LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress.
LncRNA NBR2 engages a metabolic checkpoint by regulating AMPK under energy stress.
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DOI：
10.1038/ncb3328
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发表时间：
2016-04
影响因子：
21.3
通讯作者：
Gan B
中科院分区：
文献类型：
--
作者：
Liu X;Xiao ZD;Han L;Zhang J;Lee SW;Wang W;Lee H;Zhuang L;Chen J;Lin HK;Wang J;Liang H;Gan B
长链非编码RNA（lncRNA）已成为各种细胞过程中的关键调节因子。然而，lncRNA在激酶信号传导中的潜在参与在很大程度上仍然未知。AMP活化蛋白激酶（AMPK）是细胞能量状态的重要传感器。在这里，我们表明，lncRNA NBR 2（BRCA 1基因2的邻居）是由LKB 1-AMPK途径在能量应激下诱导的。在能量应激时，NBR 2又与AMPK相互作用并促进AMPK激酶活性，从而形成前馈回路以在能量应激期间加强AMPK活化。NBR 2的消耗减弱能量应激诱导的AMPK活化，导致不受抑制的细胞周期，改变的凋亡/自噬反应，并增加体内肿瘤的发展。NBR 2被下调，其低表达与某些人类癌症的不良临床结果相关。总之，我们的研究揭示了lncRNA与代谢应激反应的耦合机制，并为进一步理解lncRNA对激酶信号的调节提供了一个广泛的框架。
Long noncoding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. However, the potential involvement of lncRNAs in kinase signaling remains largely unknown. AMP-activated protein kinase (AMPK) acts as a critical sensor of cellular energy status. Here we show that lncRNA NBR2 (neighbor of BRCA1 gene 2) is induced by the LKB1-AMPK pathway under energy stress. Upon energy stress, NBR2 in turn interacts with AMPK and promotes AMPK kinase activity, thus forming a feed-forward loop to potentiate AMPK activation during energy stress. Depletion of NBR2 attenuates energy stress-induced AMPK activation, resulting in unchecked cell cycling, altered apoptosis/autophagy response, and increased tumor development in vivo. NBR2 is down-regulated and its low expression correlates with poor clinical outcomes in some human cancers. Together, our study uncovers a mechanism coupling lncRNAs with metabolic stress response, and provides a broad framework to further understand the regulation of kinase signaling by lncRNAs.