Stress-responsive MTK1 SAPKKK serves as a redox sensor that mediates delayed and sustained activation of SAPKs by oxidative stress.

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.