Since advance online publication, the legend to Fig 2 has been amended to remove an incorrect explanation for the KD abbreviation.The posttranslational regulation of mammalian clock proteins has been assigned a time-keeping function, but seems to have more essential roles. Here we show that c-Jun N-terminal kinase (JNK), identified by inhibitor screening of BMAL1 phosphorylation at Ser 520/Thr 527/Ser 592, confers dynamic regulation on the clock. Knockdown of JNK1 and JNK2 abrogates BMAL1 phosphorylation and lengthens circadian period in fibroblasts. Mice deficient for neuron-specific isoform JNK3 have altered behavioural rhythms, with longer free-running period and compromised phase shifts to light. The locomotor rhythms are insensitive to intensity variance of constant light, deviating from Aschoff's rule. Thus, JNK regulates a core characteristic of the circadian clock by controlling the oscillation speed and the phase in response to light.
SignificanceThe cellular stress response and circadian clock system are fundamental functions in homeostatic regulation in almost all organisms. However, whether these two mechanisms are interlocked with each other, and the key molecule that links cellular stress and the circadian clock, remain unclear. Here we identify ASK family kinases that are essential for the circadian clock to respond to cellular stress, and report that Ask1 transcription is rhythmically controlled by the circadian clock. Moreover, LC-MS/MS–based proteomic analysis provides insight into a molecular mechanism in which dephosphorylation-triggered changes to the ASK complex mediate cellular stress to the circadian clock. From the perspective of cell signaling, our present findings expand previously reported roles of stress signaling toward regulation of the circadian clock.
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