Regulation of AMPK by the ubiquitin proteasome system.
Regulation of AMPK by the ubiquitin proteasome system.
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DOI：
10.1016/j.ajpath.2010.11.030
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
M. Zungu;J. Schisler;M. F. Essop;C. McCudden;C. Patterson;M. Willis
中科院分区：
文献类型：
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作者：
M. Zungu;J. Schisler;M. F. Essop;C. McCudden;C. Patterson;M. Willis
5′-AMP活化蛋白激酶（AMPK）作为代谢燃料计发挥作用，其响应于环境应激而被激活以恢复细胞能量平衡。在心脏中，AMPK协调葡萄糖和脂肪酸代谢途径的激活，以确保在需要时增加心肌ATP的产生，例如在心脏缺血/再灌注和肥大期间，导致AMPK活性增加，这可以被视为保护性和适应不良。虽然我们了解激酶对AMPK活性的基本调节，但最近的研究引入了AMPK受其他翻译后修饰（特别是泛素化）调节的概念。这些研究报道了泛素连接酶诱导细胞死亡的DFFA样效应子a泛素化AMPK的β亚基以调节其稳态蛋白水平。其他研究人员发现，AMPK调节组分，包括AMPK α亚基和AMPK激酶NUAK 1和MARK 4，可以被非典型泛素链泛素化。USP 9 X-去泛素化酶被鉴定为从NUAK 1和MARK 4两者去除泛素化。最后，AMPK激活增加泛素连接酶MAFBx/Atrogin-1和MuRF 1的表达。这些泛素连接酶调节关键的心脏转录因子以控制心肌细胞质量和重塑，从而表明AMPK可能在心脏中起作用的另一种机制。AMPK泛素化在心脏疾病中的相关性尚未得到直接测试，但它可能代表了常见心脏疾病中发生的一种重要机制，可能是治疗的靶点。
The 5′-AMP-activated protein kinase (AMPK) functions as a metabolic fuel gauge that is activated in response to environmental stressors to restore cellular energy balance. In the heart, AMPK coordinates the activation of glucose and fatty acid metabolic pathways to ensure increased production of myocardial ATP when required, such as during cardiac ischemia/reperfusion and hypertrophy, causing an increase in AMPK activity that can be viewed as both protective and maladaptive. While we understand the basic regulation of AMPK activity by kinases, recent studies have introduced the concept that AMPK is regulated by other post-translational modifications, specifically ubiquitination. These studies reported that the ubiquitin ligase cell death–inducing DFFA-like effector a ubiquitinates the β subunit of AMPK to regulate its steady-state protein levels. Other investigators found that AMPK regulatory components, including the AMPK α subunit and AMPK kinases NUAK1 and MARK4, can be ubiquitinated with atypical ubiquitin chains. The USP9X-deubiquitinating enzyme was identified to remove ubiquitination from both NUAK1 and MARK4. Lastly, AMPK activation increases the expression of the ubiquitin ligases MAFBx/Atrogin-1 and MuRF1. These ubiquitin ligases regulate key cardiac transcription factors to control cardiomyocyte mass and remodeling, thus suggesting another mechanism by which AMPK may function in the heart. The relevance of AMPK ubiquitination in cardiac disease has yet to be tested directly, but it likely represents an important mechanism that occurs in common cardiac diseases that may be targeted for therapy.