ASK family kinases mediate cellular stress and redox signaling to circadian clock.
ASK family kinases mediate cellular stress and redox signaling to circadian clock.
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DOI：
10.1073/pnas.1719298115
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发表时间：
2018-04-03
影响因子：
11.1
通讯作者：
Fukada Y
中科院分区：
文献类型：
--
作者：
Imamura K;Yoshitane H;Hattori K;Yamaguchi M;Yoshida K;Okubo T;Naguro I;Ichijo H;Fukada Y
细胞应激反应和生物钟系统是几乎所有生物体内平衡调节的基本功能。然而，这两种机制是否相互关联，以及连接细胞应激和生物钟的关键分子，目前仍不清楚。在这里，我们确定了ASK家族激酶是昼夜节律钟对细胞应激反应所必需的，并报告了Ask1转录是由昼夜节律钟节律控制的。此外，基于LC-MS/ ms的蛋白质组学分析提供了一种分子机制，在这种机制中，去磷酸化引发的ASK复合物的变化介导了细胞对生物钟的应激。从细胞信号传导的角度来看，我们目前的发现扩展了先前报道的应激信号对生物钟调节的作用。每天的行为和生理节奏是由生物钟产生的，生物钟由生物钟基因和形成转录/翻译反馈回路（ttfl）的编码蛋白组成。生物钟是一个自我维持的振荡器，灵活地响应各种时间线索，与环境的24小时周期同步。然而，将细胞压力传递给生物钟的关键分子尚不清楚。在这里，我们发现凋亡信号调节激酶（ASK）是MAPKKK家族的一员，是决定培养细胞对介质渗透变化的昼夜周期和阶段的重要介质。时钟对细胞内氧化还原状态变化的响应证明了ASK信号的生理影响。有趣的是，ttfl驱动Ask基因的节律性表达，表明Ask介导的ttfl与细胞内氧化还原的关联。在行为学分析中，Ask1、Ask2和Ask3三ko小鼠在其活动节律的昼夜周期和阶段中表现出受损的光反应。基于LC-MS/ ms的蛋白质组学分析发现了一系列ask依赖性和渗透应激反应性的蛋白质磷酸化，其中分子时钟系统的关键组成部分CLOCK在羧基端Thr843或Ser845位点被磷酸化。这些发现揭示了ask依赖性应激反应是生物钟灵活性的潜在机制。
The 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. Daily rhythms of behaviors and physiologies are generated by the circadian clock, which is composed of clock genes and the encoded proteins forming transcriptional/translational feedback loops (TTFLs). The circadian clock is a self-sustained oscillator and flexibly responds to various time cues to synchronize with environmental 24-h cycles. However, the key molecule that transmits cellular stress to the circadian clockwork is unknown. Here we identified apoptosis signal-regulating kinase (ASK), a member of the MAPKKK family, as an essential mediator determining the circadian period and phase of cultured cells in response to osmotic changes of the medium. The physiological impact of ASK signaling was demonstrated by a response of the clock to changes in intracellular redox states. Intriguingly, the TTFLs drive rhythmic expression of Ask genes, indicating ASK-mediated association of the TTFLs with intracellular redox. In behavioral analysis, Ask1, Ask2, and Ask3 triple-KO mice exhibited compromised light responses of the circadian period and phase in their activity rhythms. LC-MS/MS–based proteomic analysis identified a series of ASK-dependent and osmotic stress-responsive phosphorylations of proteins, among which CLOCK, a key component of the molecular clockwork, was phosphorylated at Thr843 or Ser845 in the carboxyl-terminal region. These findings reveal the ASK-dependent stress response as an underlying mechanism of circadian clock flexibility.
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DOI：
10.1126/science.1243417
发表时间：
2013-11-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Peek CB;Affinati AH;Ramsey KM;Kuo HY;Yu W;Sena LA;Ilkayeva O;Marcheva B;Kobayashi Y;Omura C;Levine DC;Bacsik DJ;Gius D;Newgard CB;Goetzman E;Chandel NS;Denu JM;Mrksich M;Bass J
通讯作者：
Bass J
影响因子：
7
作者：
Mertins, Philipp;Yang, Feng;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
64.5
作者：
Balsalobre, A;Damiola, F;Schibler, U
通讯作者：
Schibler, U
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
昼夜节律的代谢和能量学的融合。
DOI：
10.1126/science.1195027
发表时间：
2010-12-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bass J;Takahashi JS
通讯作者：
Takahashi JS