Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics

Steven W. Smeal, Chaitanya S. Mokashi, A. Hyun Kim, P. Murdo Chiknas and Robin E. C. Lee ()
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Steven W. Smeal: University of Pittsburgh
Chaitanya S. Mokashi: University of Pittsburgh
A. Hyun Kim: University of Pittsburgh
P. Murdo Chiknas: University of Pittsburgh
Robin E. C. Lee: University of Pittsburgh

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Temporal properties of molecules within signaling networks, such as sub-cellular changes in protein abundance, encode information that mediate cellular responses to stimuli. How dynamic signals relay and process information is a critical gap in understanding cellular behaviors. In this work, we investigate transmission of information about changing extracellular cytokine concentrations from receptor-level supramolecular assemblies of IKK kinases downstream to the NF-κB transcription factor. In a custom robot-controlled microfluidic cell culture, we simultaneously measure input-output encoding of IKK-NF-κB in dual fluorescent-reporter cells. When compared with single cytokine pulses, dose-conserving pulse trains prolong IKK assemblies and lead to disproportionately enhanced retention of nuclear NF-κB. Using particle swarm optimization, we demonstrate that a mechanistic model does not recapitulate this emergent property. By contrast, invoking mechanisms for NF-κB-dependent chromatin remodeling to the model recapitulates experiments, showing how temporal dosing that prolongs IKK assemblies facilitates switching to permissive chromatin that sequesters nuclear NF-κB. Remarkably, using simulations to resolve single-cell receptor data accurately predicts same-cell NF-κB time courses for more than 80% of our single cell trajectories. Our data and simulations therefore suggest that cell-to-cell heterogeneity in cytokine responses are predominantly due to mechanisms at the level receptor-associated protein complexes.

Date: 2025
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DOI: 10.1038/s41467-025-62837-0

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