Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot

Goberdhan, Deborah C. I.; Wilson, Clive; Harris, Adrian L.

doi:10.1016/j.cmet.2016.03.013

Cited by 229 publications

(196 citation statements)

References 78 publications

(133 reference statements)

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“…The same is true in cells lacking either TSC1 or TSC2 and exposed to low ambient amino acids: S6K and S6 phosphorylation is high, while TFE3 remains nuclear. Separate branches of mTOR signaling have been postulated and ascribed to different mTOR "hubs" potentially segregated in subcellular compartments (Goberdhan et al 2016). Our data provide mechanistic evidence of such a separate branch.…”

Section: Separable Mtor Signaling Branchessupporting

confidence: 53%

“…Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a critical multiprotein signaling hub nucleated around the protein raptor and conserved from yeast to humans that integrates intracellular and extracellular cues to regulate cellular growth and metabolism (Zoncu et al 2011;Dibble and Manning 2013;Goberdhan et al 2016). Numerous signals affect mTORC1 function, including amino acids levels, oxygen tension, and the presence of growth factors.…”

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confidence: 99%

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

et al. 2016

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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.

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Section: Separable Mtor Signaling Branchessupporting

confidence: 53%

mentioning

confidence: 99%

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

et al. 2016

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“…The classic view of mTOR action is that microenvironmental inputs channel through a single mTOR hub to give rise to a diversity of outputs influencing anabolic processes such as protein and lipid synthesis. However, emerging evidence supports the concept of multiple mTOR hubs with distinct subcellular compartments that may have distinct functions and sensitivity to drugs (Goberdhan et al 2016). Moreover, there is a growing number of reports from yeast to human cells supporting the notion that mTOR can localize to the nucleus, associate with chromatin, and directly regulate gene expression (Zhang et al 2002;Bernardi et al 2006;Li et al 2006;Cunningham et al 2007; Kantidakis et al 2010;Betz and Hall 2013;Chaveroux et al 2013).…”

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confidence: 99%

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

et al. 2017

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Androgen receptor (AR) signaling reprograms cellular metabolism to support prostate cancer (PCa) growth and survival. Another key regulator of cellular metabolism is mTOR, a kinase found in diverse protein complexes and cellular localizations, including the nucleus. However, whether nuclear mTOR plays a role in PCa progression and participates in direct transcriptional cross-talk with the AR is unknown. Here, via the intersection of gene expression, genomic, and metabolic studies, we reveal the existence of a nuclear mTOR-AR transcriptional axis integral to the metabolic rewiring of PCa cells. Androgens reprogram mTOR-chromatin associations in an AR-dependent manner in which activation of mTOR-dependent metabolic gene networks is essential for androgeninduced aerobic glycolysis and mitochondrial respiration. In models of castration-resistant PCa cells, mTOR was capable of transcriptionally regulating metabolic gene programs in the absence of androgens, highlighting a potential novel castration resistance mechanism to sustain cell metabolism even without a functional AR. Remarkably, we demonstrate that increased mTOR nuclear localization is indicative of poor prognosis in patients, with the highest levels detected in castration-resistant PCa tumors and metastases. Identification of a functional mTOR targeted multigene signature robustly discriminates between normal prostate tissues, primary tumors, and hormone refractory metastatic samples but is also predictive of cancer recurrence. This study thus underscores a paradigm shift from AR to nuclear mTOR as being the master transcriptional regulator of metabolism in PCa.

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“…AMP accumulation prompts (AMPK) to deactivate mTORC1, while ATP deprivation causes changes in the nuclear pore complex conformation, restricting localization of mTORC1-activating Rag proteins [27,36]. Both pathways result in inhibition of mTORC1, which is a highly conserved signaling hub shared between fungi and mammalian cells [37]. The mTORC1 complex is involved in regulation of a vast range of cellular protein target, having downstream effects in growth, proliferation, oxidative stress, and lipid metabolism [38–40].…”

Section: Discussionmentioning

confidence: 99%

Biguanides enhance antifungal activity against Candida glabrata

Feliu

Lord

et al. 2018

Virulence

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Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

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Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot

Cited by 229 publications

References 78 publications

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

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

Nuclear mTOR acts as a transcriptional integrator of the androgen signaling pathway in prostate cancer

Biguanides enhance antifungal activity against Candida glabrata

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