Nestlé Research, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, Lausanne, Switzerland.
School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL) Innovation Park, Lausanne, Switzerland.
FASEB J. 2019 Nov;33(11):12374-12391. doi: 10.1096/fj.201900841R. Epub 2019 Aug 19.
AMPK is a central regulator of energy homeostasis. AMPK not only elicits acute metabolic responses but also promotes metabolic reprogramming and adaptations in the long-term through regulation of specific transcription factors and coactivators. We performed a whole-genome transcriptome profiling in wild-type (WT) and AMPK-deficient mouse embryonic fibroblasts (MEFs) and primary hepatocytes that had been treated with 2 distinct classes of small-molecule AMPK activators. We identified unique compound-dependent gene expression signatures and several AMPK-regulated genes, including folliculin (), which encodes the tumor suppressor FLCN. Bioinformatics analysis highlighted the lysosomal pathway and the associated transcription factor EB (TFEB) as a key transcriptional mediator responsible for AMPK responses. AMPK-induced expression was abolished in MEFs lacking TFEB and transcription factor E3, 2 transcription factors with partially redundant function; additionally, the promoter activity of was profoundly reduced when its putative TFEB-binding site was mutated. The AMPK-TFEB-FLCN axis is conserved across species; swimming exercise in WT zebrafish induced expression in muscle, which was significantly reduced in AMPK-deficient zebrafish. Mechanistically, we have found that AMPK promotes dephosphorylation and nuclear localization of TFEB independently of mammalian target of rapamycin activity. Collectively, we identified the novel AMPK-TFEB-FLCN axis, which may function as a key cascade for cellular and metabolic adaptations.-Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K. AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR.
AMPK 是能量平衡的核心调节剂。AMPK 不仅引发急性代谢反应，还通过调节特定的转录因子和共激活因子，促进长期的代谢重编程和适应。我们在野生型 (WT) 和 AMPK 缺陷型小鼠胚胎成纤维细胞 (MEF) 和原代肝细胞中进行了全基因组转录组谱分析，这些细胞已经用 2 种不同类别的小分子 AMPK 激活剂处理过。我们确定了独特的化合物依赖性基因表达特征和几个 AMPK 调节的基因，包括编码肿瘤抑制因子 FLCN 的毛霉菌 ()。生物信息学分析突出了溶酶体途径和相关的转录因子 EB (TFEB) 作为负责 AMPK 反应的关键转录调节剂。在缺乏 TFEB 和转录因子 E3 的 MEF 中，AMPK 诱导的 表达被消除，TFEB 和转录因子 E3 具有部分冗余功能；此外，当其假定的 TFEB 结合位点发生突变时， 的启动子活性显著降低。AMPK-TFEB-FLCN 轴在物种间是保守的；WT 斑马鱼的游泳运动诱导肌肉中 表达，而在 AMPK 缺陷型斑马鱼中则显著降低。从机制上讲，我们发现 AMPK 可独立于哺乳动物雷帕霉素靶蛋白 (mTOR) 活性促进 TFEB 的去磷酸化和核定位。总的来说，我们确定了新的 AMPK-TFEB-FLCN 轴，它可能作为细胞和代谢适应的关键级联反应发挥作用。-Collodet, C., Foretz, M., Deak, M., Bultot, L., Metairon, S., Viollet, B., Lefebvre, G., Raymond, F., Parisi, A., Civiletto, G., Gut, P., Descombes, P., Sakamoto, K. AMPK 通过激活 TFEB 促进肿瘤抑制因子 FLCN 的诱导，独立于 mTOR。
