ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy
ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy
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DOI：
10.1016/j.molcel.2016.04.009
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发表时间：
2016-05-05
期刊：
影响因子：
16
通讯作者：
Lin, Sheng-Cai
中科院分区：
文献类型：
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作者：
Li, Terytty Yang;Sun, Yu;Lin, Sheng-Cai
代谢重编程是生物稳态的基础，使细胞能够在感知到燃料和生长因子的可用性改变后调整代谢途径。ULK 1和ULK 2代表将代谢应激信号传递给自噬机制的关键整合子。在这里，我们证明，在剥夺氨基酸和生长因子，ULK 1/2直接磷酸化关键的糖酵解酶，包括己糖激酶（HK），磷酸果糖激酶1（PFK 1），烯醇化酶1（ENO 1），和产酶果糖-1，6-二磷酸酶（FBP 1）。这些酶的磷酸化导致增强的HK活性以维持葡萄糖摄取，但降低的FBP 1活性以阻断产葡萄糖途径，降低的PFK 1和ENO 1活性以适度降低葡萄糖-6-磷酸并将更多的碳通量重新分配至磷酸戊糖途径（PPP），从而在细胞和生物体水平上维持细胞能量和氧化还原稳态。这些结果将ULK 1/ 2确定为一个分叉信号传导节点，该节点除了响应于营养剥夺而启动自噬之外还维持葡萄糖代谢通量。
Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/ 2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.