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

ABSTRACT: Elevated 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 ?B (NF-?B) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43°C HS had an attenuated NF-?B p65 response to Tumor Necrosis Factor ? (TNF?) treatment. The degree of inhibition of the NF-?B response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS-mediated NF-?B 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 I?B? 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-?B p65 subunit. The single cell responses exhibited "all-or-nothing" encoding. While most cells did not respond to TNF? 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 IKK? and IKK? 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-?B responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies.

SUBMITTER: Kardynska M

PROVIDER: S-EPMC5945226 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Kardyńska Małgorzata M Paszek Anna A Śmieja Jarosław J Spiller David D Widłak Wiesława W White Michael R H MRH Paszek Pawel P Kimmel Marek M

PLoS computational biology 20180430 4

Elevated 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 Fact ...[more]

PMID: 29708974

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Project description:Heat stress is poised to become a major factor negatively affecting plant performance worldwide. In terms of world food security, increased ambient temperatures are poised to reduce yields in cereals and other economically important crops. Grain amaranths are known to be productive under poor and/or unfavorable growing conditions that significantly affect cereals and other crops. Several physiological and biochemical attributes have been recognized to contribute to this favorable property, including a high water-use efficiency and the activation of a carbon starvation response. This study reports the behavior of the three grain amaranth species to two different stress conditions: short-term exposure to heat shock (HS) conditions using young plants kept in a conditioned growth chamber or long-term cultivation under severe heat stress in greenhouse conditions. The latter involved exposing grain amaranth plants to daylight temperatures that hovered around 50°C, or above, for at least 4 h during the day and to higher than normal nocturnal temperatures for a complete growth cycle in the summer of 2022 in central Mexico. All grain amaranth species showed a high tolerance to HS, demonstrated by a high percentage of recovery after their return to optimal growing conditions. The tolerance observed coincided with increased expression levels of unknown function genes previously shown to be induced by other (a)biotic stress conditions. Included among them were genes coding for RNA-binding and RNA-editing proteins, respectively. HS tolerance was also in accordance with favorable changes in several biochemical parameters usually induced in plants in response to abiotic stresses. Conversely, exposure to a prolonged severe heat stress seriously affected the vegetative and reproductive development of all three grain amaranth species, which yielded little or no seed. The latter data suggested that the usually stress-tolerant grain amaranths are unable to overcome severe heat stress-related damage leading to reproductive failure.

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

Publications

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

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