Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.
Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.
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1,6-二磷酸果糖和醛缩酶通过 AMPK 介导葡萄糖传感
DOI：
10.1038/nature23275
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发表时间：
2017-08-03
期刊：
影响因子：
64.8
通讯作者：
Lin SC
中科院分区：
文献类型：
--
作者：
Zhang CS;Hawley SA;Zong Y;Li M;Wang Z;Gray A;Ma T;Cui J;Feng JW;Zhu M;Wu YQ;Li TY;Ye Z;Lin SY;Yin H;Piao HL;Hardie DG;Lin SC
大多数细胞的主要能量来源是葡萄糖，ATP通过糖酵解和/或氧化代谢产生。葡萄糖剥夺激活AMP激活蛋白激酶（AMPK），但目前尚不清楚这种激活是否仅通过AMP或ADP（AMPK的经典激活剂）的变化发生。在这里，我们描述了一个AMP/ADP独立的机制，触发AMPK激活通过感知果糖-1，6-二磷酸（FBP）的情况下，与AMPK被逐步激活细胞外葡萄糖和细胞内FBP减少。当未被FBP占据时，醛缩酶促进至少含有v-ATP酶、调节剂、轴蛋白、肝激酶B1（LKB 1）和AMPK的溶酶体复合物的形成，先前已证明这是AMPK活化所需的。敲低醛缩酶激活AMPK，即使在细胞丰富的葡萄糖，而催化缺陷型D34 S醛缩酶突变体，仍然结合FBP，阻断AMPK的激活。无细胞重建试验表明，添加FBP破坏了轴蛋白和LKB 1与v-ATP酶和调节剂的结合。重要的是，在某些细胞类型中，AMP/ATP和ADP/ATP比率在急性葡萄糖饥饿期间保持不变，并且AMPK上的完整AMP结合位点对于AMPK活化来说是不需要的。这些结果表明，醛缩酶，以及作为一种糖酵解酶，是葡萄糖的可用性，调节AMPK的传感器。
The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.
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影响因子：
46.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.1009705107
发表时间：
2010-11-09
影响因子：
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作者：
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