Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death
Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death
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DOI：
10.1016/j.celrep.2018.08.020
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发表时间：
2018-09-04
期刊：
影响因子：
8.8
通讯作者：
Aoki, Kazuhiro
中科院分区：
文献类型：
--
作者：
Miura, Haruko;Kondo, Yohei;Aoki, Kazuhiro
应激激活蛋白激酶c-jun氨基末端激酶(JNK)和p38在响应环境胁迫信号的细胞命运决定中起着重要作用。JNK和p38之间的串扰信号正在成为炎症和应激反应中的一种重要调节机制。然而，目前尚不清楚这种串扰如何在单细胞水平上影响信号动力学、细胞间差异和细胞反应。我们建立了一个基于激酶转位报告的多路活细胞成像系统，在单细胞分辨率下同时监测JNK和p38的活性，具有高特异性和敏感性。不同的胁迫以不同的动力学激活了JNK和p38。在所有情况下，p38以交叉抑制的方式抑制JNK活性。我们证明p38通过转录和翻译后机制拮抗JNK。这种交叉抑制在应激暴露后产生JNK活性的细胞异质性。我们的数据表明，JNK活性的这种异质性在紫外线胁迫下的部分杀伤中发挥了作用。
The stress-activated protein kinases 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 inflammatory and stress responses. However, it is unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. 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 activated JNK and p38 with various dynamics. In all cases, 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 generates 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.