The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity.
The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity.
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DOI：
10.1016/j.cmet.2015.06.002
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发表时间：
2015-07-07
期刊：
影响因子：
29
通讯作者：
Dillin A
中科院分区：
文献类型：
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作者：
Heimbucher T;Liu Z;Bossard C;McCloskey R;Carrano AC;Riedel CG;Tanasa B;Klammt C;Fonslow BR;Riera CE;Lillemeier BF;Kemphues K;Yates JR 3rd;O'Shea C;Hunter T;Dillin A
FOXO家族转录因子是从蠕虫到人的生物衰老的主要决定因素之一，它们是胰岛素/胰岛素样生长因子-1信号(IIS)的下游效应因子。积极促进DAF16/FOXO稳定性和功能的分子机制尚不清楚。在这里，我们确定去泛素化酶MAX-33是IIS中必不可少的DAF-16调节因子，它稳定了DAF-16活性蛋白的水平，从而影响了DAF-16的功能，如新陈代谢、应激反应和线虫的寿命。MATH-33与DAF-16在纤维素酶和体外实验中有联系。Math-33通过主动从DAF-16中去除泛素部分，从而抵消RLE-1E3-泛素连接酶的作用，起到脱泛素酶的作用。我们的发现支持这样一个模型，即Math-33通过直接调节其泛素化状态来促进DAF-16的稳定性，以响应IIS的减少，这表明DAF-16蛋白稳定性的调节振荡在控制新陈代谢和寿命等过程中发挥了不可或缺的作用。
One of the major determinants of aging in organisms ranging from worms to man are FOXO family transcription factors, which are downstream effectors of Insulin/IGF-1 signaling (IIS). The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response and longevity in C. elegans. MATH-33 associates with DAF-16 in cellulo and in vitro. MATH-33 functions as a deubiquitylase by actively removing ubiquitin moieties from DAF-16, thus counteracting the action of the RLE-1 E3-ubiquitin ligase. Our findings support a model in which MATH-33 promotes DAF-16 stability in response to decreased IIS by directly modulating its ubiquitylation state, suggesting that regulated oscillations in the stability of DAF-16 protein play an integral role in controlling processes such as metabolism and longevity.