Deubiquitination and Activation of AMPK by USP10.
Deubiquitination and Activation of AMPK by USP10.
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USP10 去泛素化和激活 AMPK
DOI：
10.1016/j.molcel.2016.01.010
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发表时间：
2016-02-18
期刊：
影响因子：
16
通讯作者：
Lou Z
中科院分区：
文献类型：
--
作者：
Deng M;Yang X;Qin B;Liu T;Zhang H;Guo W;Lee SB;Kim JJ;Yuan J;Pei H;Wang L;Lou Z
AMP激活的蛋白激酶（AMPK）是通过感知细胞能量状态来调节代谢稳态的主要调节因子。当细胞内ATP水平在能量应激期间降低时，AMPK最初通过AMP或ADP结合和其激酶结构域的激活环内的苏氨酸残基（Thr-172）的磷酸化而被激活。在这里，我们报告了一个关键的分子机制，AMPK激活在能量应激下放大。我们发现AMPKα上的泛素化阻断了LKB 1对AMPKα的磷酸化。去泛素化酶USP 10特异性去除AMPKα上的泛素化，以促进AMPKα被LKB 1磷酸化。在能量应激下，USP 10的活性又通过AMPK介导的USP 10的Ser 76磷酸化而增强。因此，USP 10和AMPK形成关键的前馈回路，确保响应细胞能量状态的波动而放大AMPK活化。这种前馈回路的中断导致不适当的AMPK激活和多种代谢缺陷。
The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.