PT  - JOURNAL ARTICLE
AU  - Caterina Collodet
AU  - Marc Foretz
AU  - Maria Deak
AU  - Laurent Bultot
AU  - Sylviane Metairon
AU  - Benoit Viollet
AU  - Gregory Lefebvre
AU  - Frederic Raymond
AU  - Alice Parisi
AU  - Gabriele Civiletto
AU  - Philipp Gut
AU  - Patrick Descombes
AU  - Kei Sakamoto
TI  - AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR
AID  - 10.1101/499921
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 499921
4099  - http://biorxiv.org/content/early/2018/12/20/499921.short
4100  - http://biorxiv.org/content/early/2018/12/20/499921.full
AB  - AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and mouse primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including folliculin (Flcn), a gene encoding for a tumor suppressor and nutrient sensor. Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that AMPK promotes the dephosphorylation and nuclear localization of TFEB independently of mTOR activity.Collectively, we identified the AMPK-TFEB-FLCN axis as a potential key regulator for cellular and metabolic homeostasis. Moreover, data from zebrafish with physiologically and pharmacologically activated AMPK confirmed the AMPK-TFEB-FLCN cascade in vivo.AbbreviationsACCacetyl-CoA carboxylaseAICAR5-aminoimidazole-4-carboxamide ribonucleotideAMPK5’-AMP-activated protein kinaseFLCNFolliculinTFEBtranscription factor EB