα pulses can be converted to essentially digital pulses of NF-κB activity, provided that intervals between input pulses are not shorter than 1 h.ConclusionsBy including interactions involving importin-α and exportin we bring the modelling of spatiotemporal kinetics of transcription factors to a more mechanistic level. Basing on the analysis of the pursued model we estimated the information transmission rate of the NF-κB pathway as 1 bit per hour.ReviewersThis article was reviewed by Marek Kimmel, James Faeder and William Hlavacek.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0164-z) contains supplementary material.

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Signal transduction controls heterogeneous NF-κB dynamics and target gene expression through cytokine-specific refractory states

Cited by 81 publications

References 72 publications

Cell‐specific responses to the cytokine TGF β are determined by variability in protein levels

Cell‐specific responses to the cytokine TGF β are determined by variability in protein levels

Heat shock response pathways regulate stimulus-specificity and sensitivity of NF-κB signalling to temperature stress

Importins promote high-frequency NF-κB oscillations increasing information channel capacity

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