AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR
AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR
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DOI：
10.1096/fj.201900841r
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发表时间：
2019-11-01
期刊：
影响因子：
4.8
通讯作者：
Sakamoto, Kei
中科院分区：
文献类型：
--
作者：
Collodet, Caterina;Foretz, Marc;Sakamoto, Kei
AMPK是能量稳态的中心调节器。AMPK不仅能诱发急性代谢反应，而且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分析，这些细胞已用2种不同类型的小分子AMPK激活剂处理。我们确定了独特的化合物依赖性基因表达特征和几个AMPK调节基因，包括卵泡素（Flcn），它编码肿瘤抑制因子FLCN。生物信息学分析强调了溶酶体途径和相关的转录因子EB（TFEB）作为负责AMPK反应的关键转录介质。AMPK诱导的Flcn表达被废除在MEFs缺乏TFEB和转录因子E3，2转录因子与部分冗余功能;此外，Flcn的启动子活性大大降低时，其假定的TFEB结合位点突变。AMPK-TFEB-FLCN轴在物种间是保守的; WT斑马鱼中的游泳运动诱导肌肉中的Flcn表达，这在AMPK缺陷的斑马鱼中显著降低。从机制上讲，我们发现AMPK促进TFEB的去磷酸化和核定位，而不依赖于哺乳动物雷帕霉素活性的靶点。总的来说，我们确定了新的AMPK-TFEB-FLCN轴，这可能是细胞和代谢适应的关键级联反应。
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 (Flcn), 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 Flcn expression was abolished in MEFs lacking TFEB and transcription factor E3, 2 transcription factors with partially redundant function; additionally, the promoter activity of Flcn 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 Flcn 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.