The C. elegans Ortholog of USP7 controls DAF-16 stability in Insulin/IGF-1-like signaling.
The C. elegans Ortholog of USP7 controls DAF-16 stability in Insulin/IGF-1-like signaling.
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DOI：
10.1080/21624054.2015.1103429
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发表时间：
2015-10-01
期刊：
影响因子：
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通讯作者：
Hunter, Tony
中科院分区：
文献类型：
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作者：
Heimbucher, Thomas;Hunter, Tony
FOXO家族转录因子是胰岛素/IGF-1信号传导（IIS）的下游效应子，受翻译后修饰和辅调节因子（包括泛素-蛋白酶体系统（UPS）的组分）调节。在IIS中促进β-16/FOXO蛋白稳定性和功能的辅因子尚未被描述。在最近的一项研究中，我们已经确定了去泛素化酶MATH-33，哺乳动物USP 7/HAUSP的直系同源物，作为一个必不可少的β-16的辅助调节。我们发现，当IIS下调时，MATH-33可以积极稳定α-16蛋白水平。在这里，我们讨论了UPS如何调节β-16/FOXO转录因子，特别是通过E3-泛素连接酶和去泛素化酶的相互作用，这对于平衡β-16/FOXO活性和降解至关重要。最近的研究结果提出了一种有趣的可能性，即β-16/FOXO稳态水平的调节振荡在控制健康寿命和寿命延长的机制中起着不可或缺的作用。
FOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and are regulated by posttranslational modification and coregulators, including components of the ubiquitin-proteasome system (UPS). Cofactors promoting DAF-16/FOXO protein stability and function in IIS have not been described yet. In a recent study, we have identified the deubiquitylating enzyme MATH-33, the ortholog of mammalian USP7/HAUSP, as an essential DAF-16 coregulator. We found that MATH-33 actively stabilizes DAF-16 protein levels when IIS is downregulated. Here we discuss how DAF-16/FOXO transcription factors are regulated by the UPS, in particular by the interplay of E3-ubiquitin ligases and deubiquitylating enzymes, which is critical for balancing DAF-16/FOXO activity and degradation. Recent findings raise the intriguing possibility that regulated oscillations in DAF-16/FOXO steady state levels play an integral role in mechanisms controlling healthspan and lifespan extension.