A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans
A Fasting-Responsive Signaling Pathway that Extends Life Span in C. elegans
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DOI：
10.1016/j.celrep.2012.12.018
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发表时间：
2013-01-01
期刊：
影响因子：
8.8
通讯作者：
Nishida, Eisuke
中科院分区：
文献类型：
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作者：
Uno, Masaharu;Honjoh, Sakiko;Nishida, Eisuke
间歇性禁食是延长秀丽隐杆线虫和哺乳动物寿命的最有效的饮食限制方案之一。禁食刺激反应是长寿反应的关键；然而，感觉和转导禁食刺激的机制在很大程度上仍然未知。通过对秀丽隐杆线虫的综合转录组分析，我们发现AP-1 （JUN-1/FOS-1）与FOXO转录因子DAF-16一起在禁食诱导的转录变化中起核心作用。KGB-1是秀丽隐杆线虫JNKs中的一种，作为AP-1的激活剂，并在禁食时被激活。KGB-1和AP-1参与间歇性禁食诱导的长寿。通过AP-1和DAF-16，禁食诱导的SCF E3泛素连接酶复合物组分上调可增强蛋白质泛素化，减少蛋白质羰基化。因此，我们的研究结果确定了一个空腹响应的KGB-1/AP-1信号通路，该信号通路与DAF-16一起，引起介导长寿的转录变化，部分通过调节蛋白酶平衡。
Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis.