Quantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-κB signaling at the single cell level

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dc.citation.articleNumbere1006130en_US
dc.citation.issueNumber4en_US
dc.citation.journalTitlePLoS Computational Biologyen_US
dc.citation.volumeNumber14en_US
dc.contributor.authorKardyńska, Maøgorzataen_US
dc.contributor.authorPaszek, Annaen_US
dc.contributor.authorŚmieja, Jarosøawen_US
dc.contributor.authorSpiller, Daviden_US
dc.contributor.authorWidøak, Wiesøawaen_US
dc.contributor.authorWhite, Michael R.H.en_US
dc.contributor.authorPaszek, Pawelen_US
dc.contributor.authorKimmel, Mareken_US
dc.date.accessioned2018-11-15T17:16:06Zen_US
dc.date.available2018-11-15T17:16:06Zen_US
dc.date.issued2018en_US
dc.description.abstractElevated temperature induces the heat shock (HS) response, which modulates cell proliferation, apoptosis, the immune and inflammatory responses. However, specific mechanisms linking the HS response pathways to major cellular signaling systems are not fully understood. Here we used integrated computational and experimental approaches to quantitatively analyze the crosstalk mechanisms between the HS-response and a master regulator of inflammation, cell proliferation, and apoptosis the Nuclear Factor κB (NF-κB) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43°C HS had an attenuated NF-κB p65 response to Tumor Necrosis Factor α (TNFα) treatment. The degree of inhibition of the NF-κB response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS-mediated NF-κB responses while being consistent with the observed population-level responses. In particular "all-or-nothing" encoding mechanisms were involved in the HS-dependent regulation of the IKK activity and IκBα phosphorylation, while others involving transport were "analogue". In order to discriminate between these mechanisms, we used live-cell imaging of nuclear translocations of the NF-κB p65 subunit. The single cell responses exhibited "all-or-nothing" encoding. While most cells did not respond to TNFα stimulation after a 60 min HS, 27% showed responses similar to those not receiving HS. We further demonstrated experimentally and theoretically that the predicted inhibition of IKK activity was consistent with the observed HS-dependent depletion of the IKKα and IKKβ subunits in whole cell lysates. However, a combination of "all-or-nothing" crosstalk mechanisms was required to completely recapitulate the single cell data. We postulate therefore that the heterogeneity of the single cell responses might be explained by the cell-intrinsic variability of HS-modulated IKK signaling. In summary, we show that high temperature modulates NF-κB responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies.en_US
dc.identifier.citationKardyńska, Maøgorzata, Paszek, Anna, Śmieja, Jarosøaw, et al.. "Quantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-κB signaling at the single cell level." <i>PLoS Computational Biology,</i> 14, no. 4 (2018) Public Library of Science: https://doi.org/10.1371/journal.pcbi.1006130.en_US
dc.identifier.digitalQuantAnalysisen_US
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1006130en_US
dc.identifier.urihttps://hdl.handle.net/1911/103335en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleQuantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-κB signaling at the single cell levelen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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