AMP as a Low-Energy Charge Signal Autonomously Initiates Assembly of AXIN-AMPK-LKB1 Complex for AMPK Activation
AMP as a Low-Energy Charge Signal Autonomously Initiates Assembly of AXIN-AMPK-LKB1 Complex for AMPK Activation
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AMP 作为低能电荷信号自主启动 AXIN-AMPK-LKB1 复合物的组装以激活 AMPK。
DOI：
10.1016/j.cmet.2013.09.005
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发表时间：
2013-10-01
期刊：
影响因子：
29
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
--
作者：
Zhang, Ya-Lin;Guo, Huiling;Lin, Sheng-Cai
amp活化蛋白激酶（AMPK）是通过感知细胞能量状态来调节代谢稳态的主要分子。当细胞AMP/ADP水平升高时，AMPK主要通过LKB1的磷酸化被激活。然而，AMP/ADP如何导致AMPK磷酸化尚不清楚。在这里，我们证明是AMP，而不是ADP，驱动AXIN直接连接LKB1使AMPK磷酸化。在葡萄糖饥饿或aicar处理的细胞和补充外源性AMP的无细胞系统中，AXIN-AMPK-LKB1复合物的形成大大增强。AXIN的消耗消除了饥饿诱导的AMPK-LKB1共定位。重要的是，小鼠肝脏中基于腺病毒的AXIN敲低会损害AMPK的激活，并导致饥饿后脂肪肝加剧，这强调了AXIN在AMPK激活中的重要作用。这些发现证明了AMP的启动作用，并证明AXIN直接将AMP与AMPK的结合传递给LKB1的激活，揭示了AMP诱导LKB1激活AMPK的机制途径。
The AMP-activated protein kinase (AMPK) is a master regulator of metabolic homeostasis by sensing cellular energy status. AMPK is mainly activated via phosphorylation by LKB1 when cellular AMP/ADP levels are increased. However, how AMP/ADP brings about AMPK phosphorylation remains unclear. Here, we show that it is AMP, but not ADP, that drives AXIN to directly tether LKB1 to phosphorylate AMPK. The complex formation of AXIN-AMPK-LKB1 is greatly enhanced in glucose-starved or AICAR-treated cells and in cell-free systems supplemented with exogenous AMP. Depletion of AXIN abrogated starvation-induced AMPK-LKB1 colocalization. Importantly, adenovirus-based knockdown of AXIN in the mouse liver impaired AMPK activation and caused exacerbated fatty liver after starvation, underscoring an essential role of AXIN in AMPK activation. These findings demonstrate an initiating role of AMP and demonstrate that AXIN directly transmits AMP binding of AMPK to its activation by LKB1, uncovering the mechanistic route for AMP to elicit AMPK activation by LKB1.