Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.
Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.
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DOI：
10.1038/ncomms7670
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发表时间：
2015-04-10
影响因子：
16.6
通讯作者：
Sandri, Marco
中科院分区：
文献类型：
--
作者：
Milan, Giulia;Romanello, Vanina;Pescatore, Francesca;Armani, Andrea;Paik, Ji-Hye;Frasson, Laura;Seydel, Anke;Zhao, Jinghui;Abraham, Reimar;Goldberg, Alfred L.;Blaauw, Bert;DePinho, Ronald A.;Sandri, Marco
营养不良、全身炎症、癌症或感染等压力会引发分解代谢状态，其特征是肌肉蛋白水解和氨基酸释放增强，以维持肝脏糖异生和组织蛋白合成。这些条件激活 Forkhead Box (Fox) O 转录因子家族。在这里，我们报告说，由于 FoxO 在诱导自噬-溶酶体和泛素-蛋白酶体系统中的作用，肌肉特异性删除 FoxO 成员可以防止肌肉损失。值得注意的是，在低营养信号传导的情况下，我们证明 FoxO 是 Akt 活性所必需的，但不是 mTOR 信号传导所必需的。 FoxOs 控制多种应激反应途径，例如未折叠蛋白反应、ROS 解毒、DNA 修复和翻译。最后，我们鉴定了 FoxO 依赖性泛素连接酶，包括 MUSA1 和以前未表征的连接酶，称为 SMART（肌肉萎缩特异性并受转录调节）。我们的研究结果强调了 FoxO 在分解代谢条件下协调多种应激反应基因的核心功能。 FoxO 转录因子会促进肌肉萎缩，以应对营养利用率低等压力。 Milan 等人通过生成肌肉特异性 FoxO 三重基因敲除小鼠。确定 FoxO 转录网络协调自噬和蛋白酶体蛋白降解的机制。
Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy–lysosome and ubiquitin–proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress–response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions. FoxO transcription factors promote muscle atrophy in response to stresses such as low nutrient availability. By generating muscle-specific FoxO triple-knockout mice, Milan et al. identify mechanisms by which the FoxO transcriptional network coordinates autophagic and proteasomal protein degradation.
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影响因子：
4.8
作者：
Sacheck, Jennifer M.;Hyatt, Jon-Philippe K.;Goldberg, Alfred L.
通讯作者：
Goldberg, Alfred L.
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
DePinho, Ronald A.
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作者：
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通讯作者：
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