AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR.

Collodet, Caterina;Foretz, Marc;Deak, Maria;Bultot, Laurent;Sakamoto, Kei;et.al.
(2019) FASEB journal : official publication of the Federation of American Societies for Experimental Biology — Vol. 33, n° 11, p. 12374-12391 (2019)

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Authors
  • Collodet, Caterina
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  • Foretz, Marc
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  • Deak, Maria
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  • Bultot, Laurentorcid-logoUCLouvain
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  • Sakamoto, Kei
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Abstract
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.
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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. (2019). AMPK promotes induction of the tumor suppressor FLCN through activation of TFEB independently of mTOR. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(11), 12374-12391. https://doi.org/10.1096/fj.201900841R (Original work published 2019)