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

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 (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.—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. FASEB J. 33, 12374–12391 (2019). http://www.fasebj.org

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

“…AMPK is also activated by phosphorylation of two regulatory subunits by several kinases, including the energy stress-sensitive LKB [214], PKA [215], and the CAMM-GSK3β axis [216] as well as by other factors, including PPARα, associated with lipid metabolism [217] and hypoxia [218]. AMPK triggers the expression of antioxidant enzymes, notably HO-1, through Nrf2 [219,220], and improves the control of proteostasis [221] through direct activation of FOXO3 [222] and ULK1 [223] and by indirect activation of TFEB [224]; AMPK activation also improves both glucose metabolism by favoring GLUT4 translocation to the membrane [225,226] and lipid metabolism through PPARα. Finally, AMPK activation results in inhibition of mTORC following both direct phosphorylation and phosphorylation of the mTORC controller TSC [227].…”

Metformin as a Potential Neuroprotective Agent in Prodromal Parkinson's Disease—Viewpoint

“…For example, in MPTP-treated mice, metformin treatment prevented dopaminergic cell death and reduced motor impairment while decreasing α-synuclein aggregation, autophagic impairment, and ROS (82). The possible mechanism of this effect is not clear but may involve activation of AMPactivated protein kinase (AMPK) through the mitochondrial effects of metformin which in turn leads to an induction of autophagy involving in part, autophagosome formation and lysosomal biogenesis (101)(102)(103)(104). Support for a role of AMPK comes from a study in MPTP-treated mice where downstream effectors of AMPK prevented dopaminergic cell death and motor impairment (105).…”

The neuroprotective effects of α7 nicotinic acetylcholine receptor against mutant copper-zinc superoxide dismutase 1-mediated toxicity

“…In support of this, we showed that AMPK and mTOR phosphorylation were signi cantly affected by pre-treatment with BAPTA-AM and STO609, indicating activation of the AMPK pathway and inhibition of the mTOR pathway via Ca 2+ in ux following α7 nAChR activation. In addition, AMPK phosphorylation activates TFEB, which is a potential key transcription for autophagy induction upon its dephosphorylation and nuclear translocation [43]. It has been reported that under stress conditions or upon loss of function, TDP43 can regulate the nuclear translocation of TFEB in order to promote the transcription of autophagic genes.…”

“…These results suggest that α7 nAChR activation potentially induces autophagy via Ca 2+ in ux and signaling through the AMPK and mTOR pathways. α7 nAChR agonist promotes lysosomal biogenesis via nuclear translocation of transcription factor EB (TFEB) AMPK signaling activates transcription factor EB (TFEB), which is a potential key transcription in the induction of autophagy upon its dephosphorylation and nuclear translocation [43]. TFEB can enter the nucleus and bind to the E-box of the CLEAR element, which regulates the transcription of genes associated with the biogenesis of lysosomes and autophagosomes [44].…”