AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation
AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation
复制标题
GAPDH 的 AMPK 依赖性磷酸化会触发 Sirt1 激活，并且是葡萄糖饥饿时自噬所必需的
DOI：
10.1016/j.molcel.2015.10.037
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发表时间：
2015-12-17
期刊：
影响因子：
16
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Chang, Chunmei;Su, Hua;Liu, Wei
真核生物启动自噬以科普外部营养素的缺乏，这需要激活烟酰胺腺嘌呤二核苷酸（NAD（+））依赖性脱乙酰酶Sirtuin 1（Sirt 1）。然而，饥饿诱导的Sirt 1激活自噬启动的机制仍不清楚。在这里，我们证明，甘油醛3-磷酸脱氢酶（GAPDH），一种传统的糖酵解酶，是一个重要的介质AMP激活的蛋白激酶（AMPK）驱动的Sirt 1激活。在葡萄糖饥饿，但不是氨基酸饥饿，细胞质GAPDH的丝氨酸122磷酸化激活AMPK。这导致GAPDH重新分布到细胞核中。在细胞核内，GAPDH直接与Sirt 1相互作用，取代Sirt 1的抑制子并导致Sirt 1被激活。阻止GAPDH的这种转变会消除Sirt 1的激活和自噬，而通过过表达核定位的GAPDH来增强Sirt 1的激活和自噬。因此，GAPDH是葡萄糖缺乏下自噬的关键和中心调节因子，经历AMPK依赖性磷酸化和核转位以激活Sirt 1脱乙酰酶活性。
Eukaryotes initiate autophagy to cope with the lack of external nutrients, which requires the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirtuin 1 (Sirt1). However, the mechanisms underlying the starvation-induced Sirt1 activation for autophagy initiation remain unclear. Here, we demonstrate that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a conventional glycolytic enzyme, is a critical mediator of AMP-activated protein kinase (AMPK)-driven Sirt1 activation. Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. Preventing this shift of GAPDH abolishes Sirt1 activation and autophagy, while enhancing it, through overexpression of nuclear-localized GAPDH, increases Sirt1 activation and autophagy. GAPDH is thus a pivotal and central regulator of autophagy under glucose deficiency, undergoing AMPK-dependent phosphorylation and nuclear translocation to activate Sirt1 deacetylase activity.