Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics
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...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62837-0 |
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| _version_ | 1849331836311830528 |
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| author | Steven W. Smeal Chaitanya S. Mokashi A. Hyun Kim P. Murdo Chiknas Robin E. C. Lee |
| author_facet | Steven W. Smeal Chaitanya S. Mokashi A. Hyun Kim P. Murdo Chiknas Robin E. C. Lee |
| author_sort | Steven W. Smeal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bf3360abeb6f40b0900ec0c8431227e5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bf3360abeb6f40b0900ec0c8431227e52025-08-20T03:46:23ZengNature PortfolioNature Communications2041-17232025-08-0116111810.1038/s41467-025-62837-0Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamicsSteven W. Smeal0Chaitanya S. Mokashi1A. Hyun Kim2P. Murdo Chiknas3Robin E. C. Lee4Department of Computational and Systems Biology, School of Medicine, University of PittsburghDepartment of Computational and Systems Biology, School of Medicine, University of PittsburghDepartment of Computational and Systems Biology, School of Medicine, University of PittsburghDepartment of Computational and Systems Biology, School of Medicine, University of PittsburghDepartment of Computational and Systems Biology, School of Medicine, University of PittsburghAbstract 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.https://doi.org/10.1038/s41467-025-62837-0 |
| spellingShingle | Steven W. Smeal Chaitanya S. Mokashi A. Hyun Kim P. Murdo Chiknas Robin E. C. Lee Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics Nature Communications |
| title | Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics |
| title_full | Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics |
| title_fullStr | Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics |
| title_full_unstemmed | Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics |
| title_short | Time-varying stimuli that prolong IKK activation promote nuclear remodeling and mechanistic switching of NF-κB dynamics |
| title_sort | time varying stimuli that prolong ikk activation promote nuclear remodeling and mechanistic switching of nf κb dynamics |
| url | https://doi.org/10.1038/s41467-025-62837-0 |
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