AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3

Paquette, Mathieu; El–Houjeiri, Leeanna; Zirden, Linda C; Puustinen, Pietri; Blanchette, Paola; Jeong, Hyeon‐Ju; Dejgaard, Kurt; Siegel, Peter M.; Pause, Arnim

doi:10.1080/15548627.2021.1898748

Cited by 118 publications

(83 citation statements)

References 87 publications

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“…AMPK, an evolutionarily conserved serine/threonine-protein kinase, acts as an energy sensor and regulates a variety of metabolic processes ( Paquette et al, 2021 ). Previous studies reported that AMPK directly promoted intracellular autophagy by phosphorylating the essential autophagy-related proteins including ULK and mTORC1 ( Chen et al, 2020 ; Paquette et al, 2021 ; Wirth et al, 2013 ), and mTORC1 inhibited the interaction between AMPK and ULK1 ( Loffler et al, 2011 ). In our study, we demonstrated that AO markedly increased the phosphorylation of AMPK and ULK and decreased the phosphorylation of mTOR ( Figures 2 , 4 ).…”

Section: Discussionmentioning

confidence: 99%

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

Zhou

Ding

et al. 2022

Front. Pharmacol.

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Nonalcoholic fatty liver disease (NAFLD), manifested as the aberrant accumulation of lipids in hepatocytes and inflammation, has become an important cause of advanced liver diseases and hepatic malignancies worldwide. However, no effective therapy has been approved yet. Aurantio-obtusin (AO) is a main bioactive compound isolated from Cassia semen that has been identified with multiple pharmacological activities, including improving adiposity and insulin resistance. However, the ameliorating effects of AO on diet-induced NAFLD and underlying mechanisms remained poorly elucidated. Our results demonstrated that AO significantly alleviated high-fat diet and glucose-fructose water (HFSW)-induced hepatic steatosis in mice and oleic acid and palmitic acid (OAPA)-induced lipid accumulation in hepatocytes. Remarkably, AO was found to distinctly promote autophagy flux and influence the degradation of lipid droplets by inducing AMPK phosphorylation. Additionally, the induction of AMPK triggered TFEB activation and promoted fatty acid oxidation (FAO) by activating PPARα and ACOX1 and decreasing the expression of genes involved in lipid biosynthesis. Meanwhile, the lipid-lowing effect of AO was significantly prevented by the pretreatment with inhibitors of autophagy, PPARα or ACOX1, respectively. Collectively, our study suggests that AO ameliorates hepatic steatosis via AMPK/autophagy- and AMPK/TFEB-mediated suppression of lipid accumulation, which opens new opportunities for pharmacological treatment of NAFLD and associated complications.

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Section: Discussionmentioning

confidence: 99%

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

Zhou

Ding

et al. 2022

Front. Pharmacol.

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“…mTOR was demonstrated to directly phosphorylate multiple conserved serines in TFEB/TFE3, resulting in their exclusion from the nucleus (Martina et al, 2012;Roczniak-Ferguson et al, 2012;Settembre et al, 2012). More recently evidence has arisen for regulation of TFEB/TFE3 by AMPK through direct phosphorylation (Paquette et al, 2021), though mutation of the proposed AMPK sites did not affect nuclear shuttling of TFEB by AMPK, nor did the proposed AMPK sites in TFEB match the well-established AMPK substrate consensus motif, so additional mechanisms of AMPK control of TFEB must exist.…”

Section: Ll Open Access Molecularmentioning

confidence: 99%

AMPK: restoring metabolic homeostasis over space and time

2021

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The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies. ll

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“…Similarly, phosphorylation of TFEB at Ser3 by mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3), or at Ser134 and Ser138 by glycogen synthase kinase 3β (GSK3β) contributes to TFEB cytoplasmic retention by promoting its binding to the Rag GTPases-Ragulator complex and, therefore, its phosphorylation by mTORC1 (Li et al, 2016;Hsu et al, 2018). In contrast, AMPK induces nuclear activation of TFEB/TFE3 under nutrient starvation conditions or in FLCN deficient cells (Eichner et al, 2019;El-Houjeiri et al, 2019;Paquette et al, 2021). However, the mechanisms by which these pathways regulate TFEB/TFE3 are not fully characterized.…”

Section: Transcriptional Regulation Of Metabolism By Mtorc1-flcn/fnip-ampk Axismentioning

confidence: 99%

“…In osteoclast, phosphorylation at Ser462, Ser463, Ser467 and SerS469 by protein kinase C β (PKCβ) stabilizes and activates TFEB transcriptional activity (Ferron et al, 2013). Similarly, phosphorylation of TFEB and TFE3 at the C-terminal region (Ser466, Ser467 and Ser 469 in TFEB) by AMPK increases their transcriptional activity under starvation conditions, FLCN loss, or pharmacological inhibition of mTORC1 or activation of AMPK in MEFs (Paquette et al, 2021).…”

Section: Transcriptional Regulation Of Metabolism By Mtorc1-flcn/fnip-ampk Axismentioning

confidence: 99%

Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways

Reyes

Cuesta

Pause

2021

Front. Cell Dev. Biol.

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Folliculin (FLCN) is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.

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AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3

Cited by 118 publications

References 87 publications

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

AMPK: restoring metabolic homeostasis over space and time

Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways

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