A Quantitative Modular Modeling Approach Reveals the Effects of Different A20 Feedback Implementations for the NF-kB Signaling Dynamics.

Janina Mothes,Inbal Ipenberg,Claus Scheidereit,Uwe Benary,Seda Çöl Arslan,Jana Wolf

doi:10.3389/fphys.2020.00896

Janina Mothes, Inbal Ipenberg + Show 4 more

Open Access

https://doi.org/10.3389/fphys.2020.00896

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Abstract

Signaling pathways involve complex molecular interactions and are controled by non-linear regulatory mechanisms. If details of regulatory mechanisms are not fully elucidated, they can be implemented by different, equally reasonable mathematical representations in computational models. The study presented here focusses on NF-κB signaling, which is regulated by negative feedbacks via IκBα and A20. A20 inhibits NF-κB activation indirectly through interference with proteins that transduce the signal from the TNF receptor complex to activate the IκB kinase (IKK) complex. A number of pathway models has been developed implementing the A20 effect in different ways. We here focus on the question how different A20 feedback implementations impact the dynamics of NF-κB. To this end, we develop a modular modeling approach that allows combining previously published A20 modules with a common pathway core module. The resulting models are fitted to a published comprehensive experimental data set and therefore show quantitatively comparable NF-κB dynamics. Based on defined measures for the initial and long-term behavior we analyze the effects of a wide range of changes in the A20 feedback strength, the IκBα feedback strength and the TNFα stimulation strength on NF-κB dynamics. This shows similarities between the models but also model-specific differences. In particular, the A20 feedback strength and the TNFα stimulation strength affect initial and long-term NF-κB concentrations differently in the analyzed models. We validated our model predictions experimentally by varying TNFα concentrations applied to HeLa cells. These time course data indicate that only one of the A20 feedback models appropriately describes the impact of A20 on the NF-κB dynamics in this cell type.

Highlights

Transcription factor NF-κB regulates cell differentiation, proliferation, and survival
We studied the impact of the A20 feedback on the NF-κB dynamics upon a constant TNFα stimulation
The strength of the A20 feedback is varied by multiplying the transcription rate constant of the A20 mRNA (k10) with a factor, i.e., feedback strength

Summary

Introduction

Transcription factor NF-κB regulates cell differentiation, proliferation, and survival. The transcription factor NF-κB is located in the cytoplasm bound to IκBα, which prevents the translocation of NF-κB into the nucleus. E.g., with TNFα, the IκB kinase (IKK) complex is activated. Released NF-κB translocates into the nucleus and activates the transcription of a number of target genes (Hinz and Scheidereit, 2014). Two of these are NFKBIA, encoding IκBα, and TNFAIP3, encoding A20. Both proteins exhibit negative feedbacks on NFκB activation. A20 inhibits NF-κB activity indirectly through interference with proteins mediating the signal from the TNF receptor complex to the IKK complex (Lork et al, 2017). The exact molecular mechanism of the inhibitory effect of A20 on the IKK complex is still under discussion (Skaug et al, 2011; De et al, 2014; Wertz et al, 2015)

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