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Cell-to-cell heterogeneity in p38-mediated cross-inhibition of JNK causes stochastic cell death

Haruko Miura, Yohei Kondo, Michiyuki Matsuda, View ORCID ProfileKazuhiro Aoki
doi: https://doi.org/10.1101/151852
Haruko Miura
1Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
2Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
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Yohei Kondo
2Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
3Department of Basic Biology, Faculty of Life Science, SOKENDAI (Graduate University for Advanced Studies), Myodaiji, Okazaki, Aichi 444-8787, Japan.
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Michiyuki Matsuda
1Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
4Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
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Kazuhiro Aoki
2Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
3Department of Basic Biology, Faculty of Life Science, SOKENDAI (Graduate University for Advanced Studies), Myodaiji, Okazaki, Aichi 444-8787, Japan.
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  • ORCID record for Kazuhiro Aoki
  • For correspondence: k-aoki@nibb.ac.jp
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Abstract

The stress activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK) and p38, are important players in cell fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in the inflammatory and stress responses. However, it is still unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. To address these questions, we established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses, such as anisomycin, osmotic stress, and UV irradiation, and pro-inflammatory cytokines activated JNK and p38 with various dynamics. In all cases, however, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition of JNK appears to generate cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress. Our highly sensitive multiplexed imaging system enables detailed investigation into the p38-JNK interplay in single cells.

One Sentence Summary Cross-inhibition by p38 generates cell-to-cell variability in JNK activity.

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Posted March 22, 2018.
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Cell-to-cell heterogeneity in p38-mediated cross-inhibition of JNK causes stochastic cell death
Haruko Miura, Yohei Kondo, Michiyuki Matsuda, Kazuhiro Aoki
bioRxiv 151852; doi: https://doi.org/10.1101/151852
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Cell-to-cell heterogeneity in p38-mediated cross-inhibition of JNK causes stochastic cell death
Haruko Miura, Yohei Kondo, Michiyuki Matsuda, Kazuhiro Aoki
bioRxiv 151852; doi: https://doi.org/10.1101/151852

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