Cells respond to oxidative stress by inducing intracellular signaling, including stress-activated p38 and JNK MAPK (SAPK) pathways, but the underlying mechanisms remain unclear. Here, we report that the MAP three kinase 1 (MTK1) SAPK kinase kinase (SAPKKK) functions as an oxidative-stress sensor that perceives the cellular redox state and transduces it into SAPK signaling. Following oxidative stress, MTK1 is rapidly oxidized and gradually reduced at evolutionarily conserved cysteine residues. These coupled oxidation-reduction modifications of MTK1 elicit its catalytic activity. Gene knockout experiments showed that oxidative stress–induced SAPK signaling is mediated by coordinated activation of the two SAPKKKs, MTK1 and apoptosis signal–regulating kinase 1 (ASK1), which have different time and dose-response characteristics. The MTK1-mediated redox sensing system is crucial for delayed and sustained SAPK activity and dictates cell fate decisions including cell death and interleukin-6 production. Our results delineate a molecular mechanism by which cells generate optimal biological responses under fluctuating redox environments.

细胞通过诱导细胞内信号传导来响应氧化应激，包括应激激活的 p38 和 JNK MAPK (SAPK) 途径，但其潜在机制仍不清楚。在这里，我们报告 MAP 三激酶 1 (MTK1) SAPK 激酶激酶 (SAPKKK) 作为一种氧化应激传感器，可感知细胞氧化还原状态并将其转换为 SAPK 信号传导。氧化应激后，MTK1 在进化上保守的半胱氨酸残基处迅速氧化并逐渐还原。MTK1 的这些耦合氧化还原修饰引发了其催化活性。基因敲除实验表明，氧化应激诱导的 SAPK 信号传导是由两种 SAPKKK、MTK1 和凋亡信号调节激酶 1 (ASK1) 的协同激活介导的，它们具有不同的时间和剂量反应特征。MTK1 介导的氧化还原传感系统对于延迟和持续的 SAPK 活性至关重要，并决定细胞命运决定，包括细胞死亡和白细胞介素 6 的产生。我们的研究结果描绘了一种分子机制，细胞通过该机制在波动的氧化还原环境下产生最佳的生物反应。