The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue

Abstract

Noncanonical mechanistic target of rapamycin (mTOR) pathways remain poorly understood. Mutations in the tumor suppressor folliculin (FLCN) cause Birt-Hogg-Dubé syndrome, a hamartomatous disease marked by mitochondria-rich kidney tumors. FLCN functionally interacts with mTOR and is expressed in most tissues, but its role in fat has not been explored. We show here that FLCN regulates adipose tissue browning via mTOR and the transcription factor TFE3. Adipose-specific deletion of FLCN relieves mTOR-dependent cytoplasmic retention of TFE3, leading to direct induction of the PGC-1 transcriptional coactivators, drivers of mitochondrial biogenesis and the browning program. Cytoplasmic retention of TFE3 by mTOR is sensitive to ambient amino acids, is independent of growth factor and tuberous sclerosis complex (TSC) signaling, is driven by RagC/D, and is separable from canonical mTOR signaling to S6K. Codeletion of TFE3 in adipose-specific FLCN knockout animals rescues adipose tissue browning, as does codeletion of PGC-1β. Conversely, inducible expression of PGC-1β in white adipose tissue is sufficient to induce beige fat gene expression in vivo. These data thus unveil a novel FLCN-mTOR-TFE3-PGC-1β pathway-separate from the canonical TSC-mTOR-S6K pathway-that regulates browning of adipose tissue.

The complex relationship between TFEB transcription factor phosphorylation and subcellular localization

“…Figure 2 shows all the serine residues in the TFEB protein that were shown to be subject to phosphorylation by functional studies. It is worth noting that key residues and regulatory (2016), Wada et al (2016) mechanisms are conserved between TFEB, TFE3, and MITF (Martina et al, , 2014Wada et al, 2016; Fig 3).…”

“…TFE3 subcellular localization is also regulated by mTORC1-mediated phosphorylation and involves serine residues that are conserved between TFEB and TFE3 (Martina et al, 2014Wada et al, 2016). The mechanisms by which the phosphorylation of S142 and S122 affect TFEB subcellular localization are still unclear.…”

“…The mechanisms by which the phosphorylation of S142 and S122 affect TFEB subcellular localization are still unclear. TFE3 subcellular localization is also regulated by mTORC1-mediated phosphorylation and involves serine residues that are conserved between TFEB and TFE3 (Martina et al, 2014Wada et al, 2016). Data obtained from patient-derived pancreatic cancer cell lines revealed that TFEB and TFE3 nuclear translocation is mediated by specific importins; however, it is still unclear whether this is a general mechanism relevant in all cell types (Perera et al, 2015).…”

AMPK: guardian of metabolism and mitochondrial homeostasis

“…In addition, AMPK promotes the activation of transcription factor EB (TFEB; discussed below), and TFEB has been shown to directly bind to and activate the promoter of the gene encoding PGC1α, PPARGC1A , in some contexts 131 . In addition to PGC1α, AMPK has been shown to increase the expression of the mRNAs encoding PGC1β and ERRα in KRAS-driven colon cancer 132 , and TFEB and TFE3 have also been connected to PGC1β expression in some contexts 133 .…”

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

“…Furthermore, AMPK activates PGC1α (peroxisome proliferator-activated receptor gamma, coactivator 1α), a master regulator of mitochondrial biogenesis, reportedly via direct phosphorylation of PGC1α (Jäger et al, 2007) but also by promoting NAD + -dependent activation of PGC1α by Sirt1 (sirtuin 1) (Cantó et al, 2009). Interestingly, Tfeb, similar to its family member Tfe3, was recently reported to drive mitochondrial biogenesis as well (Mansueto et al, 2017; Wada et al, 2016), which offers the possibility that activation of Tfeb, or Tfe3, might be yet another mechanism by which AMPK can promote the regeneration of mitochondria. In all, AMPK coordinates mitochondrial fission and mitophagy in the acute response to mitochondrial insults, and after sustained energy stress, AMPK promotes transcriptional induction of mitochondrial biogenesis.…”